Statin-induced Diabetes: How Important is Insulin Resistance?

Waters and associates have shown that elevations of blood pressure, fasting glucose, and triglyceride (TG) concentrations are predictors of type 2 diabetes (T2DM) in statin-treated individuals (1). These changes, along with some degree of glucose intolerance, comprise the cluster of abnormalities initially designated as Syndrome X (2), secondary to a defect in insulin-stimulated glucose disposal (insulin resistance). Since insulin resistance is a predictor of type 2 diabetes (2; 3), we evaluated the possibility that significant differences in baseline prevalence of insulin resistance and glucose tolerance might exist in a population of nondiabetic persons with hypercholesterolemia.

Based on results of a previous study [4], we enrolled 107 apparently healthy individuals of European ancestry with a low-density lipoprotein cholesterol (LDL-C) concentration ≥ 3.36 mmol/L and stratified them into two groups on the basis of their TG concentrations (<1.69 vs. ≥ 1.69 mmol/L). Study protocols were approved by Stanford’s Institutional Review Board, and all persons gave informed consent. The study was performed at Stanford Medical Center; procedures on the Clinical Research Center and biochemical measurements in the Clinical Laboratory. A 75 g oral glucose tolerance test was performed after an overnight fast, and participants were classified as having normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or combined IFG and IGT by American Diabetes Association criteria [5]. Insulin resistance was quantified by the Insulin Suppression Test (IST) [6,7]. After an overnight fast, subjects were infused for 180 minutes with octreotide acetate (0.27 μg/m²/min), insulin (32 mU/m²/min) and glucose (267 mg/m²/min). Blood was drawn at 10-minute intervals from 150 to 180 minutes of the infusion to determine the steady-state plasma glucose (SSPG) and insulin concentration. Since steady-state plasma insulin concentrations were similar in all subjects, SSPG concentrations provided a direct measure of the ability of insulin to mediate disposal of the infused glucose load; the higher the SSPG concentration, the more insulin resistant the individual. Insulin resistance determined with the IST is closely correlated with values obtained with the euglycemic, hyperinsulinemic clamp technique [7]. Insulin action was also estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) [8].

The Table compares the 2 groups of individuals with elevated LDL-C concentrations divided on the basis of TG concentration. The groups were similar in age and proportion of women. Mean BMI was higher in the group with combined lipid elevations, as were mean concentrations of total cholesterol, LDL-C, and TG (by selection).

There were no differences in mean FPG concentration, but all estimates of insulin resistance (FPI and SSPG concentrations and HOMA-IR values) were significantly higher in subjects with elevated TG and LDL-C concentrations compared to those with isolated hypercholesterolemia. Furthermore, there were almost twice as many persons with prediabetes in the group with high TG and LDL-C concentrations than in the group with high LDL-C alone (59.1% vs. 30.2%, respectively).

These findings in individuals of European ancestry support results of an earlier report in East Asian volunteers [4] that nondiabetic individuals with combined elevations of LDL-C and TG concentrations are more insulin resistant and hyperinsulinemic as compared to those with only an elevated LDL-C. Thus, from both a metabolic standpoint (insulin resistance) and glucose tolerance status (increased prevalence of prediabetes), individuals with combined elevations of TG and LDL-C concentrations represent a subset of persons with hypercholesterolemia at increased risk to develop T2DM.

In addition, some mechanistic insights as to why statin-induced T2DM is more likely to occur in subjects with combined increases in TG and LDL-C concentrations are implicit in our findings. Higher SSPG concentrations during the IST demonstrate that insulin-stimulated glucose disposal is reduced in these individuals [2, 6, 7]. Furthermore, their higher HOMA-IR values are consistent with the presence of hepatic insulin resistance [9]. Whether subjects with high TG and LDL-C concentrations also have impaired ability to compensate for insulin resistance by increasing insulin secretion is not known, but the presence of peripheral and hepatic insulin resistance can explain why they would be at increased risk to develop T2DM.

In conclusion, stratification of hypercholesterolemic subjects on the basis of whether or not there is a concomitant increase in TG concentration identifies a clinical subgroup that is insulin resistant, hyperinsulinemic, and glucose intolerant. Since risk of T2DM is increased in the subgroup of nondiabetic individuals with combined high LDL-C and TG concentrations, we predict that these subjects are most likely to develop statin-induced diabetes. We also speculate that stratifying persons with a high LDL-C as in this analysis will identify two groups, varying in development of incident T2DM—one with decreased risk (high LDL-C alone) and the other at increased risk (combined TG and LDL-C elevations). However, our findings are cross-sectional, and we have no outcome data. Thus, we hope that publication of these findings will encourage investigators with significant outcome data to evaluate the hypotheses formulated above. If validated, it would greatly aid in our clinical approach to statin-treated subjects.

Table Clinical and metabolic characteristics of individuals with hypercholesterolemia divided on the basis of TG concentration

Variable	TG (mmol/L)		P value
	≥ 1.69 (n = 44)	<1.69 (n = 63)
Age (years)	51 ± 2	52 ± 2	0.72
Women, n (%)	20 (45.6)	28 (44.4)	0.92
BMI (kg/m2)	29.7 ± 0.6	26.9 ± 0.5	<0.001
Total cholesterol (mmol/L)	6.31 ± 0.09	5.64 ± 0.07	<0.001
LDL-C (mmol/L)	4.11 ± 0.08	3.85 ± 0.06	0.01
TG (mmol/L)	2.25 ± 0.06	1.22 ± 0.05	-
HDL-C (mmol/L)	1.17 ± 0.04	1.23 ± 0.04	0.31
FPG (mmol/L)	5.39 ± 0.09	5.26 ± 0.08	0.28
Glucose tolerance group, n (%)
NGT	18 (40.9)	44 (69.8)	0.005
IFG	16 (36.4)	14 (22.2)
IGT	7 (15.9)	1 (1.6)
Combined IFG and IGT	3 (6.8)	4 (6.3)
FPI (pmol/L)	99 ± 6	70 ± 5	0.001
HOMA-IR	4.04 ± 0.28	2.76 ± 0.24	0.001
SSPG (mmol/L)	11.43 ± 0.55	8.57 ± 0.46	<0.001

Data are mean ± SEM unless otherwise indicated. Means were compared by independent sample t test and proportions were compared by χ² test.

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL-C, low-density lipoprotein cholesterol; SSPG, steady-state plasma glucose TG, triglycerides.