Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials)

Abstract

The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m²), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m² <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.

Figure 1.

Incident T2DM according to baseline presence of PreDM and TG concentrations. Comparison of the rates of incident T2DM as a function of glycemic status (NFG vs PreDM) and plasma TG concentration (≤1.7 vs >1.7 mmol/1) in the 4 experimental groups, with each group stratified by treatment, placebo or atorvastatin.

Figure 2.

Hazard for T2DM according to baseline presence of PreDM and TG concentrations. Compared to reference (NFG, TG ≤1.7 mmol/l), all the other groups are significantly different (p <0.001). HRs (95% CIs) are 1.5 (1.2 to 2.0), 4.0 (3.3 to 4.9), and 6.7 (5.4 to 8.2), respectively. Models were adjusted for the following characteristics: BMI, HDL-C concentration, history of hypertension, and study.

Figure 3.

Incident T2DM according to baseline presence of PreDM and BMI. Comparison of the rates of incident T2DM as a function of glycemic status (NFG vs PreDM) and BMI (<27 vs ≥27 kg/m²) in the 4 experimental groups, with each group stratified by treatment, placebo or atorvastatin.

Figure 4.

Hazard for T2DM according to baseline presence of PreDM and BMI. Compared to reference (NFG, BMI <27 kg/m²), all the other groups are significantly different (p <0.001). HRs (95% CIs) are 1.4 (1.1 to 1.9), 3.5 (2.7 to 4.5), and 7.0 (5.6 to 8.6), respectively. Models were adjusted for the following characteristics: HDL-C concentration, history of hypertension, and study.