Why are we doing cardiovascular outcome trials in type 2 diabetes?
ABSTRACTCardiovascular disease is the leading cause of morbidity and death in people with diabetes mellitus. While worsening hyperglycemia is directly associated with poorer outcomes, studies aiming at euglycemia have failed to show an advantage over modest glucose-lowering strategies. Several diabetes drugs that were approved solely on the basis of their glucose-lowering potential were later shown to increase cardiovascular risk.
KEY POINTS
- The worldwide burden of type 2 diabetes is increasing dramatically as obesity rates increase, populations age, and people around the world adopt a Western diet.
- Diabetes increases the risk of atherosclerotic cardiovascular disease, which remains the leading cause of death in diabetic patients.
- Lowering blood glucose alone may not necessarily amount to reduction in adverse cardiovascular events.
- Clinical trials of new drugs for type 2 diabetes must prove cardiovascular safety in addition to glucose-lowering potential before the drugs gain final regulatory approval.
- Aggressive risk factor modification (smoking cessation, control of hypertension, and treatment of hyperlipidemia with statins) remains paramount in reducing cardiovascular risk in people with diabetes.
STRATEGIES TO REDUCE CARDIOVASCULAR RISK IN DIABETES
While the incidence of diabetes mellitus has risen alarmingly, the incidence of cardiovascular complications of diabetes has declined over the years. Lowering blood glucose has not been the critical factor mediating this risk reduction. In addition to smoking cessation, proven measures that clearly reduce long-term cardiovascular risk in diabetes are blood pressure control and reduction in low-density lipoprotein cholesterol with statins.
Lower the blood pressure to less than 140 mm Hg
ADVANCE.12 In the ADVANCE trial, in addition to being randomized to usual vs intensive glucose-lowering therapy, participants were also simultaneously randomized to receive either placebo or the combination of an angiotensin-converting enzyme inhibitor and a diuretic (ie, perindopril and indapamide). Blood pressure was reduced by a mean of 5.6 mm Hg systolic and 2.2 mm Hg diastolic in the active-treatment group. This moderate reduction in blood pressure was associated with an 18% relative risk reduction in death from cardiovascular disease and a 14% relative risk reduction in death from any cause.
The ACCORD trial13 lowered systolic blood pressure even more in the intensive-treatment group, with a target systolic blood pressure of less than 120 mm Hg compared with less than 140 mm Hg in the control group. Intensive therapy did not prove to significantly reduce the risk of major cardiovascular events and was associated with a significantly higher rate of serious adverse events.
Therefore, while antihypertensive therapy lowered the mortality rate in diabetic patients, lowering blood pressure beyond conventional blood pressure targets did not decrease the risk more. The latest hypertension treatment guidelines (from the eighth Joint National Committee) emphasize a blood pressure goal of 140/90 mm Hg or less in adults with diabetes.14
Prescribe a statin regardless of the baseline lipid level
The Collaborative Atorvastatin Diabetes Study (CARDS) randomized nearly 3,000 patients with type 2 diabetes mellitus and no history of cardiovascular disease to either atorvastatin 10 mg or placebo regardless of cholesterol status. The trial was terminated 2 years early because a prespecified efficacy end point had already been met: the treatment group experienced a markedly lower incidence of major cardiovascular events, including stroke.15
A large meta-analysis of randomized trials of statins noted a 9% reduction in all-cause mortality (relative risk [RR] 0.91, 99% confidence interval 0.82–1.01; P = .02) per mmol/L reduction in low-density lipoprotein cholesterol in patients with diabetes mellitus.16 Use of statins also led to significant reductions in rates of major coronary events (RR 0.78), coronary revascularization (RR 0.75), and stroke (RR 0.79).
The latest American College of Cardiology/American Heart Association guidelines endorse moderate-intensity or high-intensity statin treatment in patients with diabetes who are over age 40.17
Encourage smoking cessation
Smoking increases the lifetime risk of developing type 2 diabetes.18 It is also associated with premature development of microvascular and macrovascular complications of diabetes,19 and it leads to increased mortality risk in people with diabetes mellitus in a dose-dependent manner.20 Therefore, smoking cessation remains paramount in reducing cardiovascular risk, and patients should be encouraged to quit as soon as possible.
Role of antiplatelet agents
Use of antiplatelet drugs such as aspirin for primary prevention of cardiovascular disease in patients with diabetes is controversial. Initial studies showed a potential reduction in the incidence of myocardial infarction in men and stroke in women with diabetes with low-dose aspirin.21,22 Subsequent randomized trials and meta-analyses, however, yielded contrasting results, showing no benefit in cardiovascular risk reduction and potential risk of bleeding and other gastrointestinal adverse effects.23,24
The US Food and Drug Administration (FDA) has not approved aspirin for primary prevention of cardiovascular disease in people who have no history of cardiovascular disease. In contrast, the American Heart Association and the American Diabetes Association endorse low-dose aspirin (75–162 mg/day) for adults with diabetes and no history of vascular disease who are at increased cardiovascular risk (estimated 10-year risk of events > 10%) and who are not at increased risk of bleeding.
In the absence of a clear consensus and given the lack of randomized data, the role of aspirin in patients with diabetes remains controversial.
WHAT IS THE ROLE OF STRESS TESTING IN ASYMPTOMATIC DIABETIC PATIENTS?
People with diabetes also have a high incidence of silent (asymptomatic) ischemia that potentially leads to worse outcomes.25 Whether screening for silent ischemia improves outcomes in these patients is debatable.
The Detection of Anemia in Asymptomatic Diabetics (DIAD) trial randomized more than 1,000 asymptomatic diabetic participants to either screening for coronary artery disease with stress testing or no screening.26 Over a 5-year follow-up, there was no significant difference in the incidence of myocardial infarction and death from cardiac causes.
The guidelines remain divided on this clinical conundrum. While the American Diabetes Association recommends against routine screening for coronary artery disease in asymptomatic patients with diabetes, the American College of Cardiology/American Heart Association guidelines recommend screening with radionuclide imaging in patients with diabetes and a high risk of coronary artery disease.27
ROLE OF REVASCULARIZATION IN DIABETIC PATIENTS WITH STABLE CORONARY ARTERY DISEASE
Patients with coronary artery disease and diabetes fare worse than those without diabetes, despite revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).28
The choice of CABG or PCI as the preferred revascularization strategy was recently studied in the Future Revascularization Evaluation in Patients With DM: Optimal Management of Multivessel Disease (FREEDOM) trial.29 This study randomized 1,900 patients with diabetes and multivessel coronary artery disease to revascularization with PCI or CABG. After 5 years, there was a significantly lower rate of death and myocardial infarction with CABG than with PCI.
The role of revascularization in patients with diabetes and stable coronary artery disease has also been questioned. The Bypass Angioplasty Revascularization Investigation 2 DM (BARI-2D) randomized 2,368 patients with diabetes and stable coronary artery disease to undergo revascularization (PCI or CABG) or to receive intensive medical therapy alone.30 At 5 years, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing revascularization and those undergoing medical therapy alone. Subgroup analysis revealed a potential benefit with CABG over medical therapy in patients with more extensive coronary artery disease.31
