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Comparison between sodium-glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta-analysis.
Cho, YK, Kim, YJ, Kang, YM, Lee, SE, Park, JY, Lee, WJ, Jung, CH
Journal of diabetes investigation. 2018;(4):882-892
Abstract
AIMS/INTRODUCTION We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus. MATERIALS AND METHODS We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly. RESULTS A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] -0.01% [-0.1 mmol/mol], 95% confidence interval [CI] -0.25 to 0.22% [-2.7 to -2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD -0.90 mg/dL, 95% CI: -15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD -4.54 kg, 95% CI: -5.67 to -3.41 kg; P < 0.001). PIO/INS showed non-significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD -2.45 IU/day, 95% CI: -7.30 to 2.40 IU/day; P = 0.438). CONCLUSIONS Both PIO and SGLT2i are feasible adjunctive oral agents to pre-existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.
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Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials.
He, L, Liu, X, Wang, L, Yang, Z
Medicine. 2016;(42):e4947
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Abstract
The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: "nonalcoholic steatohepatitis," "non-alcoholic steatohepatitis," "thiazolidinedione," "pioglitazone," "rosiglitazone," "randomized," and "clinical trial." Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the control patients, TZD treatment had no significant impact on body-mass index, percentage of body fat, or serum levels of cholesterol and triglyceride. Our findings indicate that additional variables should be assessed to obtain a more comprehensive evaluation of the effects of TZD treatment on IR and comorbidity risk factors in NASH patients, and suggest that including lifestyle changes and additional insulin-sensitizing agents in TZD regimens might improve the benefits of TZD therapy for NASH.
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Comparative efficacy and safety of antidiabetic drug regimens added to stable and inadequate metformin and thiazolidinedione therapy in type 2 diabetes.
Saulsberry, WJ, Coleman, CI, Mearns, ES, Zaccaro, E, Doleh, Y, Sobieraj, DM
International journal of clinical practice. 2015;(11):1221-35
Abstract
AIMS: Determine the efficacy and safety of antidiabetic agents added-on to metformin and a thiazolidinedione (TZD) in patients with inadequately controlled type 2 diabetes (T2D). METHODS MEDLINE and CENTRAL were searched for randomised controlled trials (RCTs) evaluating the addition of an antidiabetic agent in patients with T2D inadequately controlled on stable, optimised metformin and TZD therapy (≥ 1500 mg metformin and ≥ 50% maximum TZD dose for ≥ 4 weeks). Frequentist network meta-analysis was performed on identified studies. RESULTS Eleven RCTs evaluating dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin), sulfonylureas (SUs) (glibenclamide, glimepiride), glucagon-like peptide-1 (GLP-1) analogues (exenatide, liraglutide, dulaglutide, taspoglutide) and sodium-glucose cotransporter2 (SGLT2) inhibitors (canagliflozin, empagliflozin) were identified. The mean reduction in HbA1c from baseline was significant for all agents (range, 0.55-1.17%) vs. placebo. SUs were associated with weight gain (range, 3.31-7.29 kg), while weight loss was seen with all GLP-1 analogues (range, 1.53-2.20 kg) and SGLT2 inhibitors (range, 2.08-2.95 kg) vs. placebo. Relative risk of hypoglycaemia was increased with dulaglutide, exenatide and glimepiride vs. placebo (RR range, 2.65-6.17); and trended higher with all other agents except linagliptin. GLP-1 analogues and canagliflozin reduced systolic blood pressure vs. placebo (range, 2.39-5.05 mmHg). No agent with available data increased the risk of urinary or genital tract infection vs. placebo. CONCLUSION When added to stable, optimised metformin and TZD, all evaluated antidiabetic agents reduced HbA1c; albeit not to the same degree. Moreover, agents differed in their effects on body weight, hypoglycaemia and systolic blood pressure.
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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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Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.
Tang, T, Lord, JM, Norman, RJ, Yasmin, E, Balen, AH
The Cochrane database of systematic reviews. 2010;(1):CD003053
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogaenemia and insulin resistance. Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES To assess the effectiveness of insulin sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS and menstrual disturbance. SEARCH STRATEGY We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched September 2008), the Cochrane Central Register of Controlled Trials (Cochrane Library, third Quarter 2008), CINAHL (searched September 2008), MEDLINE (January 1966 to September 2008), and EMBASE (January 1985 to September 2008). All searches were rerun 13 August 2009 17 RCTs were located and await classification. SELECTION CRITERIA Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS Thirty one trials (2537 women) were included for analysis, 27 of them using metformin and involving 2150 women. MAIN RESULTS There is no evidence that metformin improves live birth rates whether it is used alone (Pooled OR = 1.00, 95% CI 0.16 to 6.39) or in combination with clomiphene (Pooled OR = 1.48, 95% CI 1.12 to 1.95). However, clinical pregnancy rates are improved for metformin versus placebo (Pooled OR = OR 3.86, 95% C.I. 2.18 to 6.84) and for metformin and clomiphene versus clomiphene alone (Pooled OR =1.48, 95% C.I. 1.12 to 1.95) ). In the studies that compared metformin and clomiphene alone, there was no evidence of an improved live birth rate (OR= 0.67, 95% CI 0.44 to 1.02) but the pooled OR resulted in improved clinical pregnancy rate in in the clomiphene group (OR = 0.63 , 95% 0.43 to 0.92), although there was significant heterogeneity.There is also evidence that ovulation rates are improved with metformin in women with PCOS for metformin versus placebo (Pooled OR 2.12, 95% CI 1.50 to 3.0) and for metformin and clomiphene versus clomiphene alone (Pooled OR = 3.46, 95% CI 1.97 to 6.07).Metformin was also associated with a significantly higher incidence of gastrointestinal disturbance, but no serious adverse effects were reported. AUTHORS' CONCLUSIONS In agreement with the previous review, metformin is still of benefit in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited.
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Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.
Tang, T, Lord, JM, Norman, RJ, Yasmin, E, Balen, AH
The Cochrane database of systematic reviews. 2009;(4):CD003053
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogaenemia and insulin resistance. Hyperinsulinaemia is associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES To assess the effectiveness of insulin sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS and menstrual disturbance. SEARCH STRATEGY We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched September 2008), the Cochrane Central Register of Controlled Trials (Cochrane Library, third Quarter 2008), CINAHL (searched September 2008), MEDLINE (January 1966 to September 2008), and EMBASE (January 1985 to September 2008). All searches were rerun 13 August 2009 17 RCTs were located and await classification. SELECTION CRITERIA Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS Thirty one trials (2537 women) were included for analysis, 27 of them using metformin and involving 2150 women. MAIN RESULTS There is no evidence that metformin improves live birth rates whether it is used alone (Pooled OR = 1.00, 95% CI 0.16 to 6.39) or in combination with clomiphene (Pooled OR = 1.48, 95% CI 1.12 to 1.95). However, clinical pregnancy rates are improved for metformin versus placebo (Pooled OR = OR 3.86, 95% C.I. 2.18 to 6.84) and for metformin and clomiphene versus clomiphene alone (Pooled OR =1.48, 95% C.I. 1.12 to 1.95) ). In the studies that compared metformin and clomiphene alone, there was no evidence of an improved live birth rate (OR= 0.67, 95% CI 0.44 to 1.02) but the pooled OR resulted in improved clinical pregnancy rate in in the clomiphene group (OR = 0.63 , 95% 0.43 to 0.92), although there was significant heterogeneity.There is also evidence that ovulation rates are improved with metformin in women with PCOS for metformin versus placebo (Pooled OR 2.12, 95% CI 1.50 to 3.0) and for metformin and clomiphene versus clomiphene alone (Pooled OR = 3.46, 95% CI 1.97 to 6.07).Metformin was also associated with a significantly higher incidence of gastrointestinal disturbance, but no serious adverse effects were reported. AUTHORS' CONCLUSIONS In agreement with the previous review, metformin is still of benefit in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited.
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[Effects of thiazolidinediones on dyslipidemia in patients with type 2 diabetes. Are all equally vasoprotective?].
Haberbosch, W
Herz. 2007;(1):51-7
Abstract
Patients with type 2 diabetes face a high risk of cardiovascular morbidity and mortality. In these patients a whole cluster of cardiovascular risk factors is found, with insulin resistance being the most significant. Thiazolidinediones, in activating the peroxisome proliferator-activated receptor gamma, lower the insulin resistance. The two thiazolidinediones available at present, pioglitazone and rosiglitazone, do not differ in their effects on insulin resistance or glucose metabolism. They do, however, reveal very different effects on the dyslipidemia that is characteristic of diabetes, with elevated triglycerides, low high-density lipoprotein (HDL) and atherogenic small dense lipoprotein (LDL) cholesterol. Inter alia, data from a comparative study show that pioglitazone improves diabetic dyslipidemia more efficaciously than rosiglitazone. Despite similar effects on hyperglycemia (HbA1c reduction by 0.6% and 0.7%), both thiazolidinediones differ significantly in their effects on triglycerides (pioglitazone -51.9 mg/dl; rosiglitazone +13.1 mg/dl; p < 0.001), HDL cholesterol (pioglitazone +5.2 mg/dl; rosiglitazone +2.4 mg/dl; p < 0.001) and LDL cholesterol (pioglitazone +12.3 mg/dl; rosiglitazone +21.3 mg/dl; p < 0.001). LDL particle concentration was reduced with pioglitazone (n7.85%) and increased with rosiglitazone (+12%; p > 0.001). Only for pioglitazone the PROactive study, a major outcome trial, documented a significant reduction of cardiovascular outcomes. The principal secondary endpoint of death from any cause, nonfatal myocardial infarction (excluding silent myocardial infarction) or stroke was significantly reduced (16%; p = 0.027). The correlation of improved dyslipidemia, reconfirmed by PROactive, and cardiovascular prevention is yet to be resolved. However, as long as the vascular protective mechanism of pioglitazone is not conclusively resolved, findings may not be transmitted to other thiazolidinediones. For these substances, results from major outcome studies are to be required that prove a reduction of the cardiovascular risk.
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Impact of thiazolidenediones on serum lipoprotein levels.
Goldberg, RB
Current atherosclerosis reports. 2006;(5):397-404
Abstract
The thiazolidinediones, acting through peroxisome proliferator-activated receptor chi (PPARchi), affect multiple areas of metabolism. Of increasing importance is the recognition that these agents affect lipoprotein metabolism and cause changes in serum lipid and lipoprotein levels. All three thiazolidinediones, including troglitazone (which was withdrawn in the year 2000), rosiglitazone, and pioglitazone, tend to increase high-density lipoprotein (HDL) cholesterol, increase the size/decrease the density of low-density lipoprotein (LDL) particles, and raise the level of lipoprotein(a). In addition, troglitazone and pioglitazone, but not rosiglitazone, lower triglyceride levels modestly, thereby further contributing to increases in LDL and HDL size. The mechanism for these effects is still being clarified, but may involve enhancement of triglyceride clearance (in the case of pioglitazone), alteration of apolipoprotein C-III levels, reduction of hepatic lipase, and increase in ATP binding cassette A1 (ABCA1) activity. The clinical implications of these effects need further exploration.