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Interventions in type 2 diabetes mellitus and cardiovascular mortality–An overview of clinical trials

  • Benjamin Burggraaf
    Correspondence
    Corresponding author at: Franciscus Gasthuis, Department of Internal Medicine, Center for Diabetes and Vascular Medicine, PO Box 10900, 3004 BA Rotterdam, The Netherlands.
    Affiliations
    Department of Internal Medicine, Center for Diabetes and Vascular Medicine; Franciscus Gasthuis, Rotterdam, The Netherlands
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  • Manuel Castro Cabezas
    Affiliations
    Department of Internal Medicine, Center for Diabetes and Vascular Medicine; Franciscus Gasthuis, Rotterdam, The Netherlands
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      Highlights

      • Cardiovascular risk factors management is important in T2DM.
      • Blood pressure reduction, cholesterol lowering and bariatric surgery are effective.
      • Blood glucose management has not undoubtedly proven to improve cardiovascular risk.
      • New op like GLP-1 agonists and SGLT2 inhibitors show promising results.

      Abstract

      Diabetes mellitus type 2 (T2DM) has been associated with an increased cardiovascular risk. Improving glycaemia or other traditional cardiovascular risk factors may reduce cardiovascular risk in patients with T2DM. However, single risk intervention in T2DM has not provided convincing evidence in the reduction of cardiovascular risk. The aim of this paper is to provide an overview of clinical trials involving reduction of cardiovascular outcomes in patients with T2DM.
      Trials with glucose lowering therapies have shown conflicting results. Intensive therapy to reduce glycaemia has shown some benefit on composite cardiovascular endpoints but these benefits take a longer period to emerge. Recent studies with empagliflozin and glucagon-like peptide-1 (GLP-1) agonists show promising results, but the mechanisms are most likely not mediated by improved glycaemia, given the relatively rapid effects. Both LDL-cholesterol and blood pressure reduction have been proven by large meta-analysis to reduce both cardiovascular events and mortality in all patients with T2DM. Treatment of microalbuminuria and anti-platelet therapy have only been proven in diabetic patients with increased cardiovascular risk.
      Classical lifestyle interventions have been disappointing with respect to cardiovascular outcome, possibly due to limited weight reduction. So far, the strongest evidence lies on bariatric surgery and a multifactorial intervention to reduce mortality and cardiovascular events in the long term.

      Keywords

      1. Introduction

      Patients with type 2 diabetes mellitus (T2DM) have a well-established increased risk of cardiovascular disease (CVD) [
      • Fox C.S.
      • Coady S.
      • Sorlie P.D.
      • D’Agostino R.B.
      • Pencina M.J.
      • Vasan R.S.
      • et al.
      Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study.
      ,
      • Huxley R.
      • Barzi F.
      • Woodward M.
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      ,
      • Laing S.P.
      • Swerdlow A.J.
      • Slater S.D.
      • Burden A.C.
      • Morris A.
      • Waugh N.R.
      • et al.
      Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes.
      ]. In fact, CVD is the major cause of death in these patients [
      • Tancredi M.
      • Rosengren A.
      • Svensson A.-M.
      • Kosiborod M.
      • Pivodic A.
      • Gudbjornsdottir S.
      • et al.
      Excess Mortality among Persons with Type 2 Diabetes.
      ]. In 2013, worldwide 387 million people were diagnosed with diabetes and this number is expected to rise to 600 millions by the year 2030 [
      • Wild S.
      • Roglic G.
      • Green A.
      • Sicree R.
      • King H.
      Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030.
      ].
      In the early 1930s, the first studies were published showing an association between T2DM and CVD [
      • Sherrill J.W.
      Cardiovascular Disease in Diabetes Mellitus: An Analysis of Four Hundred and Twenty-Five Cases.
      ]. The famous Framingham Heart Study reported in 1979 that diabetic patients had a two- to threefold increased risk of clinical atherosclerosis [
      • Kannel W.B.
      • McGee D.L.
      Diabetes and cardiovascular disease. The Framingham study.
      ]. In 1998, Haffner et al. published a classic paper reporting that patients with T2DM, but without a history of myocardial infarction, had a similar risk of myocardial infarction compared to patients with a previous myocardial infarction [
      • Haffner S.M.
      • Lehto S.
      • Ronnemaa T.
      • Pyorala K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      ]. Two years later these data were confirmed in patients hospitalized for unstable angina pectoris or myocardial infarction [
      • Malmberg K.
      • Yusuf S.
      • Gerstein H.C.
      • Brown J.
      • Zhao F.
      • Hunt D.
      • et al.
      Impact of Diabetes on Long-Term Prognosis in Patients With Unstable Angina and Non-Q-Wave Myocardial Infarction : Results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry.
      ]. This led to intensification of treatment and prevention of cardiovascular disease in patients with T2DM. However, later studies showed some contradicting results [
      • Becker A.
      Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior cardiovascular disease 10-year follow-up of the Hoorn Study.
      ,
      • Evans J.M.M.
      • Wang J.
      • Morris A.D.
      Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies.
      ]. A meta-analysis from the Emerging Risk Factors Collaboration, with 102 prospective studies and 698,782 patients, showed an adjusted HR of 2.00 for coronary heart disease in diabetic patients. Associated risk factors were female gender, lower BMI and younger age (40–59 years) [
      • Sarwar N.
      • Gao P.
      • Seshasai S.R.K.
      • Gobin R.
      • et al.
      The Emerging Risk Factors CollaborationEmerging Risk Factors Collaboration
      Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
      ]. Other studies also found an higher cardiovascular risk in females compared to males, indicating that the so called “female-advantage” is lacking in diabetic patients [
      • Lee W.L.
      • Cheung A.M.
      • Cape D.
      • Zinman B.
      Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies.
      ]. Importantly, clustering of traditional cardiovascular risk factors as hypertension, LDL-cholesterol and obesity is frequently seen in patients with T2DM [
      • Echouffo-Tcheugui J.B.
      • Kengne A.P.
      • Author A.
      • Hubert Department of Global Health RS
      • of Public Health EUAGAUS
      • George Institute for Global H
      • et al.
      On the importance of global cardiovascular risk assessment in people with type 2 diabetes.
      ].
      For a long time, it was believed that improving glycemic conditions and traditional risk factors would lower cardiovascular risk in T2DM. The last decade, a large number of studies were published dealing with this issue. This paper intends to provide an overview of a historical perspective and recent clinical trials with glucose lowering interventions and cardiovascular risk modification aiming to reduce cardiovascular risk in patients with T2DM.

      2. Interventions aiming to reduce cardiovascular mortality in T2DM

      2.1 Blood glucose management (Table 1)

      Elevated blood glucose levels have been associated with higher cardiovascular risk [
      • Haffner S.M.
      • Lehto S.
      • Ronnemaa T.
      • Pyorala K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      ], thus it was believed that managing blood glucose levels should lead to a decrease in cardiovascular events. Many trials have been performed, and results have been controversial.
      Table 1Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at blood glucose reduction
      PopulationNFollow upInterventionOutcome
      EventsMortality
      UKDPS

      • Turner R.
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      ,
      • Turner R.
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
      , 1998



      Post-trialfollow-up
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Matthews D.R.
      • Neil H.A.W.
      10-year follow-up of intensive glucose control in type 2 diabetes.
      ,

      2008
      T2DM



      T2DM and obesity
      3867



      342



      3277
      Median 10 years10 year post-trialIntensive (sulfonylurea/ insulin or in overweight metformin) versus conventional glucose lowering strategy (diet restriction)Myocardial infarction RR 0.84 (p=0.052)



      Myocardial infarction RR 0.61 (p=0.01)



      Myocardial infarction: sulfonylurea/insulin RR 0.85 (p=0.01), metformin RR 0.67 (p=0.005)
      All-cause mortality RR 0.94 (p=0.44)

      All-cause mortality RR 0.64 (p=0.011) All-cause mortality:

      sulfonylurea/insulin RR 0.87 (p=0.007), metformin RR 0.73 (p=0.002)
      DIGAMI 1
      • Malmberg K.
      Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.
      , 1997



      Post-trial follow-up
      • Ritsinger V.
      • Malmberg K.
      • Martensson A.
      • Ryden L.
      • Wedel H.
      • Norhammar A.
      Intensified insulin-based glycaemic control after myocardial infarction: Mortality during 20 year follow-up of the randomised Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial.
      , 2014
      T2DM after myocardial infarction620Median 3.4 years





      Mean 7 years
      Intensive (>24 hour insulin infusion followed by multidose insulin) versus routine anti-diabetic therapyOverall mortality RR 0.72 (95%-CI 0.550.93)

      Overall mortality HR 0.83 (95%-CI 0.700.98)
      DIGAMI 2
      • Malmberg K.
      • Ryden L.
      • Wedel H.
      • Birkeland K.
      • Bootsma A.
      • Dickstein K.
      • et al.
      Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.
      , 2005









      Post-trial follow-up
      • Mellbin L.G.
      • Malmberg K.
      • Norhammar A.
      • Wedel H.
      • Ryden L.
      Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study.
      , 2011
      T2DM after acute myocardial infarction1253











      1145
      Mean 2.1 years











      Median 4.1 years
      Intensive (acute insulin infusion follow by 1: insulin-based glucose control or 2: standard glucose control) versus usual metabolic control1: All-cause mortality HR 1.03 (95%-CI 0.79-1.34)

      2: All-cause mortality HR 1.23 (95%-CI 0.89-1.69)

      1: All-cause mortality HR 1.17 (95%-CI 0.90-1.52)

      Cardiovascular mortality HR 1.19 (95%- CI 0.86-1.64)

      2: All-cause mortality HR 1.12 (95%-CI 0.86-1.46)

      Cardiovascular mortality HR 1.32 (95%- CI 0.97-1.81)
      PROactive
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.A.
      • Erdmann E.
      • Massi-Benedetti M.
      • Moules I.K.
      • et al.
      Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
      , 2005
      T2DM and

      macrovascular

      disease
      5238Median 34.5 monthsPioglitazone 15-45 mg versus placeboComposite of all-cause mortality, nonfatal myocardial infarction, or stroke HR 0.84 (95%-CI 0.72-0.98)

      Composite of death of any cause, nonfatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, coronary revascularization, or revascularization of the leg HR 0.90 (95%-CI 0.80-1.02)
      All-cause mortality HR 0.83 (95%-CI 0.65-1.06)
      Post-trial follow-up
      • Erdmann E.
      • Harding S.
      • Lam H.
      • Perez A.
      Ten-year observational follow-up of PROactive: A randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes.
      , 2016
      3606Mean 7.8 yearsComposite of all-cause mortality, non- fatal myocardial infarction, or stroke HR 0.98 (95%-CI 0.89-1.07)

      Composite of death of any cause, nonfatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, coronary revascularization, or revascularization of the leg HR 0.96 (95%-CI 0.88-1.04)
      All-cause mortality HR 0.93 (95%-CI 0.84-1.04)

      Cardiovascular mortality HR 0.91 (95%- CI 0.80-1.05)
      DREAM
      • Dream T.
      • Assessment D.R.
      • Investigators T.
      Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
      , 2006
      Impaired fasting glucose5269Median 3 yearsRosiglitazone 8 mg versus placeboComposite of myocardial infarction, stroke, cardiovascular death, heart failure, new angina and revascularisation HR 1.37 (95%-CI 0.97-1.94)All-cause mortality HR 0.91 (95%-CI 0.55-1.49)

      Cardiovascular mortality HR 1.20 (95%- CI 0.52-2.77)
      Dargie et al
      • Dargie H.J.
      • Hildebrandt P.R.
      • Riegger G.A.J.
      • McMurray J.J.V.
      • McMorn S.O.
      • Roberts J.N.
      • et al.
      A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure.
      , 2007
      T2DM and heart failure22452 weeksRosiglitazon 4 mg versus placeboAll-cause mortality HR 1.50 (95%-CI 0.49-4.59)

      Cardiovascular mortality HR 1.13 (95%- CI 0.30-4.25)
      ACCORD
      • Action to Control Cardiovascular Risk in Diabetes Study Group
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • Goff D.C.
      • Bigger J.T.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      , 2008
      T2DM10251Mean 3.5 years; stopped due to higher mortality intensive groupIntensive (targeting HbA1c <6.0%) versus standard (HbA1c 7.07.9%) therapyComposite nonfatal myocardial infarction, nonfatal stroke, or death cardiovascular causes HR 0.90 (95%-CI 0.78-1.04)All-cause mortality HR 1.22 (95%-CI 1.01-1.46)

      Cardiovascular mortality HR 1.35 (95%- CI 1.04-1.76)
      Post-trial follow-up
      • ACCORD Study Group Writing Committee
      9-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes.
      , 2016
      8601Mean 7.7 yearsComposite nonfatal myocardial infarction, nonfatal stroke, or death cardiovascular causes HR 0.95 (95%-CI 0.87-1.01)All-cause mortality HR 1.01 (95%-CI 0.92-1.10)

      Cardiovascular mortality HR 1.20 (95%- CI 1.03-1.40)
      ADVANCE
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • et al.
      ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      , 2008









      Post-trial follow-up
      • Zoungas S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Li Q.
      • Hirakawa Y.
      • et al.
      Follow-up of blood- pressure lowering and glucose control in type 2 diabetes.
      , 2014
      T2DM11140











      8494
      Median 5 years











      Median 5.4 years post-trial
      Intensive (gliclazide + other drug to achieve HbA1c <6.5%) versus standard glucose controlComposite of death from any cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke HR 0.94 (95%-CI 0.84-1.06)







      Composite of death from any cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke HR 1.00 (95%-CI 0.92-1.08)
      All-cause mortality HR 0.93 (95%-CI 0.83-1.06)

      Cardiovascular mortality HR 0.88 (95%- CI 0.84-1.06)

      All-cause mortality HR 1.00 (95%-CI 0.92-1.08)

      Cardiovascular mortality HR 0.97 (95%- CI 0.86-1.10)
      VADT
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      , 2009
      Veterans with T2DM1791Median 5.6 yearsIntensive (aiming 1.5% reduction in HbA1c) or standard glucose controlTime to composite of myocardial infarction, stroke, death from cardiovascular cause, congestive heart failure, surgery vascular disease, inoperable coronary disease, amputation for ischemic gangrene HR 0.88 (95%-CI 0.74-1.05)All-cause mortality HR 1.07 (95%-CI 0.81-1.42)

      Cardiovascular mortality HR 1.32 (95%- CI 0.81-2.14)
      Post-trial follow-up
      • Hayward R.A.
      • Reaven P.D.
      • Wiitala W.L.
      • Bahn G.D.
      • Reda D.J.
      • Ge L.
      • et al.
      Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.
      , 2015
      1371Median 9.8 yearsTime to first major cardiovascular events HR 0.83 (95%-CI 0.70-0.99)All-cause mortality HR 1.05 (95%-CI 0.89-1.25)

      Cardiovascular mortality HR 0.88 (95%- CI 0.64-1.20)
      RECORD
      • Home P.D.
      • Pocock S.J.
      • Beck-Nielsen H.
      • Curtis P.S.
      • Gomis R.
      • Hanefeld M.
      • et al.
      Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.
      , 2009
      T2DM on maximum dose metformin and sulfonylurea4447Median 5.5 yearsAddition rosiglitazone 4-8 mgComposite of cardiovascular death, nonfatal myocardial infarction, or stroke HR 0.93 (95%-CI 0.74-1.15)All-cause mortality HR 0.86 (95%-CI 0.68-1.08)

      Cardiovascular mortality HR 0.84 (95%- CI 0.59-1.18)
      HEART2D
      • Raz I.
      • Wilson P.W.F.
      • Strojek K.
      • Kowalska I.
      • Bozikov V.
      • Gitt A.K.
      • et al.
      Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial.
      , 2009
      T2DM and acute myocardial infarction1115Mean 2.6 years; stopped due to lack efficacyPrandial (three times daily) versus basal insulin (two times daily) strategyTime to composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome HR 1.04 (95%-CI 0.78-1.37)All-cause mortality HR 1.00 (95%-CI 0.68-1.48)

      Cardiovascular mortality HR 1.05 (95%- CI 0.69-1.60)
      BARI2D
      • Frye R.L.
      • August P.
      • Brooks M.M.
      • Hardison R.M.
      • Kelsey S.F.
      • MacGregor J.M.
      • et al.
      A randomized trial of therapies for type 2 diabetes and coronary artery disease.
      , 2009
      T2DM and stable ischemic heart disease2638Median 5.3 yearsInsulin-sensitization (metformin or thiazolidinedione) versus insulin-provision therapyComposite of all-cause mortality, myocardial infarction, or stroke 77.7% versus 75.4% (p=0.13)Survival 88.2% versus 87.9% (p=0.89)
      HOME
      • Kooy A.
      • de Jager J.
      • Lehert P.
      • Bets D.D.
      • Wulffele M.G.
      • Donker A.J.M.
      • et al.
      Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus.
      , 2009
      T2DM on insulin390Median 4.3 yearsMetformin 850 mg versus placeboMacrovascular mortality and morbidity HR 0.61 (95%-CI 0.40-0.94)
      ORIGIN
      • ORIGIN Trial Investigators
      • Gerstein H.C.
      • Bosch J.
      • Dagenais G.R.
      • Diaz R.
      • Jung H.
      • et al.
      Basal insulin and cardiovascular and other outcomes in dysglycemia.
      , 2012
      Cardiovascular risk factors plus T2DM /IFG/IGT12537Mean 6.2 yearsInsulin glargine or standard glucose controlComposite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke HR 1.02 (95%-CI 0.941.11)All-cause mortality HR 0.98 (95%-CI 0.90-1.08)

      Cardiovascular mortality HR 1.00 (95%- CI 0.89-1.13)
      SPREAD- DIMCAD
      • Hong J.
      • Zhang Y.
      • Lai S.
      • Lv A.
      • Su Q.
      • Dong Y.
      • et al.
      Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease.
      , 2013
      T2DM with coronary artery disease304Median 5.0 yearsMetformin 1500 mg versus glipizide 30 mgComposite of cardiovascular mortality, all-cause mortality, nonfatal myocardial infarction, nonfatal stroke or arterial revascularization HR 0.54 (95%-CI 0.30-0.90)
      SAVOR-TIMI
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      , 2013
      T2DM16492Median 2.1 yearsSaxagliptin 5 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, or ischemic stroke HR 1.00 (95%-CI 0.891.12)All-cause mortality HR 1.11 (95%-CI 0.97-1.27)

      Cardiovascular mortality HR 1.03 (95%- CI 0.87-1.22)
      EXAMINE
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • Nissen S.E.
      • Bergenstal R.M.
      • Bakris G.L.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      , 2013
      T2DM and myocardial infarction or unstable angina5380Median 1.5 yearsAlogliptin 6.25-25 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, or ischemic stroke HR 0.96 (95%-CI upper bound 1.16)All-cause mortality HR 0.88 (95%-CI 0.71-1.09)

      Cardiovascular mortality HR 0.85 (95%- CI 0.66-1.10)
      TECOS
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • Buse J.B.
      • Engel S.S.
      • Garg J.
      • et al.
      Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.
      , 2015
      T2DM and

      cardiovascular

      disease
      14671Median 3.0 yearsSitagliptin 50-100 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina HR 0.98 (95%-CI 0.88-1.09)All-cause mortality HR 1.01 (95%-CI 0.90-1.14)

      Cardiovascular mortality HR 1.03 (95%- CI 0.90-1.14)
      EMPA-REG
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
      , 2015
      T2DM7020Median 3.1 yearsEmpagliflozin 5 or 10 mg versus placeboComposite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke HR 0.86 (95%-CI 0.74-0.99)All-cause mortality HR 0.68 (95%-CI 0.57-0.82)

      Cardiovascular mortality HR 0.62 (95%- CI 0.49-0.77)
      ELIXA
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • et al.
      Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome.
      , 2015
      T2DM and acute coronary syndrome6068Median 25 monthsLixisenatide 10-20 mcgg versus placeboComposite of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina HR 1.02 (95%-CI 0.89-1.17)All-cause mortality HR 0.94 (95%-CI 0.78-1.13)

      Cardiovascular mortality HR 0.98 (95%- CI 0.78-1.23)
      Meta-analysis
      • Fang H.-J.
      • Zhou Y.-H.
      • Tian Y.-J.
      • Du H.-Y.
      • Sun Y.-X.
      • Zhong L.-Y.
      Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: A meta-analysis of data from 58,160 patients in 13 randomized controlled trials.
      , 2016 Fang et al
      13 randomized controlled trials58160Intensive versus standard treatmentmajor adverse cardiovascular event

      RR 0.92 (95%-CI 0.85-1.00)
      All-cause mortality HR 0.98 (95%-CI 0.84-1.07)

      Cardiovascular mortality HR 1.0 (95%- CI 0.87-1.04)
      IRIS
      • Kernan W.N.
      • Viscoli C.M.
      • Furie K.L.
      • Young L.H.
      • Inzucchi S.E.
      • Gorman M.
      • et al.
      Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.
      , 2016
      Insulin

      resistance and recent ischemic stroke or TIA
      3876Median 4.8 yearsPioglitazone 45 mg versus placeboComposite of fatal and nonfatal stroke, or myocardial infarction HR 0.76 (95%- CI 0.62-0.93)All-cause mortality HR 0.93 (95%-CI 0.73-1.17)
      LEADER
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.E.
      • Nauck M.A.
      • et al.
      Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
      , 2016
      T2DM and high CV risk9340Median 3.8 yearsLiraglutidine 1.8 mg versus placeboFirst occurrence of death from cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke HR 0.87 (95%-CI 0.78-0.97)All-cause mortality HR 0.85 (95%-CI 0.74-0.97)

      Cardiovascular mortality HR 0.78 (95%- CI 0.66-0.93)
      SUSTAIN- 6
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jodar E.
      • Leiter L.A.
      • et al.
      Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
      , 2016
      T2DM3297Mean 2 yearsSemaglutidine 0.6 or 1.0 mg versus placeboFirst occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke HR 0.74 (95%-CI 0.58-0.95)No difference
      In 1970, the University Group Diabetes Program (UGDP), was the first cardiovascular intervention trial and patients were randomized between either a variable-dose of insulin, standard-dose insulin, tolbutamide, phenformin or a placebo. The tolbutamide arm was prematurely stopped due to excess mortality (12.7% versus 4.9% in the placebo arm) [
      • Goldner M.G.
      • Knatterud G.L.
      • Prout T.E.
      Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results.
      ]. These results created major controversy, among others due to problems in the execution and design of the study. It would take over 20 years before other trials attempted to reduce cardiovascular risk in diabetes by improving glycaemia.
      The United Kingdom Prospective Diabetes Study (UKDPS), published in 1998, randomly assigned patients with newly diagnosed T2DM to either intensive treatment (sulphonylurea or insulin) or conventional glucose lowering strategy with diet restriction. Additionally, 342 overweight patients were allocated to metformin. After a median follow-up of 10 years, only a significant relative risk reduction was found for all-cause mortality and myocardial infarction in the metformin group [
      • Turner R.
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      ,
      • Turner R.
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
      ]. However, 10 years post-trial follow-up showed significant reductions in both groups for all-cause mortality and myocardial infarctions [
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Matthews D.R.
      • Neil H.A.W.
      10-year follow-up of intensive glucose control in type 2 diabetes.
      ].
      Trials studying metformin only found significant benefits on composite macrovascular events [
      • Kooy A.
      • de Jager J.
      • Lehert P.
      • Bets D.D.
      • Wulffele M.G.
      • Donker A.J.M.
      • et al.
      Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus.
      ,
      • Hong J.
      • Zhang Y.
      • Lai S.
      • Lv A.
      • Su Q.
      • Dong Y.
      • et al.
      Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease.
      ]. Discussion remains whether the beneficial effects were due to glucose lowering or to other effects of metformin such as weight loss or improvement of endothelial function [
      • Rojas L.B.
      • Gomes M.B.
      Metformin: an old but still the best treatment for type 2 diabetes.
      ].
      The peroxisome proliferator-activated receptor (PPAR)-γ agonists, or the so-called thiazolidinediones, have created major controversy and impact on the design of clinical trials. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial with rosiglitazone in subjects with impaired fasting glucose or glucose tolerance did not show cardiovascular benefit [
      • Dream T.
      • Assessment D.R.
      • Investigators T.
      Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
      ]. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study resulted in a significant reduction of the composite of mortality and macrovascular events versus placebo, but no significant reduction in mortality [
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.A.
      • Erdmann E.
      • Massi-Benedetti M.
      • Moules I.K.
      • et al.
      Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
      ]. After additional follow-up all cardiovascular benefits disappeared [
      • Erdmann E.
      • Harding S.
      • Lam H.
      • Perez A.
      Ten-year observational follow-up of PROactive: A randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes.
      ].
      In 2007, Nissen et al. published a meta-analysis reviewing rosiglitazone where an increased risk for myocardial infarction was found [
      • Nissen S.E.
      • Wolski K.
      Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
      ] resulting in a warning on the use of rosiglitazone the Food and Drug Authority (FDA) [
      • U.S. Food and Drug Administration
      Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Washington, DC.
      ]. As a result, studies had to include more patients with a longer follow-up period resulting in many studies aiming at non-inferiority compared to current therapies.
      The Rosiglitazone Evaluated for Cardiovascular Outcome in oral agent combination therapy for type 2 Diabetes (RECORD) trial did not show an increased cardiovascular risk nor a cardiovascular benefit, but there was a higher incidence of heart failure (HR 2.10) [
      • Home P.D.
      • Pocock S.J.
      • Beck-Nielsen H.
      • Curtis P.S.
      • Gomis R.
      • Hanefeld M.
      • et al.
      Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.
      ]. Another trial by Dargie et al. showed similar results in patients with preexisting heart failure [
      • Dargie H.J.
      • Hildebrandt P.R.
      • Riegger G.A.J.
      • McMurray J.J.V.
      • McMorn S.O.
      • Roberts J.N.
      • et al.
      A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure.
      ]. The reevaluation of the rosiglitazone data resulted in ending of the restrictions in 2013 by the FDA [
      • U.S. Food and Drug Administration
      FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines - FDA Drug Safety Communication. Washington, DC.
      ]. The Insulin Resistance Intervention after Stroke (IRIS) trial studied pioglitazone in patients with insulin resistance (but without diabetes) and a recent TIA or ischemic stroke. Again no difference was found in all-cause mortality, but a significant reduction infatal and nonfatal myocardial infarctions and stroke was found [
      • Kernan W.N.
      • Viscoli C.M.
      • Furie K.L.
      • Young L.H.
      • Inzucchi S.E.
      • Gorman M.
      • et al.
      Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.
      ]. In light of the beneficial results of the PROactive and the recent IRIS trial, a new interest for thiazolidinediones has emerged and it has been suggested that a combination with an SGLT2 inhibitor might offset the fluid retention [
      • DeFronzo R.A.
      • Chilton R.
      • Norton L.
      • Clarke G.
      • Ryder R.E.J.
      • Abdul-Ghani M.
      Revitalization of pioglitazone: the optimum agent to be combined with a sodium- glucose co-transporter-2 inhibitor.
      ].
      Only a few trials compared different insulin regimens. The UGDP compared a variable dose of insulin versus standard dose and no difference in mortality and cardiovascular events was found [
      • Goldner M.G.
      • Knatterud G.L.
      • Prout T.E.
      Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results.
      ]. A comparison of a three-time daily regimen with a two-time daily insulin strategy, after an acute myocardial infarction, was stopped prematurely due to a lack of efficacy [
      • Raz I.
      • Wilson P.W.F.
      • Strojek K.
      • Kowalska I.
      • Bozikov V.
      • Gitt A.K.
      • et al.
      Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial.
      ]. The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, comparing insulin glargine versus standard glucose control in patients with increased cardiovascular risk, found no difference in major cardiovascular disease outcome [
      • ORIGIN Trial Investigators
      • Gerstein H.C.
      • Bosch J.
      • Dagenais G.R.
      • Diaz R.
      • Jung H.
      • et al.
      Basal insulin and cardiovascular and other outcomes in dysglycemia.
      ]. Also no difference in survival was found in a trial comparing insulin-sensitization therapy with insulin-provision (either insulin or sulfonylureas) [
      • Frye R.L.
      • August P.
      • Brooks M.M.
      • Hardison R.M.
      • Kelsey S.F.
      • MacGregor J.M.
      • et al.
      A randomized trial of therapies for type 2 diabetes and coronary artery disease.
      ].
      Many trials have been performed evaluating intensive glucose control on cardiovascular end-points. The Diabetes Mellitus Insulin-Glucose Infusion after Myocardial Infarction (DIGAMI) study, published in 1997, compared intensive glucose control with usual metabolic control after an acute myocardial infarction. The overall mortality was significantly [
      • Malmberg K.
      Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus.
      ] and a post-trial follow-up showed that this effect attenuated slightly [
      • Ritsinger V.
      • Malmberg K.
      • Martensson A.
      • Ryden L.
      • Wedel H.
      • Norhammar A.
      Intensified insulin-based glycaemic control after myocardial infarction: Mortality during 20 year follow-up of the randomised Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial.
      ]. However, a next trial with twice the number of patients did not show a significant reduction, neither did the post-trial follow up [
      • Malmberg K.
      • Ryden L.
      • Wedel H.
      • Birkeland K.
      • Bootsma A.
      • Dickstein K.
      • et al.
      Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.
      ,
      • Mellbin L.G.
      • Malmberg K.
      • Norhammar A.
      • Wedel H.
      • Ryden L.
      Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study.
      ]. There are some differences between the studies, the second included patients with lower glucose levels at baseline and not all subjects reached their target. Furthermore, due to slow patient recruitment the study was stopped prematurely with only a third of the planned subjects included.
      In 2008 and 2009, three large randomized controlled trials were published assessing intensive versus standard glucose-lowering therapy. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was stopped due to an increase in all-cause and cardiovascular mortality in the intensive group (respectively HR 1.22 and HR 1.35) [
      • Action to Control Cardiovascular Risk in Diabetes Study Group
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • Goff D.C.
      • Bigger J.T.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      ]. A post-trial follow-up showed that the increased mortality had attenuated and there was no effect on macrovascular events [
      • ACCORD Study Group Writing Committee
      9-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes.
      ]. The Action in Diabetes and Vascular Disease: Pretarax and Diamicron Controlled Evaluation (ADVANCE) trial did not report an increased mortality; neither did it show benefits with respect to mortality and macrovascular events. The post-trial follow up also failed to show benefits [
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • et al.
      ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • Zoungas S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Li Q.
      • Hirakawa Y.
      • et al.
      Follow-up of blood- pressure lowering and glucose control in type 2 diabetes.
      ]. The ACCORD trial aimed for a stricter glucose regulation with a target HbA1c below 6% versus <6.5%. Finally, the Veterans Administration Diabetes Trial (VADT) assigned veterans to either a 1.5% reduction in HbA1c or standard therapy. Again, no reduction in all-cause or cardiovascular mortality was found [
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      ]. Interestingly, the post-trial follow-up, in which participants of VADT were followed for an additional 9.8 years revealed a significant reduction in time to first major cardiovascular event preventing 8.6 major cardiovascular events per 1000 person years. However no difference in mortality was found [
      • Hayward R.A.
      • Reaven P.D.
      • Wiitala W.L.
      • Bahn G.D.
      • Reda D.J.
      • Ge L.
      • et al.
      Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.
      ]. Looking at these three trials and with the UKDPS in mind, intensive glucose treatment does not seem to reduce cardiovascular mortality. However, after extended follow-up, there is evidence for reduction of cardiovascular events. This was also found in a meta-analysis from 2016, concluding that intensive treatment resulted in a significant relative risk reduction in time to first major cardiovascular events. There was no reduction in all-cause or cardiovascular mortality [
      • Fang H.-J.
      • Zhou Y.-H.
      • Tian Y.-J.
      • Du H.-Y.
      • Sun Y.-X.
      • Zhong L.-Y.
      Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: A meta-analysis of data from 58,160 patients in 13 randomized controlled trials.
      ].
      The last decade, several new therapeutic options have become available. GLP-1 is an incretin mainly synthesized in the intestine and secreted postprandially. The cardiovascular benefit of GLP-1 agonists is not only by stimulation of insulin release but also due to effects on inflammation, slowed gastric emptying, enhanced satiety and improved endothelial function [
      • Ussher J.R.
      • Drucker D.J.
      Cardiovascular actions of incretin-based therapies.
      ]. Three major trials have been conducted with GLP-1 agonists. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial showed no differences in mortality or the composite of cardiovascular events [
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • et al.
      Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome.
      ]. The Liraglutidin Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, with patients at high cardiovascular risk, resulted in small but significant reductions in all-cause and cardiovascular mortality and in composite cardiovascular events [
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.E.
      • Nauck M.A.
      • et al.
      Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
      ]. Furthermore, the recently published Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial, with patients on a standard regimen, also showed benefit in composite cardiovascular mortality and events [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jodar E.
      • Leiter L.A.
      • et al.
      Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
      ].
      Dipeptidyl-peptidase 4 (DDP4) inhibitors prevent breakdown of GLP-1. In 3 trials with different drugs, no reductions in cardiovascular events or mortality compared to placebo were found [
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ,
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • Nissen S.E.
      • Bergenstal R.M.
      • Bakris G.L.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      ,
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • Buse J.B.
      • Engel S.S.
      • Garg J.
      • et al.
      Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.
      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
      ]. Of note, there was a significant, unexplained increase in hospitalization of patients on saxagliptin in the Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI) trial due to heart failure [
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ]. It needs to be underlined that all three studies were designed to show non-inferiority and with algorithms to minimalize differences in HbA1c between the groups.
      Sodium-glucose transporter 2 (SGLT-2) inhibitors prevent the reabsorption of glucose in the proximal tubule, resulting in lower blood glucose levels. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) study published in 2015, with 8020 patients with T2DM at high cardiovascular risk, randomized to either empagliflozin or a matching placebo and was designed as a non-inferiority trial. The results were unexpected and surprising. After a median follow-up of 3.1 years the primary outcome, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke showed a protective effect by empagliflozin (HR 0.86; 95% confidence interval 0.74–0.99). This reduction was also seen in all-cause and cardiovascular mortality [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
      ]. Interestingly, most patients did not reach their glycemic target, therefore, other mechanisms must have been responsible for these protective effects. Since its publication, EMPA-REG has been the subject of many speculations and several mechanisms have been proposed. At this moment, no clear explanation can be given for these positive results and future trials with SGLT-2 inhibitors must show reproducible and solid results before this type of drugs can be used widely for the reduction of cardiovascular disease in T2DM. The Canagliflozin Cardiovascular Assessment Study (CANVAS) is expected to appear in 2017 and the Dapagliflozin Effect on Cardiovascular Events (DECLARE) trial is expected in 2019.

      2.2 Lipid management (Table 2)

      Diabetic dyslipidemia is characterized by increased triglycerides (TG), decreased HDL-C, increased small density LDL particles, reflected by elevated plasma apolipoprotein B levels and postprandial hyperlipidemia [
      • Taskinen M.-R.
      Diabetic dyslipidaemia: from basic research to clinical practice*.
      ]. In clinical guidelines, LDL-C lowering is the main target for lipid-lowering therapy and cardiovascular risk reduction for patients with and without diabetes. Only few studies have been performed in T2DM and most results are from studies with a subgroup analysis.
      Table 2Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at cholesterol treatment.
      PopulationNFollow upInterventionOutcome
      EventsMortality
      LDL-cholesterol reducing strategies
      4S
      • Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      , 1994







      • Pyorala K.
      • Pedersen T.R.
      • Kjekshus J.
      • Faergeman O.
      • Olsson A.G.
      • Thorgeirsson G.
      Cholesterol Lowering With Simvastatin Improves Prognosis of Diabetic Patients With Coronary Heart Disease: A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).
      , 1997
      Angina pectoris or previous myocardial infarction



      Subgroup with T2DM
      4444







      202 (4.5%)
      Median 5.4 yearsSimvastatin 20 mg versus placeboComposite of death by coronary heart disease or nonfatal myocardial infarction RR 0.66 (95%-CI 0.59-0.75)



      Composite of death by coronary heart disease or nonfatal myocardial infarction RR 0.45 (95%-CI 0.27-0.74)
      All-cause mortality RR 0.70 (95%-CI 0.58-0.85)





      All-cause mortality RR 0.57 (95%-CI 0.30-1.08)
      CARE
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • Rouleau J.L.
      • Rutherford J.D.
      • Cole T.G.
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
      , 1996
      Myocardial infarction





      Subgroup with diabetes
      4159





      586 (14.1%)
      Median 5 yearsPravastatin 40 mg versus placeboFatal coronary events or nonfatal myocardial infarction RR 0.76 (95%-CI 0.64-0.91)

      Fatal coronary events or nonfatal myocardial infarction RR 0.75 (95%-CI 0.57-1.00)
      Overall mortality RR 0.91 (95%-CI 0.74-1.12)
      LIPID
      • The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
      Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels.
      , 1998
      Coronary heart disease







      Subgroup with diabetes
      9014







      782 (8.7%)
      Mean 6.1 yearsPravastatin 40 mg versus placeboDeath from coronary heart disease and nonfatal myocardial infarction RR 0.76 (95%-CI 0.68-0.85)

      Death from coronary heart disease and nonfatal myocardial infarction
      All-cause mortality RR 0.78 (95%-CI 0.69-0.87)

      Cardiovascular mortality RR 0.78 (95%-CI 0.65-0.87)
      ALLHAT-LLT
      ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
      The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
      , 2002
      Hypercholesterolemia and hypertension





      Subgroup with

      T2DM
      10355







      3638 (35.1%)
      Median 4.8 yearsPravastatin 20 or 40 mg versus usual careDeath from coronary heart disease and nonfatal myocardial infarction RR 0.91 (95%-CI 0.79-1.04)

      Death from coronary heart disease and nonfatal myocardial
      All-cause mortality RR 0.99 (95%-CI 0.89-1.11)





      All-cause mortality RR 1.03 (95%-CI 0.86-1.22)
      LIPS
      • Serruys P.W.J.C.
      • de Feyter P.
      • Macaya C.
      • Kokott N.
      • Puel J.
      • Vrolix M.
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      , 2002
      Stable or unstable angina pectoris or silent ischemia after PCI





      Subgroup with diabetes
      1677









      202 (12%)
      Median 3.9 yearsFluvastatin 80 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, or reintervention procedure RR 0.78 (95%-CI 0.64-0.95)

      Composite of cardiovascular death, nonfatal myocardial infarction, or reintervention procedure RR 0.53 (95%-CI 0.29-0.97)
      All-cause mortality HR 0.69 (95%-CI 0.45-1.07)

      Cardiovascular mortality HR 0.69 (95%-CI 0.46-1.02)



      No significant difference in cardiovascular mortality
      GREACE
      • Athyros V.G.
      • Papageorgiou A.A.
      • Mercouris B.R.
      • Athyrou V.V.
      • Symeonidis A.N.
      • Basayannis E.O.
      • et al.
      Treatment with Atorvastatin to the National Cholesterol Educational Program Goal Versus “Usual” Care in Secondary Coronary Heart Disease Prevention.
      , 2002







      • Athyros V.G.
      • Papageorgiou A.A.
      • Symeonidis A.N.
      • Didangelos T.P.
      • Pehlivanidis A.N.
      • Bouloukos V.I.
      • et al.
      Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus.
      , 2003
      Coronary heart disease









      Subgroup with

      diabetes
      1600









      313 (19.6%)
      Mean 3 yearsAtorvastatin 10-80 mg versus usual careComposite of death, nonfatal myocardial infarction, unstable angina, congestive heart failure, revascularization, and stroke RR 0.49 (95%-CI 0.27-0.73)

      Composite of all-cause and coronary mortality, coronary morbidity, and stroke RR 0.42 (p<0.0001)
      All-cause mortality RR 0.57 (95%-CI 0.39-0.78)

      Coronary mortality RR 0.53 (95%-CI 0.27-0.74)



      All-cause mortality RR 0.48 (p=0.049)

      Coronary mortality RR 0.38 (p=0.042)
      PROSPER

      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • Bollen E.L.
      • Buckley B.M.
      • Cobbe S.M.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      , 2002
      Elderly with history of vascular disease





      Subgroup with diabetes
      5804







      320 (5.5%)
      Mean 3.2 yearsPravastatin 40mg versus placeboCoronary heart disease death and nonfatal myocardial infarction, fatal or nonfatal stroke HR 0.85 (95%-CI 0.74-0.97)

      Coronary heart disease death and nonfatal myocardial infarction, fatal or nonfatal stroke HR 1.27 (95%-CI 0.90-1.80)
      ASCOT-LLA

      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • Wedel H.
      • Beevers G.
      • Caulfield M.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomis.
      , 2003
      Hypertension







      Subgroup with T2DM
      19342







      2532 (13.1%)
      Median 3.3 year; stopped due to substantial benefit by treatmentAtorvastatin 10 mg versus placeboNonfatal myocardial infarction or fatal coronary heart disease HR 0.65 (95%-CI 0.50-0.83)



      Nonfatal myocardial infarction or fatal coronary heart disease HR 0.84 (95%-CI 0.55-1.29)
      All-cause mortality HR 0.87 (95%-CI 0.71-1.06)

      Cardiovascular mortality HR 0.90 (95%-CI 0.66-1.22)
      HPS
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleigh P.
      • Peto R.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      , 2003
      Coronary artery disease













      Subgroup with diabetes













      Subgroup with diabetes, without CAD
      20536













      5963

      (29%)











      2912
      Mean 5 yearsSimvastatin 40 mg

      versus placebo
      Composite of nonfatal myocardial infarctions or coronary death RR 0.73 (95%-CI 0.67-0.79)

      Composite of major coronary events, stroke, and revascularization RR 0.76 (95%-CI 0.72-0.81)Composite of nonfatal myocardial infarctions or coronary death RR 0.73 (95%-CI 0.62-0.85)Composite of major coronary events, stroke, and revascularization RR 0.78 (95%-CI 0.70-0.87)

      Composite of nonfatal myocardial infarctions or coronary death RR 0.67 (p=0.0003)
      CARDS
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • Hitman G.A.
      • Neil H.A.W.
      • Livingstone S.J.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      , 2004
      T2DM and hypertension, retinopathy, microalbuminuria or smoking2838Median 3.9 years; stopped rules efficacy metAtorvastatin 10 mg versus placeboComposite of acute coronary heart disease, coronary revascularization, or stroke RR 0.63 (95%-CI 0.48-0.83)All-cause mortality RR 0.73 (95%-CI 0.52-1.01)

      Cardiovascular mortality RR 0.68 (95%-CI 0.55-0.85)
      4D
      • Wanner C.
      • Krane V.
      • Marz W.
      • Olschewski M.
      • Mann J.F.E.
      • Ruf G.
      • et al.
      Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.
      , 2005





      Post-trial follow-up
      • Krane V.
      • Schmidt K.-R.
      • Gutjahr-Lengsfeld L.J.
      • Mann J.F.E.
      • Marz W.
      • Swoboda F.
      • et al.
      Long-term effects following 4 years of randomized treatment with atorvastatin in patients with type 2 diabetes mellitus on hemodialysis.
      , 2016
      T2DM on hemodialysis1255Median 4 years





      Median 11.5 years
      Atorvastatin 20 mg versus placeboComposite of myocardial infarction, cardiac death or stroke RR 0.92 (95%- CI 0.77-1.10)

      Composite of myocardial infarction, cardiac death or stroke RR 0.91 (95%-CI 0.78-1.07)
      Aspen
      • Knopp R.H.
      • D’Emden M.
      • Smilde J.G.
      • Pocock S.J.
      Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin- dependent diabetes mellitus (ASPEN).
      ,

      2006
      T2DM both with or without a history of coronary heart disease2410Median 4 yearsAtorvastatin 10 mg versus placeboComposite of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, cardiac arrest, worsening or unstable angina requiring hospitalization HR 0.90 (95%-CI 0.73-1.12)No difference in mortality
      Meta-analysis
      • Kearney P.M.
      • Blackwell L.
      • Collins R.
      • Keech A.
      • Simes J.
      • et al.
      Cholesterol Treatment Trialists’ (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      , 2008

      Cholesterol Treatment Trialists
      14 randomized trials18686Mean 4.3 yearsPer mmol/L LDL-c reduction by statinMajor cardiovascular event RR 0.79 (99%-CI 0.72-0.86)All-cause mortality RR 0.91 (99%-CI 0.82-1.01)

      Vascular mortality RR 0.87 (99%-CI 0.76-1.00)
      IMPROVE-IT
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • McCagg A.
      • White J.A.
      • Theroux P.
      • et al.
      Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
      , 2015
      Patients hospitalized after acute coronary syndrome









      Subgroup with diabetes
      18144













      4933 (27.3%)
      Median 6 yearsEzetimibe 10 mg and simvastatin 40 mg versus simvastatin 40 mgComposite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke HR 0.94 (95%-CI 0.89-0.99)

      Composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke HR 0.86 (95%-CI 0.78-0.94)
      FOURIER
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • Honarpour N.
      • Wiviott S.D.
      • Murphy S.A.
      • et al.
      Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.
      , 2017
      Patients with atherosclerotic cardiovascular disease25564Median 2.2 yearsAlirocumab versus placeboComposite of death from cardiovascular disease, myocardial infarction stroke, hospitalization for unstable angina, or coronary revascularization HR 0.85 (95%-CI 0.70-0.92)Cardiovascular mortality HR 1.05 (95%-CI 0.88-1.25)
      HDL-cholesterol raising strategies
      AIM-HIGH
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • Chaitman B.R.
      • Desvignes-Nickens P.
      • Koprowicz K.
      • et al.
      Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy.
      , 2011
      Low level of HDL-cholesterol













      Subgroup with diabetes
      3414















      1157 (33.9%)
      Mean 3 years; stopped due to lack of efficacyExtended-release niacin 1500-2000mg versus placeboComposite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization HR 1.02 (95%-CI 0.87-1.21)

      No difference in primary endpoint

      (p=0.21)
      dal-OUTCOMES
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • Ballantyne C.M.
      • Barter P.J.
      • Brumm J.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.
      , 2012
      Recent acute coronary syndrome









      Subgroup with

      diabetes
      15871











      3882 (24.5%)
      Median 31 months; stopped for futilityDalcetrapib 600 mg versus placeboComposite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation HR 1.04 (95%-CI 0.93-1.16)

      Composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation HR 0.99 (95%-CI 0.87-1.14)
      Fibrates
      VA-HIT
      • Robins S.J.
      • Collins D.
      • Wittes J.T.
      • Papademetriou V.
      • Deedwania P.C.
      • Schaefer E.J.
      • et al.
      Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.
      , 2002
      Men with known CVD



      Subgroup with

      T2DM
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • Nelson D.B.
      • Elam M.B.
      • Schaefer E.J.
      • et al.
      Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT).
      2531



      769 (30.4%)
      Mean 5.1 yearsGemfibrozil 1200 mg versus placeboCoronary heart disease event: RR 0.78 (95%-CI 0.66-0.94)

      Composite of coronary heart disease: death, nonfatal myocardial infarction and stroke: HR 0.68 (95%-CI 0.53-0.88)




      CHD death HR 0.59 (95%-CI 0.39-0.91)
      FIELD
      • Keech A.
      • Simes R.J.
      • Barter P.
      • Best J.
      • Scott R.
      • Taskinen M.R.
      • et al.
      Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
      , 2005
      T2DM without statin9792Mean 5 yearsFenofibrate 200 mg versus placeboComposite of cardiovascular death, myocardial infarction, stroke and coronary and carotid revascularization HR 1.19 (95%-CI 0.90-1.57)All-cause mortality HR 1.11 (95%-CI 0.95-1.29)

      Cardiovascular mortality HR 1.11 (95%-CI 0.87-1.41)
      ACCORDLIPID
      • ACCORD Study Group
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • Crouse J.R.
      • Leiter L.A.
      • et al.
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      , 2010
      T2DM and statin5518Mean 4.7 yearsFenofibrate 200 mg versus placeboComposite nonfatal myocardial infarction, nonfatal stroke or death from cardiovascular cause HR 0.92 (95%-CI 0.79-1.08)All-cause mortality HR 1.61 (95%-CI 0.75-1.10)

      Cardiovascular mortality HR 0.86 (95%-CI 0.66-1.12)
      In primary prevention, treatment with statins resulted in conflicting results. Treatment of patients with hypercholesterolemia and hypertension with pravastatin or atorvastatin did not show significant reductions in both all-cause and cardiovascular mortality [
      ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
      The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
      ,
      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • Wedel H.
      • Beevers G.
      • Caulfield M.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomis.
      ]. Only one primary prevention study specifically aimed at diabetic patients has been performed. The Collaborative Atorvastatin Diabetes Study (CARDS) randomized patients, with either hypertension, retinopathy, microalbuminuria or smoking, between atorvastatin or placebo. Significant reductions in major cardiovascular events and cardiovascular mortality were found, but not in all-cause mortality [
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • Hitman G.A.
      • Neil H.A.W.
      • Livingstone S.J.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      ]. The Heart Protection Study (HPS) included a group of diabetic patients without coronary artery disease. In this subgroup a significant reduction in coronary mortality and nonfatal myocardial infaction was found [
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleigh P.
      • Peto R.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      ].
      In secondary prevention, the landmark Scandinavian Simvastatin Survival Study (4S), published in 1994, randomized patients with angina pectoris or a previous myocardial infarction to either simvastatin or placebo. A significant reduction in major cardiovascular events was found in the T2DM subgroup, but the benefit of all-cause mortality, found in the total study group, was not reproduced in the diabetes subgroup [
      • Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      ,
      • Pyorala K.
      • Pedersen T.R.
      • Kjekshus J.
      • Faergeman O.
      • Olsson A.G.
      • Thorgeirsson G.
      Cholesterol Lowering With Simvastatin Improves Prognosis of Diabetic Patients With Coronary Heart Disease: A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).
      ]. However, the diabetes subgroup only consisted of 4.5% of subjects from the total study population.
      Concerning diabetes subgroups of patients with coronary heart disease, three trials evaluated treatment with pravastatin and only the Cholesterol And Recurrent Event (CARE) trial showed significant reductions in a composite of fatal coronary events or nonfatal myocardial infarctions [
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • Rouleau J.L.
      • Rutherford J.D.
      • Cole T.G.
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
      ,
      • The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
      Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels.
      ,
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • Bollen E.L.
      • Buckley B.M.
      • Cobbe S.M.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      ]. The Pravastatin in Elderly Individuals at risk of Cardiovascular Disease (PROSPER) trial even found a non-significant higher incidence of macrovascular events after treatment with pravastatin, however the diabetes subgroup was small (5.5%) and the study was performed with elderly patients [
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • Bollen E.L.
      • Buckley B.M.
      • Cobbe S.M.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      ]. In the Greek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study, with patients with coronary heart disease, atorvastatin treatment showed a significant reduction of all-cause mortality, coronary mortality and coronary morbidity, including the diabetes subgroup [
      • Athyros V.G.
      • Papageorgiou A.A.
      • Mercouris B.R.
      • Athyrou V.V.
      • Symeonidis A.N.
      • Basayannis E.O.
      • et al.
      Treatment with Atorvastatin to the National Cholesterol Educational Program Goal Versus “Usual” Care in Secondary Coronary Heart Disease Prevention.
      ,
      • Athyros V.G.
      • Papageorgiou A.A.
      • Symeonidis A.N.
      • Didangelos T.P.
      • Pehlivanidis A.N.
      • Bouloukos V.I.
      • et al.
      Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus.
      ]. Both, simvastatin and fluvastatin, in both the total study groups as well as in the diabetes subgroups, reduced major cardiovascular events [
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleigh P.
      • Peto R.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      ,
      • Serruys P.W.J.C.
      • de Feyter P.
      • Macaya C.
      • Kokott N.
      • Puel J.
      • Vrolix M.
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      ]. In contrast, the “Deutche Diabetes Dialysis Studie” (4D) trial with T2DM patients on hemodialysis did not show any benefit from atorvastatin, neither did the 2016 post-trial follow-up [
      • Wanner C.
      • Krane V.
      • Marz W.
      • Olschewski M.
      • Mann J.F.E.
      • Ruf G.
      • et al.
      Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.
      ,
      • Krane V.
      • Schmidt K.-R.
      • Gutjahr-Lengsfeld L.J.
      • Mann J.F.E.
      • Marz W.
      • Swoboda F.
      • et al.
      Long-term effects following 4 years of randomized treatment with atorvastatin in patients with type 2 diabetes mellitus on hemodialysis.
      ]. The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-insulin-dependent Diabetes Mellitus (ASPEN) initially started as secondary prevention in diabetic patients but due to changes in treatment and prevention guidelines also patients without a prior history of myocardial infarction were included. Treatment with atorvastatin failed to demonstrate a significant reduction in a composite of cardiovascular events and also no significant benefit in mortality was found [
      • Knopp R.H.
      • D’Emden M.
      • Smilde J.G.
      • Pocock S.J.
      Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin- dependent diabetes mellitus (ASPEN).
      ].
      A meta-analysis from the Cholesterol Treatment Trialists Collaboration in 2008, which included 14 randomized trials and 18,686 individuals with diabetes, focused on the reduction in cardiovascular risk with statin therapy. After a mean follow-up of 4.3 years a significant reduction in major vascular events per 1 mmol/L LDL-C reduction (RR 0.79) was found, irrespective of the baseline characteristics or prior history of vascular disease. Only a proportional reduction in all-cause mortality was found [
      • Kearney P.M.
      • Blackwell L.
      • Collins R.
      • Keech A.
      • Simes J.
      • et al.
      Cholesterol Treatment Trialists’ (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      ].
      Besides statins, other options are also available for LDL-c lowering. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed a reduction in the composite of cardiovascular events by adding ezetimibe on top of simvastatin in patients hospitalized after an acute coronary syndrome [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • McCagg A.
      • White J.A.
      • Theroux P.
      • et al.
      Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
      ]. More importantly, treatment with the novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors seems promising. Recently, the first cardiovascular outcome trial was published, which included 36.6% of subjects with diabetes. In the Further Cardiovascular Outcome Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) patients with atherosclerotic cardiovascular disease who were on statins were treated either with evolucumab or placebo. After a follow-up of 48 weeks, a significant reduction in the composite cardiovascular endpoint (HR 0.85) and cardiovascular events was found [
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • Honarpour N.
      • Wiviott S.D.
      • Murphy S.A.
      • et al.
      Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.
      ]. A second trial, with a different PCSK9 inhibitor, alirocumab is expected in the course of 2017 [
      • Sattar N.
      • Preiss D.
      • Robinson J.G.
      • Djedjos C.S.
      • Elliott M.
      • Somaratne R.
      • et al.
      Lipid- lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: A meta-analysis of individual patient data.
      ].
      Other options are also available for improving the lipemic spectrum. Two HDL-C raising trials, with either niacin or dalcetrapid, were stopped prematurely due to futility [
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • Chaitman B.R.
      • Desvignes-Nickens P.
      • Koprowicz K.
      • et al.
      Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy.
      ,
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • Ballantyne C.M.
      • Barter P.J.
      • Brumm J.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.
      ]. Three trials have been published with cardiovascular endpoints with fibrates, of which two trials were specifically designed for patients with diabetes, however no cardiovascular benefit was found [
      • Keech A.
      • Simes R.J.
      • Barter P.
      • Best J.
      • Scott R.
      • Taskinen M.R.
      • et al.
      Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
      ,
      • ACCORD Study Group
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • Crouse J.R.
      • Leiter L.A.
      • et al.
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      ]. However, treatment with fibrates reduces TG and improves HDL-c levels [
      • Rubins H.B.
      • Robins S.J.
      Conclusions from the VA-HIT study.
      ] and both studies included subjects with normal TG levels were included. Within subgroups with high TG and low HDL-c levels significant cardiovascular benefit were found [
      • Keech A.
      • Simes R.J.
      • Barter P.
      • Best J.
      • Scott R.
      • Taskinen M.R.
      • et al.
      Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
      ,
      • ACCORD Study Group
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • Crouse J.R.
      • Leiter L.A.
      • et al.
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      ]. The Veterans Affair High-density lipoprotein cholesterol Intervention Trial (VA-HIT), in men with a cardiovascular history (and low HDL-c and high TGs) randomized between either gemfibrozil or a matching placebo, showed a significant reduction in cardiovascular risk in the T2DM subgroup [
      • Robins S.J.
      • Collins D.
      • Wittes J.T.
      • Papademetriou V.
      • Deedwania P.C.
      • Schaefer E.J.
      • et al.
      Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.
      ,
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • Nelson D.B.
      • Elam M.B.
      • Schaefer E.J.
      • et al.
      Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT).
      ]. Within diabetic subjects with high TG and low HDL-cholesterol levels, treatment with fibrates seem to reduce cardiovascular risk but also no effect on mortality was found.

      2.3 Blood pressure management (Table 3)

      The Hypertension Optimal Treatment (HOT) was the first trial to compare different blood pressure (BP) regiments and showed that reduction of the diastolic BP ≤80 mmHg led to a significant reduction in cardiovascular events in diabetic patients with hypertension [
      • Kjeldsen S.E.
      • Hedner T.
      • Jamerson K.
      • Julius S.
      • Haley W.E.
      • Zabalgoitia M.
      • et al.
      Hypertension Optimal Treatment (HOT) Study: Home Blood Pressure in Treated Hypertensive Subjects.
      ]. The UKDPS showed that an increase in BP was related to a higher prevalence of micro- and macrovascular disease, but also suggested that tight BP control in patients with T2DM can be beneficial [
      • Turner R.
      • Matthews D.
      • Neil A.
      • Mcelroy H.
      Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.
      ]. However, the 10-year post trial follow-up showed that all these effects did not sustain probably because the differences in BP were lost [
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Neil H.A.W.
      • Matthews D.R.
      Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes.
      ]. The ACCORD trial, also comparing intensive versus regular BP therapy in diabetic patients at high cardiovascular risk, did not result in a significant reduction in the composite of cardiovascular endpoints and in the intensive BP lowering arm a higher number of serious adverse events occurred [
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • Berl T.
      • Pohl M.A.
      • Lewis J.B.
      • et al.
      Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes.
      ]. However, the follow-up showed a significant reduction in the composite of cardiovascular endpoints [
      • Margolis K.L.
      • O’Connor P.J.
      • Morgan T.M.
      • Buse J.B.
      • Cohen R.M.
      • Cushman W.C.
      • et al.
      Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the accord randomized trial.
      ].
      Table 3Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at blood pressure.
      PopulationNFollow upInterventionOutcome
      EventsMortality
      HOT
      • Kjeldsen S.E.
      • Hedner T.
      • Jamerson K.
      • Julius S.
      • Haley W.E.
      • Zabalgoitia M.
      • et al.
      Hypertension Optimal Treatment (HOT) Study: Home Blood Pressure in Treated Hypertensive Subjects.
      , 1998
      Hypertension18790Mean 3.8 yearsDiastolic blood pressure lowering, ≤90mmHg, ≤85mmHg, or ≤80mmHgNo significant reduction in major cardiovascular events between target groups
      Subgroup with diabetes1501 (8%)51% reduction in cardiovascular events (p=0.005) between diastolic blood pressure ≤90 vs ≤80 mmHg
      UKDPS
      • Turner R.
      • Matthews D.
      • Neil A.
      • Mcelroy H.
      Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.
      , 1998
      T2DM and hypertension1148Median 8.4 yearsTight (aiming blood pressure <150/85 mmHg) versus less tight (aiming <180/105 mmHg) blood pressure controlAny diabetes related end point RR 0.76 (95%-CI 0.62-0.92)All-cause mortality HR 0.82 (95%-CI 0.63-1.08)

      Diabetes related death RR 0.68 (95%-CI 0.49-0.94)
      10-year follow-up
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Neil H.A.W.
      • Matthews D.R.
      Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes.
      , 2008
      88410-years post trialAny diabetes related end point RR 0.93 (p=0.31)All-cause mortality HR 0.82 (p=0.17)

      Diabetes related death RR 0.84 (p=0.12)
      HOPE
      Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
      , 2000
      Increased cardiovascular risk9299Median 4.5 years; stopped due to rules efficacy metRamipril 10 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, or stroke RR 0.78 (95%-CI 0.70-0.86)All-cause mortality RR 0.84 (95%-CI 0.75-0.95)

      Cardiovascular mortality RR 0.0.74 (95%-CI 0.64-0.87)
      Subgroup with T2DM
      • Patel V.
      • Panja S.
      • Venkataraman A.
      Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators.
      3577 (38.5%)Composite of cardiovascular death, nonfatal myocardial infarction, or stroke RR 0.75 (95%-CI 0.64-0.88)All-cause mortality RR 0.76 (95%-CI 0.63-0.92)

      Cardiovascular mortality RR 0.63 (95%-CI 0.49-0.79)
      RENAAL
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • Keane W.F.
      • Mitch W.E.
      • Parving H.-H.
      • et al.
      Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy.
      , 2001
      T2DM with nephropathy1513Mean 3.4 yearsLosartan 50-100 mg versus placeboComposite of morbidity and mortality from cardiovascular disease was similarAll-cause mortality RR 1.02 (95%-CI 0.81-1.27)
      LIFE
      • Dahlof B.
      • Devereux B.R.
      • Kjeldsen S.E.
      Cardiovascular morbidity and mortality in the losartan intervention for end point reduction in hypertension study (LIFE): a randomised trial against atenolol.
      , 2002
      Hypertension and left ventricular hypertrophy9193Mean 4.7 yearsLosartan versus atenololComposite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke RR 0.87 (95%-CI 0.77-0.98)Cardiovascular mortality RR 0.89 (95%-CI 0.73-1.07)
      Subgroup with T2DM
      • Lindholm L.H.
      • Ibsen H.
      • Dahlof B.
      • Devereux R.B.
      • Beevers G.
      • De Faire U.
      • et al.
      Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol.
      1196Composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke RR 0.76 (95%-CI 0.58-0.98)All-cause mortality RR 0.61 (95%-CI 0.45-0.84)

      Cardiovascular mortality RR 0.63 (95%-CI 0.42-0.95)
      IDNT
      • Berl T.
      • Hunsicker L.G.
      • Lewis J.B.
      • Pfeffer M.A.
      • Porush J.G.
      • Rouleau J.-L.
      • et al.
      Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy.
      , 2003
      T2DM with nephropathy and hypertension1715Mean 2.6 yearsIrbesartan 300 mg versus placeboComposite of cardiovascular death, myocardial infarction, stroke and revascularization HR 0.90 (95%-CI 0.74-1.10)

      Myocardial infarction HR 0.90 (95%-CI 0.60-1.33)
      Cardiovascular mortality HR 1.08 (95%-CI 0.72-1.60)
      Amlodipine 10 mg versus placeboComposite of cardiovascular death, myocardial infarction, stroke and revascularization HR 1.00 (95%-CI 0.83-1.21)

      Myocardial infarction HR 0.58 (95%-CI 0.37-0.92)
      Cardiovascular mortality HR 0.79 (95%-CI 0.51-1.22)
      Meta-analysis
      • Strippoli G.F.M.
      • Craig M.C.
      • Schena F.P.
      • Craig J.C.
      Role of blood pressure targets and specific antihypertensive agents used to prevent diabetic nephropathy and delay its progression.
      , 2006

      Strippoli et al
      16 randomized trials for primary prevention7603ACEi versus placebo for reducing microalbuminuriaAll-cause mortality RR 0.81 (95%-CI 0.64-1.03)
      43 randomized trials with diabetic nephropathy7739ACEi versus placebo for reducing microalbuminuriaAll-cause mortality RR 0.79 (95%-CI 0.85-0.99)
      ARB versus placebo for reducing microalbuminuriaAll-cause mortality RR 0.99 (95%-CI 0.85-1.17)
      ADVANCE
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Woodward M.
      • et al.
      ADVANCE Collaborative Group
      Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
      , 2007
      T2DM with history of cardiovascular disease or presence of cardiovascular risk factor11140Mean 4.3 yearsPerindopril 4 mg and indapamide 1.25 mg versus placeboComposite of death from any cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke HR 0.92 (95%-CI 0.81-1.04)All-cause mortality HR 0.86 (95%-CI 0.75-0.98)

      Cardiovascular mortality HR 0.82 (95%-CI 0.68-0.98)
      6-year post-trial follow-up
      • Zoungas S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Li Q.
      • Hirakawa Y.
      • et al.
      Follow-up of blood- pressure lowering and glucose control in type 2 diabetes.
      , 2015
      8494Median 5.9 years post-trialComposite of death from any cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke HR 0.92 (95%-CI 0.85-1.00)All-cause mortality HR 0.91 (95%-CI 0.84-0.99)

      Cardiovascular mortality HR 0.88 (95%-CI 0.77-0.99)
      ACCOMPLISH
      • Jamerson K.
      • Weber M.A.
      • Bakris G.L.
      • Dahlof B.
      • Pitt B.
      • Shi V.
      • et al.
      Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients.
      , 2008
      Patients with hypertension and increased cardiovascular risk11506Mean 36 monthsAmlodipine 5 mg versus hydrochlorothiazide 12.5 mg on top of benazepril 20 mgComposite of cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization HR 0.80 (95%-CI 0.72-0.90)All-cause mortality HR 0.90 (95%-CI 0.76-1.07)

      Cardiovascular mortality HR 0.80 (95%-CI 0.62-1.03)
      Diabetes subgroup
      • Weber M.A.
      • Bakris G.L.
      • Jamerson K.
      • Weir M.
      • Kjeldsen S.E.
      • Devereux R.B.
      • et al.
      Cardiovascular Events During Differing Hypertension Therapies in Patients With Diabetes.
      2842 (24.7%)Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization HR 0.79 (95%-CI 0.68-0.92)All-cause mortality HR 1.02 (95%-CI 0.80-1.29)

      Cardiovascular mortality HR 0.84 (95%-CI 0.60-1.18)
      ONTARGET
      • Yusuf S.
      • Teo K.K.
      • Pogue J.
      • Dyal L.
      • Copland I.
      • Schumacher H.
      • et al.
      Telmisartan, ramipril, or both in patients at high risk for vascular events.
      , 2008
      History of cardiovascular events25620Median 56 monthsRamipril 10 mg versus Telmisartan 80 mgComposite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure RR 1.01 (95%-CI 0.94-1.09)All-cause mortality RR 0.98 (95%-CI 0.90-1.07)

      Cardiovascular mortality RR 1.00 (95%-CI 0.89-1.12)
      Diabetes subgroup with end-organ failureRamipril 10 mg versus combinationComposite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure HR 0.99 (95%-CI 0.92-1.07)

      No benefit
      All-cause mortality RR .07 (95%-CI 0.98-1.16)

      Cardiovascular mortality RR 1.04 (95%-CI 0.93-1.17)
      ACCORD
      • ACCORD Study Group
      • Cushman W.C.
      • Evans G.W.
      • Byington R.P.
      • Goff D.C.
      • Grimm R.H.
      • et al.
      Effects of intensive blood-pressure control in type 2 diabetes mellitus.
      , 2010
      T2DM with history of cardiovascular disease or presence of cardiovascular risk factor4733Mean 4.7 yearsIntensive (systolic <120mmHg) versus regular (<140mmHg) therapyComposite nonfatal myocardial infarction, nonfatal stroke, or death cardiovascular causes HR 0.88 (95%-CI 0.73-1.06)All-cause mortality HR 1.07 (95%-CI 0.85-1.35)

      Cardiovascular mortality HR 1.06 (95%-CI 0.74-1.52)
      Follow-up,
      • Margolis K.L.
      • O’Connor P.J.
      • Morgan T.M.
      • Buse J.B.
      • Cohen R.M.
      • Cushman W.C.
      • et al.
      Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the accord randomized trial.
      , 2016
      Mean 3.7 years follow-upComposite nonfatal myocardial infarction, nonfatal stroke, or death cardiovascular causes HR 0.74 (95%-CI 0.55-1.00)Cardiovascular mortality HR 0.81 (95%-CI 0.58-1.14)
      DIRECT-protect-2
      • Tillin T.
      • Orchard T.
      • Malm A.
      • Fuller J.
      • Chaturvedi N.
      The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study.
      , 2011
      T2DM with mild retinopathy1905Mean 4.7 yearsCandersartan 16 or 32 mg versus placeboMacrovascular complications HR 0.84 (95%-CI 0.57-1.25)
      ROADMAP
      • Haller H.
      • Ito S.
      • Izzo J.L.
      • Januszewicz A.
      • Katayama S.
      • Menne J.
      • et al.
      Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes.
      , 2011
      T2DM4447Mean 3.2 yearsOlmersartan 40 mg versus placebo for prevention of microalbuminuriaComposite of cardiovascular complications or death from cardiovascular cause HR 1.00 (95%-CI 0.75-1.33)All-cause mortality HR 1.70 (95%-CI 0.90-3.22)

      Cardiovascular mortality HR 4.94 (95%-CI 1.43-17.06)
      ALTITUDE
      • Parving H.-H.
      • Brenner B.M.
      • McMurray J.J.V.
      • de Zeeuw D.
      • Haffner S.M.
      • Solomon S.D.
      • et al.
      Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
      , 2012
      T2DM with albuminuria or cardiovascular disease8561Mean 32.9 monthsAliskiren 300 mg versus placeboComposite of time to cardiovascular death or first occurrence of cardiac arrest with resuscitation, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for heart failure, end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy HR 1.08 (95%-CI 0.98-1.20)
      VA NEPHRON-D
      • Fried L.F.
      • Emanuele N.
      • Zhang J.H.
      • Brophy M.
      • Conner T.A.
      • Duckworth W.
      • et al.
      Combined angiotensin inhibition for the treatment of diabetic nephropathy.
      , 2013
      T2DM and nephropathy1448Median 2.2 years

      Stopped due to safety concern
      Lisinopril 10-40mg versus placebo on top of losartan 100 mg for improving proteinuriaComposite of myocardial infarction, heart failure, or stroke HR 0.97 (95%-CI 0.76-1.23)All-cause mortality HR 0.97 (95%-CI 0.76-1.23)
      Meta-analysis
      • Emdin C.A.
      • Rahimi K.
      • Neal B.
      • Callender T.
      • Perkovic V.
      • Patel A.
      Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.
      , 2015

      Emdin et al
      40 randomized trials100354Per 10 mmHg systolic blood pressure reductionCardiovascular events RR 0.89 (95%-CI 0.83-0.95)All-cause mortality RR 0.87 (85%-CI 0.78-0.96)
      Meta-analysis
      • Persson F.
      • Lindhardt M.
      • Rossing P.
      • Parving H.-H.
      Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: A systematic review.
      , 2016 Persson et al
      6 randomized trial for prevention of diabetic nephropathy16921Treatment with ACEi or ARBsAll-cause mortality RR 0.91 (95%-CI 0.83-1.01)
      Meta-analysis
      • Brunstrom M.
      • Carlberg B.
      Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and metaanalyses.
      , 2016

      Brunstrom et al
      47 randomized trials73738Baseline systolic blood pressure >150 mmHgMyocardial infarction RR 0.74 (95%-CI 0.63-0.91)All-cause mortality RR 0.89 (95%-CI 0.80-0.99)

      Cardiovascular mortality RR 0.75 (95%-CI 0.57-0.99)
      Baseline systolic blood pressure <150 mmHgMyocardial infarction RR 0.74 (95%-CI 0.63-0.91)All-cause mortality RR 0.89 (95%-CI 0.80-0.99)

      Cardiovascular mortality RR 0.75 (95%-CI 0.57-0.99)
      Baseline systolic blood pressure <140 mmHgMyocardial infarction RR 1.00 (95%-CI 0.87-1.15)All-cause mortality RR 1.05 (95%-CI 0.95-1.16)

      Cardiovascular mortality RR 1.15 (95%-CI 1.00-1.32)
      The ADVANCE trial also studied high risk diabetic patients. The fixed combination of perindopril and indapamide versus placebo resulted in a significant reduction in all-cause and cardiovascular mortality, but no significant reduction in macrovascular events [
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Woodward M.
      • et al.
      ADVANCE Collaborative Group
      Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
      ]. In the post-trial follow-up these benefits attenuated but remained [
      • Zoungas S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Li Q.
      • Hirakawa Y.
      • et al.
      Follow-up of blood- pressure lowering and glucose control in type 2 diabetes.
      ].
      Importantly, besides reduction of BP, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) have another important role in diabetes care by reducing urinary albumin excretion, which is an independent risk factor for cardiovascular disease [
      • Gerstein H.C.
      • Mann J.F.
      • Yi Q.
      • Zinman B.
      • Dinneen S.F.
      • Hoogwerf B.
      • et al.
      Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.
      ]. Several trials aimed to improve cardiovascular outcomes by reducing urinary albumin excretion. In the Heart Outcome Prevention Evaluation (HOPE) trial, in which patients were included with a history of cardiovascular events or diabetes with an additional CV risk factor, participants were randomized between either ramipril or placebo. Per study design, no differences in BP reduction between groups were found. However, ramipril resulted in reductions in all-cause and cardiovascular mortality and the composite of macrovascular events. Furthermore, also benefits on overt nephropathy were found [
      • Patel V.
      • Panja S.
      • Venkataraman A.
      Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators.
      ]. The irbesartan in patients with nephropathy due to Type 2 Diabetes (IDNT) trial, randomized T2DM patients with nephropathy to either irbesartan, amlodipine or placebo. All groups had the same target BP for which other medication was allowed. Treatment with irbesartan showed a significant benefit on slowing the progression of nephropathy [
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • Berl T.
      • Pohl M.A.
      • Lewis J.B.
      • et al.
      Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes.
      ]. However, no differences in mortality and cardiovascular events were found [
      • Berl T.
      • Hunsicker L.G.
      • Lewis J.B.
      • Pfeffer M.A.
      • Porush J.G.
      • Rouleau J.-L.
      • et al.
      Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy.
      ]. In other trials in diabetic patients treated to specific BP targets, the addition of ARBs versus placebo slowed the progression of nephropathy, with no significant effects on mortality and morbidity [
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • Keane W.F.
      • Mitch W.E.
      • Parving H.-H.
      • et al.
      Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy.
      ,
      • Haller H.
      • Ito S.
      • Izzo J.L.
      • Januszewicz A.
      • Katayama S.
      • Menne J.
      • et al.
      Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes.
      ,
      • Fried L.F.
      • Emanuele N.
      • Zhang J.H.
      • Brophy M.
      • Conner T.A.
      • Duckworth W.
      • et al.
      Combined angiotensin inhibition for the treatment of diabetic nephropathy.
      ]. A meta-analysis from 2006, showed renoprotective benefits in patients with established diabetic nephropathy, however only ACEi also showed a reduction of all-cause mortality (RR 0.79) [
      • Strippoli G.F.M.
      • Craig M.C.
      • Schena F.P.
      • Craig J.C.
      Role of blood pressure targets and specific antihypertensive agents used to prevent diabetic nephropathy and delay its progression.
      ]. In diabetic patients without nephropathy, ACEi and ARBs did not reduce mortality, but delayed the onset of microalbuminuria [
      • Strippoli G.F.M.
      • Craig M.C.
      • Schena F.P.
      • Craig J.C.
      Role of blood pressure targets and specific antihypertensive agents used to prevent diabetic nephropathy and delay its progression.
      ,
      • Persson F.
      • Lindhardt M.
      • Rossing P.
      • Parving H.-H.
      Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: A systematic review.
      ]. Importantly, most of these trials did not aimed at BP reduction and especially given the benefits found in the HOPE trial, hypertensive diabetic subjects with microalbuminuria should be treatment with either ACEi or ARBs. Other trials studied ACEi or ARB for cardiovascular outcomes in BP management. In patients with T2DM and mild retinopathy, treatment with ARB versus placebo did not result in cardiovascular benefit [
      • Tillin T.
      • Orchard T.
      • Malm A.
      • Fuller J.
      • Chaturvedi N.
      The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study.
      ] and in diabetic patients and high cardiovascular risk neither ACEi versus ARB or ACEi versus a combination resulted benefit [
      • Yusuf S.
      • Teo K.K.
      • Pogue J.
      • Dyal L.
      • Copland I.
      • Schumacher H.
      • et al.
      Telmisartan, ramipril, or both in patients at high risk for vascular events.
      ]. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) studied the effect of losartan versus atenolol in subjects with hypertension and left ventricular hypertrophy. Treatment with losartan resulted in significant reductions on the composite of cardiovascular events and mortality in the diabetic subgroup [
      • Lindholm L.H.
      • Ibsen H.
      • Dahlof B.
      • Devereux R.B.
      • Beevers G.
      • De Faire U.
      • et al.
      Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol.
      ]. Other combinations have also been studied, the combination of ACEi with a calcium channel blocker led to a reduction in combined cardiovascular outcomes compared to ACEi and a diuretic [
      • Jamerson K.
      • Weber M.A.
      • Bakris G.L.
      • Dahlof B.
      • Pitt B.
      • Shi V.
      • et al.
      Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients.
      ,
      • Weber M.A.
      • Bakris G.L.
      • Jamerson K.
      • Weir M.
      • Kjeldsen S.E.
      • Devereux R.B.
      • et al.
      Cardiovascular Events During Differing Hypertension Therapies in Patients With Diabetes.
      ]. Finally, treatment with aliskiren (a renin antagonist) on top of usual therapy did not result in benefit. This trial was terminated prematurely due to adverse events [
      • Parving H.-H.
      • Brenner B.M.
      • McMurray J.J.V.
      • de Zeeuw D.
      • Haffner S.M.
      • Solomon S.D.
      • et al.
      Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
      ].
      Two recent meta-analysis, including patients with and without a history of cardiovascular disease, showed benefit due to blood pressure lowering in patients with T2DM. Each 10 mmHg lowering of systolic BP was associated with a significant lower risk of all-cause mortality and cardiovascular events. Patients with a baseline BP of >140 mmHg had significant reduction in cardiovascular events and mortality [
      • Emdin C.A.
      • Rahimi K.
      • Neal B.
      • Callender T.
      • Perkovic V.
      • Patel A.
      Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Brunstrom M.
      • Carlberg B.
      Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and metaanalyses.
      ]. Surprisingly, when baseline BP was <140 mmHg, an increased risk for cardiovascular mortality was found. The authors proposed that this could be due to an impaired blood flow to end-organs.

      2.4 Lifestyle intervention (Table 4)

      The Look AHEAD (Action for Health in Diabetes) trial is the only trial aiming at an intensive lifestyle intervention in T2DM designed to evaluate cardiovascular outcomes. Overweight or obese patients with T2DM were randomized between intensive lifestyle intervention (promoting weight loss by decreased caloric intake and increased physical activity) and regular diabetes support. The trial was stopped prematurely due to the lack of effect. Though the weight loss was greater in the intervention group (6.0% versus 3.5%), the primary outcome, a composite of cardiovascular events did not differ nor did mortality [
      • Look AHEAD Research Group
      • Wing R.R.
      • Bolin P.
      • Brancati F.L.
      • Bray G.A.
      • Clark J.M.
      • et al.
      Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
      ]. Importantly, the achieved weight loss attenuated over time and the trial was stopped prematurely due to lack of effect. However, since the median duration of DM was only 5 years, one would expect that macrovascular complications of diabetes could take longer to emerge. Even though the difference in definitive weight loss between the groups was only 2.5%, significant reductions in hospitalizations, number of medications, and health-care costs were found [
      • Espeland M.A.
      • Glick H.A.
      • Bertoni A.
      • Brancati F.L.
      • Bray G.A.
      • Clark J.M.
      • et al.
      Impact of an Intensive Lifestyle Intervention on Use and Cost of Medical Services Among Overweight and Obese Adults With Type 2 Diabetes: The Action for Health in Diabetes.
      ].
      Table 4Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at a lifestyle intervention.
      PopulationNFollow upInterventionOutcome
      EventsMortality
      Look-AHEAD
      • Look AHEAD Research Group
      • Wing R.R.
      • Bolin P.
      • Brancati F.L.
      • Bray G.A.
      • Clark J.M.
      • et al.
      Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
      , 2013
      T2DM and overweight or obese5145Median 9.6 years; stopped due to futilityIntensive versus standard lifestyle interventionComposite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina HR 0.95 (95%-CI 0.83–1.09)All-cause mortality HR 0.85 (95%-CI 0.69–1.04)

      Cardiovascular mortality HR 0.88 (95%-CI 0.61–1.29)

      2.5 Bariatric surgery (Table 5)

      The Swedish Obesity Study (SOS) randomized 4047 obese patients to either bariatric surgery or usual care. In the total study group a 29% reduction in overall mortality was found and in the diabetic subgroup of 607 patients a significant reduction in cardiovascular events was found [
      • Sjöström L.
      • Narbro K.
      • Sjöström C.D.
      • Karason K.
      • Larsson B.
      • Wedel H.
      • et al.
      Effects of bariatric surgery on mortality in Swedish obese subjects.
      ,
      • Romeo S.
      • Maglio C.
      • Burza M.A.
      • Pirazzi C.
      • Sjöholm K.
      • Jacobson P.
      • et al.
      Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes.
      ]. When comparing these results with the Look-AHEAD, the improved cardiovascular outcome found in the SOS trial could be explained by both a greater weight loss (16% versus 6%) and an improved glycaemia (in the Look-AHEAD no reduction of glycated A1c was found). In a study from 2015 by Mingrone et al., with 60 patients and a mean follow-up of 5 years, no cardiovascular endpoints occurred during the study period [
      • Mingrone G.
      • Panunzi S.
      • De Gaetano A.
      • Guidone C.
      • Iaconelli A.
      • Nanni G.
      • et al.
      Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial.
      ]. In an observational cohort study by Eliasson et al. from 2015, data from 6132 obese patients with T2DM were compared with matched controls from other databases. After a median follow-up period of 3.5 years, significant reductions in overall and cardiovascular mortality were found in patients who underwent a gastric bypass [
      • Eliasson B.
      • Liakopoulos V.
      • Franzén S.
      • Näslund I.
      • Svensson A.-M.
      • Ottosson J.
      • et al.
      Cardiovascular disease and mortality in patients with type 2 diabetes after bariatric surgery in Sweden: a nationwide, matched, observational cohort study.
      ]. These studies suggest benefits with regard to cardiovascular mortality and events by bariatric surgery in patients with T2DM.
      Table 5Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at bariatric surgery.
      PopulationNFollow upInterventionOutcome
      EventsMortality
      SOS
      • Sjöström L.
      • Narbro K.
      • Sjöström C.D.
      • Karason K.
      • Larsson B.
      • Wedel H.
      • et al.
      Effects of bariatric surgery on mortality in Swedish obese subjects.
      , 2007
      Obese patients4047Mean 16 yearsBariatric surgery versus usual careAll-cause mortality HR 0.71 (95%-CI 0.54–0.92)
      • Romeo S.
      • Maglio C.
      • Burza M.A.
      • Pirazzi C.
      • Sjöholm K.
      • Jacobson P.
      • et al.
      Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes.
      , 2012
      Subgroup with T2DM607 (15%)Mean 13.3 yearsComposite of myocardial infarction or stroke HR 0.63 (95%-CI 0.45–0.90)
      Mingrone et al.
      • Mingrone G.
      • Panunzi S.
      • De Gaetano A.
      • Guidone C.
      • Iaconelli A.
      • Nanni G.
      • et al.
      Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial.
      , 2015
      T2DM and obesity60Mean 5 years follow-upMedical treatment versus gastric bypass versus biliopancreatic diversionNo deaths during study
      Eliasson et al.
      • Eliasson B.
      • Liakopoulos V.
      • Franzén S.
      • Näslund I.
      • Svensson A.-M.
      • Ottosson J.
      • et al.
      Cardiovascular disease and mortality in patients with type 2 diabetes after bariatric surgery in Sweden: a nationwide, matched, observational cohort study.
      , 2015
      T2DM and obesity6132 and matched database controlsMedian 3.5 yearsBariatric surgery versus matched controlsMyocardial infarction HR 0.51 (95%-CI 0.29–0.91)All-cause mortality HR 0.42 (95%-CI 0.30–0.57)

      Cardiovascular mortality HR 0.41 (95%-CI 0.10–0.90)

      2.6 Multifactorial intervention (Table 6)

      The Steno-2 trial showed that a multifactorial intervention (with either tight glucose regulation, the use of renin-angiotensin system blockers, aspirin, and lipid lowering agents) resulted in lower cardiovascular events compared to conventional therapy [
      • Gaede P.
      • Vedel P.
      • Larsen N.
      • Jensen G.V.H.
      • Parving H.-H.
      • Pedersen O.
      Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.
      ]. Furthermore, after an additional observational follow-up the significant reduction in cardiovascular events remained and also the total and cardiovascular mortality was significantly lower [
      • Gæde P.
      • Lund-Andersen H.
      • Parving H.-H.
      • Pedersen O.
      Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes.
      ].
      Table 6Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at a multifactorial intervention.
      PopulationNFollow upInterventionOutcome
      EventsMortality
      STENO-2
      • Gaede P.
      • Vedel P.
      • Larsen N.
      • Jensen G.V.H.
      • Parving H.-H.
      • Pedersen O.
      Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.
      , 2003
      T2DM and microalbuminuria160Mean 7.8 yearsIntensive (aiming behavior modification and pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria and aspirin) versus conventional treatmentComposite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation HR 0.47 (95%-CI 0.24–0.73)
      Post-trial follow-up
      • Gæde P.
      • Lund-Andersen H.
      • Parving H.-H.
      • Pedersen O.
      Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes.
      , 2008
      Mean 5.5 years post-trialComposite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, coronary-artery bypass grafting, percutaneous coronary intervention or revascularization for peripheral atherosclerotic arterial disease, and amputation because of ischemia HR 0.41 (95%-CI 0.25–0.67)All-cause mortality HR 0.54 (95%-CI 0.32–0.89)

      Cardiovascular mortality HR 0.41 (95%-CI 0.19–0.94)
      ADDITION
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.H.M.
      • Sandbæk A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      , 2011
      Screen detected T2DM3057Mean 5.3 yearsIntensive treatment of risk factors (HbA1c <7.0%, blood pressure < 135/85 mmHg, and total cholesterol <5.0 mmol/L, aspirin) versus routine care of diabetesComposite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, revascularization, and non-traumatic amputation HR 0.83 (95%-CI 0.65–1.05)All-cause mortality HR 0.91 (95%-CI 0.69–1.21)
      In contrast, the Anglo-Danish-Dutch study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION) randomized patients with screen detected T2DM to intensive treatment of multiple risk factors versus routine care. After a median of 6.2 years of follow-up, no significant benefit was seen in the intensive treatment group for a composite of cardiovascular events [
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.H.M.
      • Sandbæk A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      ]. However, this study was conducted in 4 countries and the intensive treatment did differ between these countries.

      2.7 Anti-platelet therapy (Table 7)

      The effect of anti-platelet therapy in secondary prevention for the total population has been shown in two different meta-analyses [
      • Fanaroff A.C.
      • Hasselblad V.
      • Roe M.T.
      • Bhatt D.L.
      • James S.K.
      • Steg P.G.
      • et al.
      Antithrombotic agents for secondary prevention after acute coronary syndromes: A systematic review and network meta-analysis.
      ,
      Antithrombotic Trialists’ (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      ]. Several trials included diabetic patients only. The Early Treatment of Diabetic Retinopathy Study (ETDRS), published in 1992, reported the effect of aspirin 650 mg daily in both primary and secondary prevention. The study consisted of patients with both T1DM and T2DM and treatment with high dose of aspirin did not result in benefits regarding mortality and cardiovascular events, however a reduction in fatal and nonfatal myocardial infarction was found [
      • Ferris F.L.
      • Kassoff A.
      • Buzney S.M.
      • McMeel J.W.
      • Weiter J.J.
      • Doyle G.J.
      • et al.
      Aspirin effects on mortality and morbidity in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report 14.
      ]. Furthermore, a 1994 meta-analysis showed, in secondary prevention including trials with diabetic subgroups, treatment with antiplatelet therapy significantly reduces risk for serious vascular events [
      Antiplatelet Trialists’ Collaboration
      Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration.
      ]. The same results were found in a sub analysis of the Antithrombotic Trialists’ meta-analysis. The effect of major vascular events was equal among subjects with and without diabetes (respectively RR 0.88 versus 0.87; however, the confidence interval of diabetic subjects indicated a non-significant effect). Several trials in primary prevention solely have been published using aspirin as antiplatelet therapy, with only one showing a reduction in cardiovascular mortality [
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • Uemura S.
      • Kanauchi M.
      • Doi N.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      ,
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • Cobbe S.
      • Taylor R.
      • Prescott R.
      • et al.
      The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      ,
      • Sacco M.
      • Pellegrini F.
      • Roncaglioni M.C.
      • Avanzini F.
      • Tognoni G.
      • Nicolucci A.
      • et al.
      Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial.
      ]. The meta-analysis by the Antithrombotic Trialists’ included 6 trials with 95000 patients (with 4000 diabetic subjects), found a significant reduction in vascular events (RR 0.88) [
      Antithrombotic Trialists’ (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      ], however no specific data from diabetic patients was available. In a meta-analysis by the American Diabetes Association (ADA); with 9 trials including several studies with subgroup data on diabetic patients, a non-significant risk reduction was found for fatal and nonfatal myocardial infarction and for stroke. Since several meta-analyses showed a modest-sized reduction the ADA recommends to use aspirin only in diabetic patients with increased cardiovascular risk [
      • Pignone M.
      • Alberts M.J.
      • Colwell J.A.
      • Cushman M.
      • Inzucchi S.E.
      • Mukherjee D.
      • et al.
      Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes: A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College.
      ].
      Table 7Randomized, controlled, cardiovascular outcome trials in patients with T2DM aiming at anti-platelet therapy.
      PopulationNFollow upInterventionOutcome
      EventsMortality
      ETDRS
      • Ferris F.L.
      • Kassoff A.
      • Buzney S.M.
      • McMeel J.W.
      • Weiter J.J.
      • Doyle G.J.
      • et al.
      Aspirin effects on mortality and morbidity in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report 14.
      , 1992
      Both T1DM and T2DM (48.8% with CVD)3711Mean 5.0 yearsAspirin 650 mg versus placeboFatal and nonfatal myocardial infarctions RR 0.83 (95%-CI 0.66-1.04)All-cause mortality HR 0.91 (95%-CI 0.75-1.11)

      Cardiovascular mortality HR 0.87 (95%-CI 0.72-1.05)
      Meta-analysis
      Antiplatelet Trialists’ Collaboration
      Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration.
      , 2016 Antiplatelet trialist collaboration
      145 randomized trials





      Diabetes
      51144





      4502
      Anti-platelet therapy for secondary preventionComposite of vascular death, myocardial infarction or stroke OR 0.75 (95%-CI 0.71-0.79)

      Risk reduction of 38 ± 12 vascular events per 1000 diabetic patients treated (p=0.002)
      PPP
      • Sacco M.
      • Pellegrini F.
      • Roncaglioni M.C.
      • Avanzini F.
      • Tognoni G.
      • Nicolucci A.
      • et al.
      Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial.
      , 2003
      T2DM, without a history of cardiovascular event1031Median 3.6 yearsAspirin 100 mg versus placebo; stopped due to benefit in non-diabetic groupComposite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke RR 0.90 (95%-CI 0.50-1.62)All-cause mortality RR 1.23 (95%-CI 0.69- 2.19)

      Cardiovascular mortality RR 1.23 (95%-CI 0.48-3.16)
      JPAD
      • Ogawa H.
      • Nakayama M.
      • Morimoto T.
      • Uemura S.
      • Kanauchi M.
      • Doi N.
      • et al.
      Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.
      , 2008
      T2DM; without cardiovascular disease2539Median 4.4 yearsAspirin 81 or 100 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, atherosclerotic events, or peripheral artery disease HR 0.80 (95%-CI 0.58-1.10)All-cause mortality HR 0.90 (95%-CI 0.57-1.14)

      Cardiovascular mortality HR 0.10 (95%-CI 0.01-0.79)
      POPADAD
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • Cobbe S.
      • Taylor R.
      • Prescott R.
      • et al.
      The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      , 2008
      Both T1DM and T2DM; without cardiovascular disease1276Median 6.7 yearsAspirin 100 mg versus placeboComposite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, amputation above ankle for critical limb ischemia HR 0.98 (95%-CI 0.76-1.26)All-cause mortality HR 0.93 (95%-CI 0.71-1.24)

      Cardiovascular mortality HR 1.23 (95%-CI 0.79-1.93)
      Meta-analysis
      Antithrombotic Trialists’ (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      , 2009

      Antithrombotic Trialists
      6 trials for primary prevention

      16 trials for secondary prevention
      95000



      17000















      4000 diabetes
      Aspirin for primary and secondary preventionPrimary: Composite of cardiovascular death, myocardial infarction or stroke RR 0.88 (95%-CI 0.82-0.94)

      Secondary: Composite of cardiovascular death, myocardial infarction or stroke RR 0.81 (95%-CI 0.75-0.87)











      Composite of cardiovascular death, myocardial infarction or stroke RR 0.92 (95%-CI 0.64-1.32)
      Primary: All-cause mortality RR 0.95 (95%-CI 0.88-1.02)

      Cardiovascular mortality RR 0.97 (95%- CI 0.87-1.09)

      Secondary: Cardiovascular mortality RR 0.91 (95%-CI 0.87-1.00)
      Meta-analysis
      • Pignone M.
      • Alberts M.J.
      • Colwell J.A.
      • Cushman M.
      • Inzucchi S.E.
      • Mukherjee D.
      • et al.
      Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes: A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College.
      , 2010 ADA
      9 randomized trials11787Aspirin for primary preventionFatal and nonfatal myocardial infarction RR 0.91 (95%-CI 0.79-1.05)

      Stroke RR 0.90 (0.71-1.13)

      3. Implications

      Overall, bariatric surgery, LDL-C lowering and blood pressure lowering have proven to reduce cardiovascular risk in subjects with T2DM. Blood glucose management reduces diabetic complications, however cardiovascular benefits are less clear where mainly found in follow-up studies. Treatment with metformin and both liraglutide and empagliflozin improves cardiovascular outcomes, however the latter might confer protection by other mechanisms than the glucose lowering effect. More trials with the drug, and preferably different compounds, need to be performed.Despite the number of trials aiming to reduce cholesterol, only the CARDS trial did specifically include T2DM. However, many trials provided evidence with subgroup analyses of patients with T2DM and a meta-analysis of the CTT showed clear cardioprotective results. For blood pressure management, more trials have been performed in diabetic cohort and results show clear benefit. Importantly, hypertension and hypercholesterolemia in subjects with T2DM should be treated even without a history of cardiovascular disease. Lifestyle intervention did not result in cardiovascular benefits, but trials with bariatric surgery have shown effects on mortality and cardiovascular events suggesting that weight loss by a strict lifestyle intervention might be beneficial. Furthermore, a modest difference in weight loss by intensive lifestyle intervention resulted in lower costs and less hospitalizations.The effect of antiplatelet therapy in primary prevention has not been proven in diabetic patients specifically, however in the total population a clear benefit has been proven. Also, reduction of microalbuminuria reduces mortality in subjects with diabetic nephropathy and the HOPE trial showed benefit in patient with increased cardiovascular risk. Therefore, the ADA advices to treat diabetic patients at increased cardiovascular risk for both even though strong evidence is lacking.

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