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Effect of Lipid Lowering Drugs on Type 2 Diabetes

Jul 30, 2016

ETC-1002 may offer new therapeutic option that does not decrease glycemic control.

Diabetes, hypertension and hypercholesterolemia are each independent risk factors for coronary artery disease (CAD); concomitant occurrence of these factors may lead to a collective increase in CAD risk. Lipid management, blood pressure control and glycemic control is a basic component in the management of diabetes. This is achieved in part through diabetes self-management, education, exercise and improved diet. It is therefore important that glucose metabolism not be adversely affected when patients take lipid lowering treatment. Patients with type 2 diabetes are at higher risk for cardiovascular disease and many fail to achieve their low density lipoprotein cholesterol (LDL-C) goal on statin therapy. Statin use in patients with diabetes mellitus is braced by a large body of clinical data demonstrating reduced risk for CVD. Recent studies proposed an increased risk for deterioration of glycemic control and new onset diabetes mellitus associated with statin use. However, other recent studies show patients with improved glucose disposal, insulin sensitivity and integrative markers of diabetes.

The purpose of this study, which is a placebo controlled double blind parallel group, was to evaluate the lipid altering effects of ETC-1002 in patients with both elevated LDL-C and type 2 diabetes mellitus. ETC-1002 was in phase 2 clinical development to treat hypercholesterolemia. Volunteers were divided into two groups, the placebo and the ETC-1002 group. Baseline and demographic characteristics were generally similar. ANCOVA model was the statistical analysis used. BMI for the ETC-1002 group was slightly higher with 30.6 vs 29.2 kg/m2. Almost all patients were on monotherapy of metformin since they were receiving treatment for diabetes with hypertension being frequently reported. Median fasting triglyceride was higher in the ETC-1002 group than in the placebo group. At day 29 LDL-C was reduced by 42.9% for the ETC-1002 group compared with 4.0% for the placebo group. The amount of LDL-C lowering seemed to be dose related and the difference from placebo remained highly significant [95% CI, -32.5, -20.7; P< 0.0001]. ETC-1002 treatment did not result in a worsening of glycemic control. A post hoc analysis showed a significant reduction of daily peak glucose with ETC-1002 treatment compared with placebo between hours of 6 AM and 12 PM [95% CI, -46.3, -2.5; P=0.0295]. ETC-1002 was generally safe and well tolerated.

Another study, which was a randomized, double blind, placebo controlled, parallel group, multi-site trial, was conducted at 19 sites in Japan. Subjects with diagnosis of type 2 diabetes mellitus and hypercholesterolemia aged 20 to 75 years were part of the inclusion criteria. Also, those who were taking oral diabetic drugs or insulin or both were included in the trial. Subjects were excluded if their triglyceride value exceeded 400 mg/dl, an HbA1c of ≥8.4%. The primary endpoint was to examine the safety of ezetimibe when compared to a placebo with regard to change in HbA1c from baseline to week 24, whilst the secondary endpoint compared ezetimibe to placebo for change in glycoalbumin and fasting plasma from baseline to week 24. 152 subjects were randomized to treatment n=75 to ezetimibe 10 mg and n=77 to placebo. Approximately 2/3 of subjects were males, majority of subjects had coexisting disease. At baseline mean HbA1c was 7.0%, glycoalbumin was 17.3% and fasting plasma glucose was 126.3 mg/dl. There was however no significant difference in exacerbation of diabetes between treatment group (P=0.78). Change from baseline was statistically significant for all 5 lipid parameters in subjects treated with ezetimibe 10 mg (P<0.05) but was not statistically significant in subjects who received placebo. No serious adverse effects, deaths or AEs leading to the study discontinuation were reported.

There was a substantial LDL-C lowering with ETC-1002 120 mg treatment versus placebo. Although statins are widely prescribed for the treatment of hypercholesterolemia in patients with type 2 diabetes, increase in hemoglobin A1C and fasting plasma glucose have been reported with statin therapy. For the other study, it showed that 10 mg of ezetimibe was statistically non inferior to the placebo group with respect to change in the HbA1c. Lipid parameters between ezetimibe and placebo were statistically significant at 24 weeks except for HDL-C. The study had some weaknesses, such the population size being limited to only Japanese patients and therefore not generalizable to other populations. In conclusion, 10 mg of ezetimibe does not result in an abnormal glucose metabolism over 24 weeks in Japanese patients with type 2 diabetes and hypercholesterolemia.

Practice Pearls:

  • Type 2 diabetes patients are at higher risk for cardiovascular disease and many fail to achieve their low –density lipoprotein-cholesterol goal on statin therapy.
  • ETC-1002 may offer a potential novel therapeutic approach that is well tolerated and can significantly lower LDL-C and high sensitivity C-reactive protein in patients with type 2 diabetes without worsening glycemic control.
  • Ezetimibe does not result in an abnormal glucose metabolism and was generally well tolerated with reduction of atherogenic lipid parameters.


Digenio A, et al. “Lipid-lowering drug improves glucose control in type 2 diabetes.” Diabetes Care. Web. July 2016.

Gutierrez Maria J et al. “Efficacy and Safety of ETC-1002, a Novel Investigational Low-Density Lipoprotein-Cholesterol-Lowering Therapy for the Treatment of Patients with Hypercholesterolemia and Type 2 Diabetes Mellitus”. Arteriosclerosis, Thrombosis & Vascular Biology. 34(3):676-683, March 2014. Web. July 11 2016.

Saito Itori et al. “A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia”. Lipids Health Dis. May 2015 (14). Web. July 11 2016.