Antihyperglycemic drugs and cardiovascular outcomes in type 2 diabetes

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ABSTRACTIn patients with diabetes, a complex and controversial relationship exists between intensive glycemic control and cardiovascular (CV) outcomes. Although the value of glucose-lowering agents in preventing microvascular complications associated with diabetes has been established, along with reductions in ischemic coronary events, active treatment in one major glycemic-control trial resulted in an unexplained increase in CV-associated mortality and total deaths compared with controls. Questions of CV safety with specific glucose-lowering agents along with the mechanisms underlying their effects on CV events have not been fully answered, underscoring the need for additional well-designed, long-term randomized controlled trials (RCTs) to prove their CV safety vs an active comparator. The CV benefits of one sodium-glucose cotransporter-2 inhibitor reported in an RCT await confirmation in ongoing trials.


  • Long-term randomized controlled trials have established the value of intensive glycemic control in reducing CV outcomes in patients with type 2 but only after many years of follow-up.
  • Despite reductions in ischemic coronary events, some clinical trials have reported unexplained increases in CV-associated mortality and total deaths in patients receiving intensive glycemic control.
  • Trials reporting the impact of specific glucose-lowering agents on CV events have reported perplexing, sometimes contradictory results, underscoring the need for additional trials.



The essential value of glycemic control in preventing microvascular and neuropathic complications was established in the Diabetes Control and Complications Trial (DCCT)1 and the United Kingdom Prospective Diabetes Study (UKPDS),2 conducted in patients with type 1 and type 2 diabetes, respectively. However, it took another 10 or more years of observational follow-up of those cohorts to demonstrate statistically significant atherosclerotic cardiovascular (CV) disease benefits resulting from the intensive glycemic control achieved during those trials, as reported in the DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC)3 and the UKPDS follow-up studies.4 Overall, it took more than 20 years of observational follow-up of the original intensive glucose-treatment cohort of DCCT/EDIC to show a significant decline in total deaths compared with the conventional treatment cohort.5

In patients with type 2 diabetes, the relationship between intensive glycemic control and CV benefits is somewhat controversial, particularly in view of negative CV outcomes from several long-term clinical trials in subjects older than the UKPDS subjects and with longer duration of diabetes:

  • ACCORD trial (Action to Control Cardiovascular Risk in Diabetes)6,7
  • ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation)8,9
  • VADT: (Veteran Affairs Diabetes Trial).10,11

The controversy was spurred by an unexplained increase in total deaths in ACCORD,6,7 despite a reduction in ischemic coronary events. In the VADT,10,11 a significant decline was reported for major CV events, but not total deaths, after a median of 9.8 years of observational follow-up.11 In the ADVANCE cohort,8,9 a reduction in total deaths or CV events was not seen after 5.4 years of additional follow-up.9 Some of these differences in outcomes between the UKPDS and these other long-term trials may well reflect the younger aged and the newly diagnosed patients in the UKPDS population, and differences in specific glucose-lowering strategies. Nevertheless, this remains an unsettled issue.


Another poorly understood question relates to the impact of specific glucose-lowering agents on CV events, regardless of the glucose control. Table 1 lists the studies of the currently available agents. Studies such as the UKPDS have investigated the question of intensive hyperglycemia control compared with standard, less intensive control.

The question of CV safety with glucose-lowering agents was highlighted in a 2007 meta-analysis of 42 short-term studies with rosiglitazone that reported significantly worse myocardial infarction (MI) risks along with increased mortality from all CV causes that was borderline significant (P = .06).12 This finding, however, was not confirmed in the only randomized controlled trial (RCT) completed with rosiglitazone.13 The controversy led the US Food and Drug Administration (FDA) to issue a 2008 guidance statement recommending that all new diabetes drugs undergo a long-term, noninferiority RCT to prove their CV safety vs an active comparator.14 Before the FDA mandate, few clinical trials had addressed the long-term effects of glucose-lowering drugs on CV outcomes in patients with type 2 diabetes.

In the UKPDS, the only primary prevention trial thus far, investigators used first-generation sulfonylureas (glyburide and chlorpropamide) with or without insulin as the intensive control strategy in 3,867 patients newly diagnosed with type 2 diabetes.2 After a median follow-up of 10 years, the active treatment group had a borderline benefit in fatal and nonfatal MI (16% reduction in relative risk for MI; P = .052) compared with the nondrug treatment.

Additionally, a small subgroup of overweight patients in the UKPDS who were randomized to metformin (N = 342) had 36% (P = .010) lower risk of all-cause mortality and 39% (P = .011) lower risk of MI compared with conventional treatment.15 This benefit occurred despite a more modest hemoglobin A1c (HbA1c) reduction (0.6%) in the metformin group than in the entire UKPDS trial (0.9%).

The mechanism underlying these impressive CV benefits remains unclear in view of the nonglucose effects of metformin, such as lack of weight gain. Metformin also has been reported to reduce generation of advanced glycosylation end products and oxidative damage to apolipoprotein B100 in patients with type 2 diabetes.16

One curious but unexplained finding in the UKPDS was an increase in both diabetes-related deaths (relative risk [RR], 1.96; P = .039) and total deaths (RR, 1.60; P = .04) in a subgroup of 268 patients in whom metformin was added to sulfonylurea therapy; however, the number of total deaths was relatively small, 47 deaths in the metformin added group and 31 deaths in the sulfonylurea group.15 Because of the absence of proven CV benefits with any other diabetes drug thus far, metformin is generally the preferred initial drug in all treatment guidelines.

The relative effects of metformin and sulfonylureas when used as the initial monotherapy regimen have been studied in several large observational studies.17–20 In general, there appears to be a consistent pattern of significantly increased CV events and total mortality—by 20% to 50%—in those treated with sulfonylureas, with or without prior CV disease. However, these analyses were not based on RCTs.

In two RCTs—NAVIGATOR Study Group21 and STOP-NIDDM Trial22—patients with impaired glucose tolerance were recruited with the primary aim of preventing progression to diabetes. In the NAVIGATOR trial, the short-acting insulin secretagogue nateglinide did not reduce CV events or the progression to diabetes.21 In the other study, acarbose, an alpha-glucosidase inhibitor, significantly reduced CV events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28–0.85; P = .03)22 and also prevented progression to diabetes. (P < .002).23 Although the number of CV events in that 3-year study was small, a meta-analyses of seven studies using acarbose therapy in patients with diabetes also found a significant reduction in composite CV events (HR, 0.65; P < .007), including MIs.24 A long-term, much larger RCT with acarbose is in progress.25

Following the demonstration of strikingly protective effects of metformin on CV events in the UKPDS,16 two major trials of thiazolidinediones (TZDs) investigated the effects of insulin sensitization on CV events.13,26 Pioglitazone in patients with long duration type 2 diabetes mellitus and pre-existing CV disease was reported to marginally reduce major CV outcomes (HR, 0.84; 95% CI, 0.72–98; P < .03),26 whereas rosiglitazone in patients with a shorter duration of diabetes was found to be noninferior to the control group.13 In both trials, however, there was a twofold increased risk for hospitalization for heart failure and increased risk for bone fractures in women,13,26 but without an increased risk for mortality.27 Furthermore, in the BARI 2D trial in patients with diabetes and established CV disease, adding rosiglitazone did not significantly reduce propensity-matched CV outcomes, compared with insulin secretagogues or insulin.28 Thus, while TZDs appear to have no major adverse effects on CV outcomes, the other associated adverse effects limit their use.

In a 1-year study of the efficacy and CV safety of the dopaminergic agent quick-release bromocriptine, an FDA-approved drug for diabetes, there was a marked decrease in incidence of composite CV end points (HR, 0.60; 95% CI, 0.37–0.96).29 However, there also was a 47% dropout rate and a small number of total events; thus, the implications remain inconclusive.

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Newer oral and noninsulin therapies to treat type 2 diabetes mellitus

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