Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

Abstract

BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P = 0.057 for interaction). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

National Trends in Nonstatin Use and Expenditures Among the US Adult Population From 2002 to 2013: Insights From Medical Expenditure Panel Survey

“…Over the study period, total gross domestic product‐adjusted costs associated with nonstatins peaked at more than $9 billion in 2008‐2009. The slightly lower rates of nonstatin LLT use seen since then may have been due to a series of trials mostly demonstrating no cardiovascular outcome benefits of nonstatin LLT 3, 4, 5. However, despite weak evidence for clinical improvement from fibrates and net harm from niacin, in 2012‐2013 they accounted for $2.5 billion and $873 million in annual national expenditure, respectively.…”

“…This was highlighted in the 2013 American Heart Association/American College of Cardiology guidelines for cholesterol management, which reflected weak evidence for nonstatin medications observed by several randomized controlled trials, including ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression),3 AIM‐HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcome),4 and ACCORD (Action to Control Cardiovascular Risk in Diabetes) 5. However, a recently published American College of Cardiology expert consensus document, written after the publication of IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)6 and FOURIER (Further Cardiovascular Outcomes Research With PCK9 Inhibition in Subjects With Elevated Risk),7 provides clinical guidance for nonstatin use but noted that the evidence base for the various agents is heterogeneous given that several medications in this class such as niacin, fibrates, and bile acid sequestrants lack strong contemporary evidence 8.…”

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…In the IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trial evaluating the addition of ezetimibe concomitant with statin therapy, which lowered LDL‐C levels below previous targets to a median level of 53 mg/dL in 18 144 patients with recent acute coronary syndromes (27% of whom had diabetes mellitus),11 individuals with diabetes mellitus had significantly greater relative and absolute benefit in improved cardiovascular outcomes than those without diabetes mellitus 14. Clinical outcomes studies for niacin (AIM‐HIGH [Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes] and HPS2‐THRIVE [Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events]) and fenofibrate (ACCORD [Action to Control Cardiovascular Risk in Diabetes] and FIELD [Fenofibrate Intervention and Event Lowering in Diabetes]) did not demonstrate significant cardiovascular benefits in individuals with diabetes mellitus, although there was a suggestion of benefit in subgroups with very high triglyceride levels in the fenofibrate studies 15, 16, 17, 18. Because of increased risk of adverse events (AEs) and lack of evidence of meaningful benefits as seen in cardiovascular outcomes trials,15, 16, 17 the US Food and Drug Administration (FDA) has recently rescinded its approval of the combined use of statins with niacin extended‐release tablets or fenofibric acid delayed‐release capsules 19.…”

“…Clinical outcomes studies for niacin (AIM‐HIGH [Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes] and HPS2‐THRIVE [Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events]) and fenofibrate (ACCORD [Action to Control Cardiovascular Risk in Diabetes] and FIELD [Fenofibrate Intervention and Event Lowering in Diabetes]) did not demonstrate significant cardiovascular benefits in individuals with diabetes mellitus, although there was a suggestion of benefit in subgroups with very high triglyceride levels in the fenofibrate studies 15, 16, 17, 18. Because of increased risk of adverse events (AEs) and lack of evidence of meaningful benefits as seen in cardiovascular outcomes trials,15, 16, 17 the US Food and Drug Administration (FDA) has recently rescinded its approval of the combined use of statins with niacin extended‐release tablets or fenofibric acid delayed‐release capsules 19. These nonstatin therapies only produce moderate LDL‐C‐lowering effects and have side effects that limit their use 11, 15, 16, 17…”

“…Because of increased risk of adverse events (AEs) and lack of evidence of meaningful benefits as seen in cardiovascular outcomes trials,15, 16, 17 the US Food and Drug Administration (FDA) has recently rescinded its approval of the combined use of statins with niacin extended‐release tablets or fenofibric acid delayed‐release capsules 19. These nonstatin therapies only produce moderate LDL‐C‐lowering effects and have side effects that limit their use 11, 15, 16, 17…”