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Effects of Basal Insulin on Lipid Profile Compared to Other Classes of Antihyperglycemic Agents in Type 2 Diabetic Patients.
Rigato, M, Avogaro, A, Vigili de Kreutzenberg, S, Fadini, GP
The Journal of clinical endocrinology and metabolism. 2020;(7)
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.
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Sodium-Glucose Co-Transporter 2 Inhibitors Compared with Sulfonylureas in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A Meta-Analysis of Randomized Controlled Trials.
Chen, Z, Li, G
Clinical drug investigation. 2019;(6):521-531
Abstract
BACKGROUND AND OBJECTIVE When metformin is insufficient for patients with type 2 diabetes mellitus (T2DM), the optimal adjunctive therapy is unclear. This meta-analysis was to compare the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors with sulfonylureas (SUs) as second-line therapy in patients with T2DM inadequately controlled on metformin. METHODS We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing SGLT2 inhibitors with SUs as add-on to metformin. Our primary endpoints were glycemic control, hypoglycemia, and change in weight. We assessed pooled data using a random-effects model. RESULTS Five trials involving 4300 participants were included in our meta-analysis. Compared with SUs, SGLT2 inhibitors led to no significant reduction in changes in HbA1c (mean difference [MD] - 0.06; 95% confidence interval [CI] [- 0.12, 0.08]), but less hypoglycemia as add-on to metformin (odds ratio [OR] 0.12; 95% CI [0.07, 0.21]). SGLT2 inhibitors led to a reduction in weight by about 3.5 kg; however, SUs caused a gain in weight by about 1 kg (MD - 4.39; 95% CI [- 4.64, - 4.14]). SGLT2 inhibitors also showed a reduction in blood pressure, but increased the incidence of genital tract infections compared with SUs. Interestingly, subgroup analysis by duration of interventions showed that reduction of HbA1c from baseline was similar between the two groups at 12-52 weeks, but SGLT2 inhibitors led to a greater reduction in HbA1c at 104-208 weeks. CONCLUSIONS Despite similar glycemic efficacy in a relatively short term, SGLT2 inhibitors are more effective in the longer term than SUs as add-on to metformin. In addition, SGLT2 inhibitors produce less hypoglycemic events and lead to greater reductions in weight and blood pressure compared with SUs.
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Comparison of antidiabetic drugs added to sulfonylurea monotherapy in patients with type 2 diabetes mellitus: A network meta-analysis.
Qian, D, Zhang, T, Tan, X, Zheng, P, Liang, Z, Xie, J, Jiang, J, Situ, B
PloS one. 2018;(8):e0202563
Abstract
AIMS: This study aimed to investigate the efficacy and safety of dual therapy comprising sulfonylurea (SU) plus antidiabetic drugs for the treatment of type 2 diabetes mellitus (T2DM). METHODS We searched the PubMed, Cochrane library, and Embase databases for randomized clinical trials (≥24 weeks) published up to December 28, 2017. Subsequently, we conducted pairwise and network meta-analyses to calculate the odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) of the outcomes. RESULTS The final analyses included 24 trials with a total of 10,032 patients. Compared with placebo, all treatment regimens were associated with a significantly higher risk of hypoglycemia, except the combinations of SU plus sodium-glucose co-transporter-2 inhibitor (SGLT-2i) [OR, 1.35 (95% CI: 0.81 to 2.25)] or alpha-glucosidase inhibitor (AGI) [OR, 1.16 (95% CI: 0.55 to 2.44)]. Notably, the combination of SU plus glucagon-like peptide-1 receptor agonist (GLP-1RA) was associated with the most significant increase in the risk of hypoglycemia. Furthermore, all SU-based combination regimens reduced the glycated hemoglobin (HbA1c) and fasting plasma glucose levels (FPG). However, only combinations containing SGLT-2i [MD, -1.00 kg (95% CI: -1.73 to -0.27)] and GLP-1RA [MD, -0.56 kg (95% CI: -1.10 to -0.02)] led to weight loss. CONCLUSIONS Our findings highlight the importance of considering the risk of hypoglycemia when selecting antidiabetic drugs to be administered concomitantly with SU. Although all classes of antidiabetic drugs improved glucose control when administered in combination with SU, SGLT-2i might be the best option with respect to factors such as hypoglycemia and body weight.
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Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycaemic drugs: A Bayesian meta-analysis of survival data.
Bain, S, Druyts, E, Balijepalli, C, Baxter, CA, Currie, CJ, Das, R, Donnelly, R, Khunti, K, Langerman, H, Leigh, P, et al
Diabetes, obesity & metabolism. 2017;(3):329-335
Abstract
AIM: To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM). MATERIALS AND METHODS A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used. RESULTS The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin. CONCLUSIONS The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs.
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Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis.
Phung, OJ, Sobieraj, DM, Engel, SS, Rajpathak, SN
Diabetes, obesity & metabolism. 2014;(5):410-7
Abstract
AIMS: Guidelines for type 2 diabetes recommend add-on agents when metformin alone fails to provide adequate glycaemic control. However, early combination therapy may benefit health outcomes. We conducted a systematic review and meta-analysis to investigate this question. METHODS We searched MEDLINE and Cochrane CENTRAL (up to July 2012) without language restrictions. We sought randomized controlled trials (RCTs) evaluating initial combination therapy with metformin versus metformin monotherapy in patients with untreated type 2 diabetes. Weighted mean differences (WMDs) for changes from baseline and relative risks (RRs) [with 95% confidence intervals (CIs)] were calculated using random-effects model. RESULTS In 15 RCTs (N = 6693), the mean age range was 48.4-62.7 years; mean baseline glycosylated haemoglobin (A1c) was 7.2-9.9% and mean diabetes duration was 1.6-4.1 years, with median follow-up of 6 months and with 13 comparisons for A1c change, 14 comparisons for A1c goal attainment of <7% and 13 comparisons for change in fasting plasma glucose (FPG). Drugs combined with metformin included thiazolidinediones (TZDs), insulin secretagogues, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium glucose transporterase (SGLT-2) inhibitors. Compared to metformin alone, combination therapy with metformin provided statistically significant reductions in A1c (WMD -0.43%, 95% CI -0.56, -0.30), increases in attainment of A1c goal of less than 7% (RR 1.40, 95% CI 1.33-1.48) and reductions in FPG (WMD -14.30 mg/dl, 95% CI -16.09, -12.51). CONCLUSIONS These results suggest a potential benefit of initial combination therapy on glycaemic outcomes in diabetes compared to metformin monotherapy across a wide range of baseline A1c levels. Further research should explore if early combination treatment may also affect longer term health outcomes in diabetes.
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The effect of a dual combination of noninsulin antidiabetic drugs on lipids: a systematic review and network meta-analysis.
Dai, X, Wang, H, Jing, Z, Fu, P
Current medical research and opinion. 2014;(9):1777-86
Abstract
OBJECTIVE As an ever widening array of anti-hyperglycemic agents are now available, the effect of these drugs on lipids is increasingly complex and controversial. The present meta-analysis was designed to clarify the effect of a dual combination of noninsulin anti-hyperglycemic agents on lipids in type 2 diabetes. METHODS Randomized controlled trials comparing different dual combinations of antidiabetic drugs were identified by searching PubMed, Cochrane Library, and Embase. Study selection, data abstraction and quality assessment were carried out by two reviewers independently. Change in low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride and total cholesterol were pooled by both traditional meta-analysis and network meta-analysis. RESULTS Eighteen studies with a total of 10,222 patients were included. Network meta-analysis suggested that metformin + dipeptidyl peptidase-4 inhibitors (DPP-4) (LDL cholesterol: -0.19 mmol/L; HDL cholesterol: 0.06 mmol/L; triglycerides: -0.73 mmol/L; total cholesterol: -0.4 mmol/L) and metformin + glucagon-like peptide-1 (GLP-1) agonist (LDL cholesterol: -0.3 mmol/L; HDL cholesterol: 0.06 mmol/L; triglycerides: -0.64 mmol/L; total cholesterol: -0.5 mmol/L) were associated with relatively larger beneficial effects on the lipid profile among all combinations. Compared with metformin + thiazolidinedione, metformin + GLP-1 agonist (mean difference: -0.38; 95% confidence interval [CI]: -0.66 to -0.10) significantly decreased LDL cholesterol. Metformin + thiazolidinedione showed a larger increase than metformin + sulfonylurea in HDL cholesterol (mean difference: 0.1; 95% CI: 0.01 to 0.21). CONCLUSIONS The effect of a dual combination of noninsulin anti-hyperglycemic agents on lipids is moderate to small, with metformin + DPP-4 inhibitor and metformin + GLP-1 agonist showing consistent beneficial effects on LDL cholesterol, HDL cholesterol, triglycerides and total cholesterol. Future trials are needed to confirm these findings.
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Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies.
Rao, AD, Kuhadiya, N, Reynolds, K, Fonseca, VA
Diabetes care. 2008;(8):1672-8
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Abstract
OBJECTIVE Observational studies assessing the association of combination therapy of metformin and sulfonylurea on all-cause and/or cardiovascular mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the effects of combination therapy of sulfonylureas and metformin on the risk of all-cause mortality and cardiovascular disease (CVD) among people with type 2 diabetes. RESEARCH DESIGN AND METHODS A MEDLINE search (January 1966-July 2007) was conducted to identify observational studies that examined the association between combination therapy of sulfonylureas and metformin on risk of CVD or all-cause mortality. From 299 relevant reports, 9 were included in the meta-analysis. In these studies, combination therapy of metformin and sulfonylurea was assessed, the risk of CVD and/or mortality was reported, and adjusted relative risk (RR) or equivalent (hazard ratio and odds ratio) and corresponding variance or equivalent was reported. RESULTS The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetes prescribed combination therapy of sulfonylureas and metformin were 1.19 (0.88-1.62) for all-cause mortality, 1.29 (0.73-2.27) for CVD mortality, and 1.43 (1.10-1.85) for a composite end point of CVD hospitalizations or mortality (fatal or nonfatal events). CONCLUSIONS The combination therapy of metformin and sulfonylurea significantly increased the RR of the composite end point of cardiovascular hospitalization or mortality (fatal and nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy, or sulfonylurea monotherapy); however, there were no significant effects of this combination therapy on either CVD mortality or all-cause mortality alone.