Statins Are Associated With Increased Insulin Resistance and Secretion

Abstract

Objective: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk.

Approach and results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01).

Conclusions: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.

Trial registration: ClinicalTrials.gov NCT02437084.

Keywords: atorvastatin; cardiovascular disease; glucose; insulin resistance; insulin secretion.

Figure 1. Study Participant Flow

GGIT indicates graded glucose infusion test; OGTT, oral glucose tolerance test; and IST, insulin suppression test.

Figure 2. Effect of Atorvastatin Treatment on Insulin Resistance and Insulin Secretion

In panel A, waterfall plot depicts percent change in insulin resistance, measured by steady-state plasma glucose (SSPG), during the insulin suppression test (N=70). The mean (95% CI) percent change in SSPG concentration was 15 (6 – 23) mg/dL. One sample t test was used to compare mean percent change in SSPG to zero (no change). In Panel B, baseline and end-of-study insulin secretion rate (ISR) mean (SEM) values are plotted against the incremental increase in plasma glucose during the graded glucose infusion test (N=64). Baseline and end-of-study ISR area under the curve (ISR_AUC) means were compared by paired sample t test after log-transformation of ISR_AUC values.

Figure 3. Relationship between Change in Insulin Resistance and Change in Insulin Secretion after Atorvastatin Treatment

The four-quadrant scatterplot shows data on 63 individuals who underwent both the insulin suppression test and the graded glucose infusion test. Number of subjects in each quadrant is shown. Percent change was calculated by using the formula: [(end-of-study value) - (baseline value) / baseline value] x 100. ISR_AUC indicates insulin secretion rate area-under-the-curve and SSPG, steady-state plasma glucose.

Figure 4. Changes in Insulin Resistance and Insulin Secretion in Subgroups after Atorvastatin Treatment

Forest plots depict changes in insulin resistance (Panel A) and insulin secretion (Panel B) in the whole group and in subgroups based on baseline characteristics: insulin resistance status, sex, race/ethnicity, age, BMI, TG, glucose tolerance, and diagnosis of the MetSyn. Data are means and 95% CIs. Within each subgroup, means were compared by independent samples t tests. Only the differences in insulin resistance (Panel A) between insulin sensitive and insulin resistant subgroups were significantly different (P=0.002). AGT indicates abnormal glucose tolerance; BMI, body mass index; ISR_AUC, insulin secretion rate area under the curve; MetSyn, metabolic syndrome; NGT, normal glucose tolerance; NHW, Non-Hispanic white; SSPG, steady-state plasma glucose, and TG, triglycerides.