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.
CAN DIABETES THERAPY CAUSE HARM?
New diabetes drugs must show no cardiovascular harm
Several drugs that were approved purely on the basis of their potential to reduce blood glucose were reevaluated for impact on adverse cardiovascular outcomes.
Muraglitazar is a peroxisome proliferator-activated receptor agonist that was shown in phase 2 and 3 studies to dramatically lower triglyceride levels in a dose-dependent fashion while raising high-density lipoprotein levels and being neutral to low-density lipoprotein levels. It also lowers blood glucose. The FDA Advisory Committee voted to approve its use for type 2 diabetes based on phase 2 trial data. But soon after, a meta-analysis revealed that the drug was associated with more than twice the incidence of cardiovascular complications and death than standard therapy.32 Further development of this drug subsequently ceased.
A similar meta-analysis was performed on rosiglitazone, a drug that has been available since 1997 and had been used by millions of patients. Rosiglitazone was also found to be associated with a significantly increased risk of cardiovascular death, as well as death from all causes.33
In light of these findings, the FDA in 2008 issued new guidelines to the diabetes drug development industry. Henceforth, new diabetes drugs must not only lower blood glucose, they must also be shown in a large clinical trial not to increase cardiovascular risk.
Current trials will provide critical information
Numerous trials are now under way to assess cardiovascular outcomes with promising new diabetes drugs. Tens of thousands of patients are involved in trials testing dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 agonists, sodium-glucose-linked transporter-2 agents, and a GPR40 agonist. Because of the change in guidelines, results over the next decade should reveal much more about the impact of lowering blood glucose on heart disease than we learned in the previous century.
Two apparently neutral but clinically relevant trials recently examined cardiovascular outcomes associated with diabetes drugs.
EXAMINE.34 The Examination of Cardiovascular Outcomes Study of Alogliptin Versus Standard of Care study randomized 5,380 patients with type 2 diabetes and a recent acute coronary syndrome event (acute myocardial infarction or unstable angina requiring hospitalization) to receive either alogliptin (a DPP-4 inhibitor) or placebo in addition to existing standard diabetes and cardiovascular therapy. Patients were followed for up to 40 months (median 18 months). Hemoglobin A1c levels were significantly lower with alogliptin than with placebo, but the time to the primary end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was not significantly different between the two groups.
SAVOR.35 The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DM (SAVOR–TIMI 53) trial randomized more than 16,000 patients with established cardiovascular disease or multiple risk factors to either the DPP-4 inhibitor saxagliptin or placebo. The patients’ physicians were permitted to adjust all other medications, including standard diabetes medications. The median treatment period was just over 2 years. Similar to EXAMINE, this study found no difference between the two groups in the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke, even though glycemic control was better in the saxagliptin group.
Thus, both drugs were shown not to increase cardiovascular risk, an FDA criterion for drug marketing and approval.
CONTROL MODIFIABLE RISK FACTORS
There has been an alarming rise in the incidence of diabetes and obesity throughout the world. Cardiovascular disease remains the leading cause of death in patients with diabetes. While elevated blood glucose in diabetic patients leads to increased cardiovascular risk, efforts to reduce blood glucose to euglycemic levels may not lead to a reduction in this risk and may even cause harm.
Success in cardiovascular risk reduction in addition to glucose-lowering remains the holy grail in the development of new diabetes drugs. But in the meantime, aggressive control of other modifiable risk factors such as hypertension, smoking, and hyperlipidemia remains critical to reducing cardiovascular risk in diabetic patients.
