Statin treatment is associated with insulin sensitivity decrease in type 1 diabetes mellitus: A prospective, observational 56-month follow-up study

Highlights

• We assessed whether statins might decrease insulin sensitivity in type 1 diabetes.

• Patients on statins experienced a greater decrease in insulin sensitivity.

• Patients on statins showed metabolic control worsening during 56 months.

• The use of statins was an independent risk factor for insulin sensitivity decrease.

Background

Statins are effective in the primary and secondary prevention of cardiovascular events in individuals with and without diabetes. Emerging evidence, however, suggests that statins might reduce insulin sensitivity and secretion in healthy population and in type 2 diabetes.

Objective

We aimed to investigate the effect of statin therapy introduction on insulin sensitivity in patients with type 1 diabetes mellitus (T1DM).

Methods

This prospective observational 56-month long study included 832 randomly selected T1DM patients aged 25 to 61 years. Uncontrolled dyslipidemia and clinician-perceived need for treatment, rather than randomization, were basis for individuals being started on either atorvastatin or simvastatin (10–40 mg); N = 345, 41.47%. Patients on statin treatment were compared with those unexposed to statin. Insulin sensitivity was assessed using equation derived from euglycemic-hyperinsulinemic clamp studies–estimated glucose disposal rate.

Results

Patients who started statin therapy (N = 345, 59.42% atorvastatin and 40.58% simvastatin) experienced a greater decrease in insulin sensitivity (19.27% vs 12.82% P < .001) and metabolic control deterioration compared with statin-free group. The risk of decrease in insulin sensitivity attributable to statin use was 36.7% (hazard ratio 1.36; 95% confidence interval 1.31–1.43) after adjustment for age, gender, disease duration, smoking status, and the concomitant antihypertensive therapy.

Conclusion

Although there is still a lack of a clear molecular explanation on the adverse effects of statin therapy on insulin sensitivity, we showed that it deteriorates insulin sensitivity in T1DM. The cardiovascular benefits of statin treatment might outweigh the risk of developing insulin resistance, but, the possible metabolic control worsening merits to be considered.

Introduction

Statins represent a class of medications widely used in hypercholesterolemia treatment.¹ They act by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an intracellular enzyme, which plays a central role in cholesterol production.² Most statins are similar in structure to the enzyme's substrate, HMG-CoA, and act as competitive inhibitors. Inhibition of this enzyme by statins translates into lowering low-density lipoprotein (LDL) cholesterol via enhanced LDL receptor expression.3, 4 As high LDL levels are causally associated with increased cardiovascular disease (CVD), statin treatment is effective in the primary and secondary prevention of CVD that is generally safe and well tolerated.5, 6, 7, 8 Emerging evidence, however, suggests that long-term statin treatment is associated with type 2 diabetes mellitus (T2DM) occurrence.9, 10, 11, 12 Although mechanisms underlying the association of statin therapy with diabetes remain unclear,¹³ recent data suggest that statin treatment may increase the risk of T2DM due to decreases in both insulin sensitivity and insulin secretion.¹²

Although insulin resistance (IR) typically characterizes T2DM, whereas the insulin deficiency is a primary defect in patients with type 1 diabetes mellitus (T1DM), there are suggestions that there is a certain degree of IR in T1DM.14, 15 The mechanisms of IR in T1DM is likely due to a combination of supraphysiological levels of exogenous insulin and obesity. In the past, it was thought that IR in T1D was primarily related to hyperglycemia¹⁶; however, it was recently proposed that adults with T1DM have both impaired glucose utilization and impaired insulin-induced nonesterified fatty acid suppression, independent of glycemic control.¹⁷ Skeletal muscle IR is a known feature of T1DM and is due to decreased glucose transport into myocytes from impaired insulin-stimulated upregulation of GLUT4 mRNA.¹⁸

The data linking statins with increase in IR are especially concerning because this class of drugs are used by millions of diabetic patients worldwide.¹⁹ Thus, it would be of special clinical interest to investigate the effect of statins on glycemic control in T1DM patients without endogenous insulin secretion. Here, we analyzed the effect of statin therapy introduction on metabolic control and insulin sensitivity in T1DM patients during 56 months of prospective, observational follow-up.