Original ArticleStatin treatment is associated with insulin sensitivity decrease in type 1 diabetes mellitus: A prospective, observational 56-month follow-up study
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.
Section snippets
Participants and clinical measurement at the baseline study
The study was performed in 2010 to 2015 at the In-Patient Department of Diabetology of the Vuk Vrhovac University Hospital, Medical School University of Zagreb, Croatia and included 832 (345, 41.47% starting statin treatment) randomly selected T1DM patients aged 25 to 61 years. Histories and complete physical examination and laboratory tests were performed in all subjects to exclude diseases other than T1DM or medications that might affect insulin sensitivity. Type 1 diabetes was defined by
Results
Patients who started statin therapy (N = 345, 41.47%; 59.42% atorvastatin; and 40.58% simvastatin) were older, had lower insulin sensitivity, and higher rate of hypertension, that is, they revealed higher rate of cardiovascular risk factors (Table 1). They experienced a greater decrease in insulin sensitivity (19.27% vs 12.82%, P < .001) and metabolic control deterioration accounting for increase in body weight, HbA1c, total daily insulin requirement, and blood pressure compared with
Discussion
We investigated the association of statin treatment with the risk of insulin sensitivity decrease and its effect on metabolic control in a cohort of T1DM patients during 56-month follow-up. Our study reports several findings: (1) statin therapy introduction was associated with a 36% increased risk of reduced insulin sensitivity after adjustment for confounding factors; (2) no significant difference was found between atorvastatin and simvastatin on the risk of IR; and (3) statin treatment was
Acknowledgment
Authors' contributions: L.D. designed and intellectually supervised the study. Both the authors did the data acquisition, interpreted the data, and wrote the article.
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