Background

Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for the development of atherosclerotic disease. Statin therapy reduces LDL-C and cardiovascular events in patients with or without cardiovascular disease. Previous studies have shown an increased incidence of diabetes with statin therapy.¹ Additionally, high-dose statin therapy has been associated with a greater risk of new-onset diabetes compared with a moderate-intensity statin.² In a large randomized trial of patients with recent acute coronary syndrome, ezetimibe, a non-statin lipid-lowering drug that decreases intestinal absorption of cholesterol, added to simvastatin showed a greater reduction in LDL-C and cardiovascular events than simvastatin alone.³ However, the effect of adding ezetimibe to a statin on the incidence of new-onset diabetes is unknown.

Methods

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (Thrombolysis in Myocardial Infarction 40) (IMPROVE-IT [TIMI 40]) investigators conducted a double-blind, randomized trial of 18,144 patients with acute coronary syndrome within 10 days of enrollment. The study included patients with LDL-C levels 50-100 mg/dL if already on lipid-lowering therapy and 50-125 mg/dL if not on lipid-lowering therapy. Study participants were randomized 1:1 to either a combination of simvastatin (40 mg) and ezetimibe (10 mg) or simvastatin (40 mg) and placebo. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke.

To explore the effect of ezetimibe on the incidence of new-onset diabetes, a subgroup analysis was performed in 12,254 patients who did not previously have diabetes. New-onset diabetes was defined as the initiation of an anti-hyperglycemic medication, two consecutive fasting glucose levels >7 mmol/L (126 mg/dL), or both.⁴ The investigators compared the incidence of new-onset diabetes in simvastatin-/ezetimibe-treated patients versus simvastatin monotherapy.

Results

Of the 12,254 patients who did not previously have diabetes, 1,414 (11.5%) developed diabetes during a mean follow-up of 75 months. There was no significant difference in the development of diabetes in patients treated with simvastatin/ezetimibe compared with simvastatin alone (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.15; P = 0.46) (Figure 1). Similar findings were observed when sensitivity analyses were performed using different definitions of new-onset diabetes.

Figure 1

Conclusion

When added to statin therapy, ezetimibe does not increase the risk of new-onset diabetes. Furthermore, this combination appears safe and more effective than statin monotherapy in reducing LDL-C and cardiovascular events.

Commentary/Perspective

Several primary and secondary prevention studies have shown that lowering LDL-C significantly reduces the risk of cardiovascular morbidity and mortality. Lifestyle changes and statins are the cornerstone for reducing LDL-C and cardiovascular risk in patients with hypercholesterolemia. However, several analyses have shown an increased risk of developing diabetes with statin use. Consequently, the U.S. Food and Drug Administration added a warning to the labeling of all statins. Nevertheless, the same studies also demonstrated that the small risk of developing diabetes with statin therapy was significantly outweighed by the substantial reduction in cardiovascular events.

Despite using intensive lipid-lowering therapy, a significant proportion of patients fail to achieve an optimal LDL-C level and maintain an elevated risk of cardiovascular events. In previous trials, adding a non-statin, lipid-lowering agent to a statin conferred no further benefit over statin monotherapy. IMPROVE-IT is the first randomized clinical trial to show improved cardiovascular outcomes by adding a non-statin lipid-lowering agent to statin therapy. This trial strengthens the hypothesis that a lower LDL-C level is better and suggests that this benefit is not limited to statins only.

Many clinicians will find the IMPROVE-IT data convincing and use ezetimibe in addition to a statin, targeting an LDL-C level less than 50 mg/dL in high-risk patients. This well-timed subgroup analysis of the IMPROVE-IT trial can reassure clinicians that ezetimibe is safe and does not increase the risk of developing diabetes. Previously, the effect of ezetimibe on the risk of incident diabetes had not been investigated in a large clinical trial. Earlier, small, non-randomized studies in patients with diabetes showed a decrease in fasting plasma glucose and reduced insulin resistance with ezetimibe, suggesting a favorable influence on glycemic control.⁵ Furthermore, another recent subgroup analysis of the IMPROVE-IT trial demonstrated greater relative and absolute benefit of ezetimibe added to simvastatin in diabetics, when compared with non-diabetic patients.⁶

Overall, this study reaffirms that ezetimibe is safe and does not increase the risk of developing diabetes. In addition, this trial reinforces the value of lowering LDL-C to even lower levels (<50 mg/dL), regardless of the agent used.

References

1. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet 2010;375:735-42.
2. Preiss D, Seshasai SRK, Wels P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 2011;305:2556-64.
3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
4. Presented by Dr. Michael Blazing at the European Society of Cardiology Congress, London, September 1, 2015.
5. Tsunoda T, Nozue T, Yamada M, et al. Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. Diabetes Res Clin Pract 2013;100:46-52.
6. Presented by Dr. Robert Giugliano at the European Society of Cardiology Congress, London, August 31, 2015.

Keywords: Acute Coronary Syndrome, Angina, Unstable, Azetidines, Blood Glucose, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Confidence Intervals, Diabetes Mellitus, Double-Blind Method, Drug Combinations, Fasting, Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hypoglycemic Agents, Incidence, Insulin Resistance, Intestinal Absorption, Life Style, Lipoproteins, LDL, Myocardial Infarction, Random Allocation, Research Personnel, Risk Factors, Secondary Prevention, Simvastatin, Stroke

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