Effects of Basal Insulin on Lipid Profile Compared to Other Classes of Antihyperglycemic Agents in Type 2 Diabetic Patients

Mauro Rigato; Angelo Avogaro; Saula Vigili de Kreutzenberg; Gian Paolo Fadini

Disclosures

J Clin Endocrinol Metab. 2020;105(7):2464-2474. 

In This Article

Abstract and Introduction

Abstract

Objective: The lipid profile represents a driver of cardiovascular risk in type 2 diabetes. The effect of chronic insulin therapy on cholesterol levels is unclear. We aim to evaluate the effect of basal insulin on lipid profile compared to other classes of antihyperglycemic agents in type 2 diabetic patients.

Design: We performed a meta-analysis of randomized controlled trials reporting changes of lipid parameters in type 2 diabetic patients randomly assigned to basal insulin or other classes of anti-hyperglycemic agents.

Results: The levels of total (TC) and low-density lipoprotein cholesterol (LDL-C) appeared to be significantly reduced by therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) in comparison to basal insulin (mean difference [MD] –3.80; 95% CI [–6.30 to –1.30] mg/dL, P < .001 and –4.17; 95% CI [–6.04 to –2.30] mg/dL, P < .0001), whereas no difference was detected between basal insulin and dipeptidyl peptidase-4 inhibitors (DPP4-I) or standard therapy (sulfonylurea ± metformin). Thiazolidinediones (TZD) produced a significant improvement in high-density lipoprotein cholesterol (HDL-C) (MD 3.55; 95% CI: 0.55 to 6.56 mg/dL, P = .02) but were associated with an increase in TC and LDL-C (MD 16.20; 95% CI: 9.09 to 23.31 mg/dL, P < .001 and 5.19: 95% CI: –3.00 to 13.39 mg/dL, P = .21). Basal insulin was superior to standard therapy in triglyceride reduction (MD 3.8; 95% CI: 0.99 to 6.63 mg/dL, P = .008).

Conclusions: GLP-1RA were superior to basal insulin in the control of TC and LDL-C. Basal insulin effectively reduced serum triglycerides. TZD led to improvement in HDL-C. DPP4-I and standard therapy did not have any significant effect on lipid levels.

Introduction

Type 2 diabetes mellitus is a chronic disease characterized by a progressive loss of beta-cell function.[1] As result, the proportion of patients who maintain target glucose levels declined steadily over time and, after 9 years from diagnosis, approximately 20% require insulin therapy.[2,3] Over the past decades, some data have suggested that insulin might accelerate atherogenesis, increasing the incidence of cardiovascular (CV) events and mortality.[4,5] In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, no increase in the risk of CV death and nonfatal myocardial infarction was observed in patients randomly assigned to glargine.[6] Therefore, whether insulin therapy exposes patients to an increased risk of CV events is debatable. Insulin has been shown to increase mitochondrial-derived reactive oxygen species, leading to platelet dysfunction, but its direct effect on plasma lipids is much less clear.[7,8] Acute normalization of glycemic control with insulin can rapidly improve serum lipids, especially triglycerides (TG), but the effect of chronic insulin therapy on cholesterol levels is unclear.[9] At the end of the ORIGIN trial, both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were similar between glargine and nonglargine arms, suggesting that chronic insulin treatment with long-acting insulin analogue did not have a major effect on lipid profile. Conversely, Gerstein et al reported a significant amelioration in TG and non–high-density lipoprotein cholesterol (HDL-C) in patients randomly assigned to basal insulin compared to controls.[10] Today, there are several glucose-lowering medications with potential ancillary effects on lipid profile. In this context, few reports directly compared the effect of different classes of antihyperglycemic agents on lipids. Monami and colleagues assessed the effect of dipeptidyl peptidase-4 inhibitors (DPP4-I), pioglitazone, insulin secretagogues, and acarbose on plasma lipids, when compared to placebo. They found that DPP4-I, acarbose, and pioglitazone had a more favorable effect on lipid profile than sulfonylureas.[11] In a network meta-analysis, the dual combination therapy with metformin plus DPP4-I or glucagon-like peptide-1 receptor agonists (GLP-1RA) led to a greater improvement in lipid profile.[12] In a direct comparison, Wang and colleagues found similar efficacy of sitagliptin and GLP-1RA in the reduction of cholesterol.[13] Further analysis showed that treatments with GLP-1RA were associated with modest reductions in TC, LDL-C, and TG but no significant improvement in HDL-C.[14] To our knowledge, no study directly compared the effect of noninsulin agents vs basal insulin on lipid profile.

We herein present a systemic review and meta-analysis of randomized controlled trials comparing the effect of different classes of antihyperglycemic agents vs basal insulin on lipid profile of type 2 diabetic patients.

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