Role of Oral Agents in Improving Cardiovascular Prognosis in Diabetes Mellitus–Reply–I

We appreciate Dr Hirsch's kind comments regarding our recent article and are delighted to respond to his opinion that glucose-lowering drugs should not be included among the evidence-based strategies that have been shown to reduce the incidence of adverse cardiovascular (CV) events. His assertion highlights one of the most important unresolved dilemmas in modern medicine: If elevated glucose levels powerfully increase the risk of CV disease, why have we been unable to prove that lowering glucose back toward normal improves CV prognosis? There is no doubt that an abnormally elevated blood glucose level is a pernicious CV risk factor.1 The EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk) study showed that, during 6 years of follow-up, glycated hemoglobin (HbA1c) levels were highly correlated in a direct fashion with risk of all-cause mortality.2 In that study, for every 0.5% increase in HbA1c levels greater than 5% for men and 6% for women, the relative risk of adverse CV events increased by approximately 25%.2 Similarly, the observational UKPDS (United Kingdom Prospective Diabetes Study)35 found a 14% change in the risk of myocardial infarction (MI) for each 1% change in mean HbA1c level.3 Despite the fact that approximately 70% of patients with diabetes mellitus (DM) die of CV disease,4 glucose-lowering therapy has not been conclusively shown to improve CV outcomes. This missing evidence is not due to a lack of prospective DM studies; during the 9 decades that have elapsed since Dr Frederick Banting discovered insulin, scores of randomized trials of glucose-lowering therapies have repeatedly failed to firmly establish a cardioprotective role for these drugs. The University Group Diabetes Project, a widely publicized early failure, reported that the sulfonylurea tolbutamide significantly increased CV death compared with placebo.5 Subsequently, UKPDS randomized patients to either intensive treatment (with either a sulfonylurea or insulin) or conventional therapy (predominantly diet alone) and found HbA1c values of 7% and 7.9%, respectively, while receiving treatment.6 Intensive insulin therapy yielded a statistically insignificant trend toward reduction in the risk of MI in type 2 DM after 10 years of follow-up. More recently, 3 large randomized trials that tested the “lower is better” approach to treating hyperglycemia also failed to prove that an intensive glucose-lowering strategy is superior to a less aggressive glycemic control for reducing CV events.7-9 The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial actually showed a higher CV mortality in patients with type 2 DM randomized to intensive glycemic control after 3.5 years of follow-up. Subgroup analysis suggested that intensive glycemic control may have reduced the risk of fatal and nonfatal CV events in patients with no documented coronary heart disease (CHD) at baseline.7 The VADT (Veterans Affairs Diabetes Trial) compared intensive and standard treatment strategies in patients with type 2 DM and found no significant difference in the incidence of a major CV event after a median follow-up of 5.6 years.8 ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) showed no difference between intensive control and standard control groups in macrovascular outcomes but showed a lower risk of nephropathy with intensive control after a median follow-up of 5 years.9 Therefore, the cumulative findings from ACCORD, ADVANCE, and VADT suggest that an intensive glycemic control strategy does not significantly reduce macrovascular events and may even be harmful to older patients with long-standing DM and/or established CHD at baseline. In contrast, younger patients with shorter duration of DM and no documented CV disease appear to benefit from a more intensive glucose-lowering strategy.7-9 Importantly, hypoglycemia was more common in the intensive therapy arms of all 3 of these recent trials7-9 and also in the UKPDS.6 Possibly, CV toxicity caused by recurrent hypoglycemia induced by an aggressive glycemic control strategy (especially one that uses insulin and/or a sulfonylurea) overwhelms the potential CV benefits of a more normal HbA1c. This would be particularly true for patients with conditions that predispose to adverse CV events, such as CHD and other structural heart disease. Thus, it is not surprising that individuals with long-standing DM and/or existing CV disease appear to be particularly susceptible to the cardiotoxicity associated with aggressive glycemic control and hypoglycemia. Besides hypoglycemia, another possible reason for the recurring failure of glucose-lowering strategies to improve CV prognosis is the use of fasting glucose or HbA1c as the primary target of treatment. Postprandial hyperglycemia is associated with increased risk of CV events in patients with and without type 2 DM.10,11 Even in the setting of controlled fasting glucose levels, postprandial spikes in glucose will powerfully increase risk of CV events.10,11 Taken together, these data suggest that the most logical and effective approaches to improve CV prognosis of type 2 DM would use therapies that (1) improve glycemic control without leading to hypoglycemia and (2) effectively lower postprandial glucose excursions. In fact, outcome data suggest that these 2 features are the common denominators of the therapeutic strategies that have been shown in prospective trials to reduce CV events. A lower all-cause mortality was reported in the metformin arm of the UKPDS 34 trial that randomized overweight or obese patients with type 2 DM to metformin or conventional therapy (primarily diet).12 Metformin, as compared with a sulfonylurea or insulin, was associated with a greater risk reduction in all-cause mortality and stroke, but not MI, and a lower risk of hypoglycemia.12 Proactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) randomized patients with type 2 DM to receive pioglitazone or placebo in addition to standard of care during a 3-year period. A statistically significant improvement in the secondary end point of the composite of all-cause mortality, nonfatal MI, and stroke was noted in the pioglitazone arm.13 The pioglitazone arm also showed a nonsignificant favorable trend in the primary end point of composite adverse CV and peripheral artery disease events.13 The NIDDM (STOP-Noninsulin-Dependent Diabetes Mellitus) trial is a large randomized, placebo-controlled trial that assesses acarbose for preventing DM in patients with pre-DM.14 Acarbose, a nonsystemic medication that decreases postprandial hyperglycemia by blocking α-glucosidase, was associated with a 49% lower risk of CV events during the 3.3-year randomized trial. Recent evidence provides promise for bile acid sequestrants, especially colesevelam, and bariatric surgery to safely improve glucose control and reduce clinical events in patients with DM.15-17 In conclusion, we agree with Dr Hirsh that the foremost treatment of DM is strict control of the associated CV risk factors, particularly hypertension and dyslipidemia. Glycemic control is important for preventing microvascular complications, such as retinopathy, nephropathy, and neuropathy, and may confer macrovascular CV benefits when optimal treatments are used in appropriate patients. However, controversy remains regarding the optimal targets for glucose control and whether specific agents are superior to others. The American Dietetic Association/American College of Cardiology/American Heart Association recommendations for HbA1c target are less than 7%.18 Available data suggest that aggressive control beyond this goal does not provide benefit and might be harmful, particularly in elderly patients with a long duration (>10 years) of DM and those with established CHD. In contrast, younger patients with relatively recently diagnosed DM and no known CHD might benefit from a more aggressive approach. Finally, a therapeutic strategy that targets postprandial hyperglycemia, while avoiding agents that cause hypoglycemia, seems to offer the best chance of improving long-term CV health in patients with type 2 DM.