Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis.
ABSTRACT: Guidelines recommend metformin as the first-line oral treatment for type 2 diabetes. We conducted a systematic review to assess whether the use of second- and third-generation sulfonylurea agents is associated with benefits and harms in terms of patient-important outcomes compared with metformin.We searched several electronic databases and other sources for randomized clinical trials published to August 2011. We included trials that compared sulfonylurea versus metformin monotherapy among patients 18 years or older with type 2 diabetes and that had an intervention period of at least 24 weeks. We assessed risk of bias and extracted data related to interventions and outcomes. The risk of random errors was assessed by trial sequential analysis.We included 14 trials (4560 participants). All trials were judged to be at high risk of bias. Data on patient-important outcomes were sparse. Compared with metformin, sulfonylurea did not significantly affect all-cause mortality (relative risk [RR] 0.98, 95% confidence interval [CI] 0.61 to 1.58) or cardiovascular mortality (RR 1.47, 95% CI 0.54 to 4.01). Sulfonylurea significantly decreased the risk of nonfatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93). However, the definition of this outcome varied among trials, and trial sequential analysis showed that more trials are needed before reliable conclusions can be drawn. No differences between sulfonylurea and metformin were found for change in fasting blood glucose level or glycosylated hemoglobin concentration in the random-effects model. Sulfonylurea resulted in greater weight gain compared with metformin, a finding confirmed in the trial sequential analysis. Significantly more patients in the sulfonylurea arm than in the metformin arm had mild hypoglycemia (RR 2.95, 95% CI 2.13 to 4.07) and severe hypoglycemia (RR 5.64, 95% CI 1.22 to 26.00).Some evidence suggests that, compared with metformin, second- and third-generation sulfonylureas may not affect all-cause or cardiovascular mortality but may decrease the risk of nonfatal macrovascular outcomes among patients with type 2 diabetes. They may also increase the risk of hypoglycemia. In general, the available data were too few and inconsistent to provide firm evidence concerning patient-important outcomes in relation to the benefits and harms of sulfonylurea versus metformin monotherapy.
Project description:To compare the efficacy and safety of metformin, glyburide, and insulin in treating gestational diabetes mellitus (GDM), a meta-analysis of randomized controlled trials (RCTs) was conducted. PubMed, Embase, CINAHL, Web of Science, and Cochrane Library to November 13, 2018, were searched for RCT adjusted estimates of the efficacy and safety of metformin, glyburide, and insulin treatments in GDM patients. There were 41 studies involving 7703 GDM patients which were included in this meta-analysis; 12 primary outcomes and 24 secondary outcomes were detected and analyzed. Compared with metformin, insulin had a significant increase in the risk of preeclampsia (RR, 0.57; 95% CI, 0.45 to 0.72; P < 0.001), NICU admission (RR, 0.75; 95% CI, 0.64 to 0.87; P < 0.001), neonatal hypoglycemia (RR, 0.57; 95% CI, 0.49 to 0.66; P < 0.001), and macrosomia (RR, 0.68; 95% CI, 0.55 to 0.86; P < 0.05). To the outcomes of birth weight and gestational age at delivery, insulin had a significant increase when compared with metformin (MD, 114.48; 95% CI, 37.32 to 191.64; P < 0.01; MD, 0.23; 95% CI, 0.12 to 0.34; P < 0.001; respectively). Of the two groups between glyburide and metformin, metformin had lower gestational weight gain compared with glyburide (MD, 1.67; 95% CI, 0.26 to 3.07; P < 0.05). Glyburide had a higher risk of neonatal hypoglycemia compared with insulin (RR, 1.76; 95% CI, 1.32 to 2.36; P < 0.001). This meta-analysis found that metformin could be a safe and effective treatment for GDM. However, clinicians should pay attention on the long-term offspring outcomes of the relative data with GDM patients treated with metformin. Compared with insulin, glyburide had a higher increase of neonatal hypoglycemia. The use of glyburide in pregnancy for GDM women appears to be unclear.
Project description:OBJECTIVE:To assess the efficacy and safety of oral antidiabetic drugs (OADs) in gestational diabetes mellitus (GDM) in comparison to insulin. METHODS:A meta-analysis of randomized controlled trials was conducted. The efficacy and safety of OADs in comparison to insulin in GDM patients were explored. Studies were identified by conducting a literature search using the electronic databases of Medline, CENTRAL, CINAHL, LILACS, Scopus and Web of Science in addition to conducting hand search of relevant journals from inception until October 2013. RESULTS:Thirteen studies involving 2,151 patients met the inclusion criteria. These studies were randomized controlled trials of metformin and glyburide in comparison to insulin therapy. Our results indicated a significant increase in the risk for preterm births (RR, 1.51; 95% CI, 1.04-2.19, p = 0.03) with metformin compared to insulin. However, a significant decrease in the risk for gestational hypertension (RR, 0.54; 95% CI, 0.31-0.91, p = 0.02) was found. Postprandial glucose levels also decreased significantly in patients receiving metformin (MD, -2.47 mg/dL; 95% CI, -4.00, -0.94, p = 0.002). There was no significant difference between the two groups for the remaining outcomes. There were significant increases in the risks of macrosomia (RR, 2.34; 95% CI, 1.18-4.63, p = 0.03) and neonatal hypoglycemia (RR, 2.06; 95% CI, 1.27-3.34, p = 0.005) in the glyburide group compared to insulin whereas results for the other analyzed outcomes remained non-significant. CONCLUSION:The available evidence suggests favorable effects of metformin in treating GDM patients. Metformin seems to be an efficacious alternative to insulin and a better choice than glyburide especially those with mild form of disease.
Project description:Prior research suggests that warfarin, when given concomitantly with some sulfonylureas, may increase the risk of serious hypoglycemia. However, the clinical significance remains unclear. We examined rate ratios (RRs) for the association between serious hypoglycemia and concomitant use of warfarin with either sulfonylureas or metformin using a self-controlled case series design and US Medicaid claims (supplemented with Medicare claims) from 1999 to 2011. Across all risk windows combined, warfarin was associated with an elevated rate of serious hypoglycemia when given concomitantly with glimepiride (RR, 1.47; 95% confidence interval (CI), 1.07-2.02) and metformin (RR, 1.73; 95% CI, 1.38-2.16). Particularly in the late risk window (>120 days since beginning concomitancy), most of the RRs for warfarin were elevated: glipizide (RR, 1.72; 95% CI, 1.29-2.29), glyburide (RR, 1.57; 95% CI, 1.15-2.15), metformin (RR, 2.26; 95% CI, 1.67-3.05), and glimepiride (RR, 1.56; 95% CI, 0.97-2.50). These results are consistent with a previously hypothesized hypoglycemic effect of warfarin in patients with type 2 diabetes through inhibition of the carboxylation of osteocalcin.
Project description:Background:Accumulating evidence suggests that patients with type 2 diabetes mellitus and hyperinsulinemia are at an increased risk of developing malignancies. It remains to be fully elucidated whether the use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affects cancer incidence in subjects with type 2 diabetes mellitus. Objective:A systematic review and meta-analysis was performed to compare the risk of cancer incidence associated with monotherapy with metformin compared with monotherapy with sulfonylureas in type 2 diabetes mellitus patients. Methods:Search was performed throughout MEDLINE/PubMed, EMBASE, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov up until December 2018. In this meta-analysis, each raw data (unadjusted) and study-specific (adjusted) relative risks (RRs) was combined and the pooled unadjusted and adjusted RRs with the 95% CI were calculated using the random-effects model with inverse-variance weighting. Heterogeneity among the studies was evaluated using I 2 statistics. Publication bias was evaluated using the funnel plot asymmetry test. The Newcastle-Ottawa scale (NOS) was used to assess the study quality. Results:A total of 8 cohort studies were included in the meta-analysis. Obvious heterogeneity was noted, and monotherapy with metformin was associated with a lower risk of cancer incidence (unadjusted RR = 0.74, 95% CI: 0.55-0.99, I 2 = 97.89%, p < 0.00001; adjusted RR = 0.76, 95% CI: 0.54-1.07, I 2 = 98.12%, p < 0.00001) compared with monotherapy with sulfonylurea, using the random-effects model with inverse-variance weighting. Conclusions:According to this review, the monotherapy with metformin appears to be associated with a lower risk of cancer incidence than monotherapy with sulfonylurea in patients with type 2 diabetes. This analysis is mainly based on cohort studies, and our findings underscore the need for large-scale randomized controlled trials to establish the effect of metformin monotherapy, relative to sulfonylureas monotherapy on cancer.
Project description:INTRODUCTION:The aim of this study was to evaluate the efficacy and safety of initial combination therapy compared with monotherapy in drug-naïve type 2 diabetes patients. METHODS:MEDLINE, Embase and the Cochrane Central Register of Controlled Trials were searched for randomized clinical trials of initial combination therapy with hypoglycemic agents compared with monotherapy. Those which satisfied the search criteria were included in the meta-analysis. Weighted mean difference and relative risks were calculated. RESULTS:A total of 36 studies were included in the meta-analysis. Compared with metformin monotherapy, initial combination therapy with metformin plus another anti-diabetes drug exhibited significant reductions in glycated hemoglobin (HbA1c) (p?<?0.001). Most of the combination therapies had a similar risk of hypoglycemia (p?>?0.05), with the exception of combinations of sulfonylurea/glinide and metformin or combinations of thiazolidinedione and metformin. Compared with dipeptidyl peptidase-4 (DPP-4) inhibitor monotherapy, initial combination therapy with DPP-4 inhibitor plus another anti-diabetes drug showed a significant decrease in HbA1c (p?<?0.001) and a similar risk of hypoglycemia (p?>?0.05). Compared with monotherapy with other anti-diabetes drugs, initial combination therapies also resulted in significant HbA1c reductions, a similar risk of hypoglycemia and similar risks of other adverse events. CONCLUSION:Compared with monotherapy, all initial combination therapies resulted in significant HbA1c reductions. Compared with metformin monotherapy, initial combination therapies with DPP-4 inhibitors plus metformin, sodium/glucose cotransporter 2 inhibitors and metformin, respectively, were associated with similar risks of hypoglycemia, but initial combination therapies with sulfonylurea plus metformin, thiazolidinedione and metformin, respectively, were associated with higher risks of hypoglycemia. FUNDING:AstraZeneca Ltd. (China). TRIAL REGISTRATION:Registration number CRD42017060717 in PROSPERO.
Project description:PURPOSE:Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes. METHODS:We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes. RESULTS:Among 42,217 new metformin users and 42,217 matched-new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR]?=?0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use. CONCLUSIONS:In this large cohort study that accounted for time-related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations.
Project description:We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of TZDs in treatment of diabetes mellitus patients with renal impairment. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials. Randomized controlled trials (RCTs), cohort studies, and case-control studies that investigated the effects of TZDs in patients with diabetes and renal impairment were eligible. Outcomes included glycosylated hemoglobin, fasting plasma glucose, serum lipids, and patient-important outcomes (i.e. hypoglycemia, weight, edema, cardiovascular events and mortality). 19 RCTs and 3 cohort studies involving 21,803 patients with diabetes and renal impairment were included. Meta-analysis of RCTs showed that TZDs could significantly reduce HbA1c (MD -0.64, 95%CI -0.93 to -0.35), FPG (MD -26.27, 95%CI -44.90 to -7.64) and increase HDL levels (MD 3.70, 95%CI 1.10, 6.29). TZDs could increase weight (MD 3.23, 95% CI 2.29 to 4.16) and risk of edema (RR 2.96, 95% CI 1.22 to 7.20). Their effects on risk of hypoglycemia (RR 1.46, 95% CI 0.65 to 3.29), heart failure (RR 0.64, 95% CI 0.15 to 2.66), angina (RR 1.45, 95% CI 0.23 to 8.95) and all-cause mortality (RR 0.40, 95% CI 0.08 to 2.01) are uncertain. Results from cohort studies were similar to RCTs.
Project description:Background:Antidiabetic medications (ADMs) can alter the risk of different types of cancer, but the relationship between lung cancer incidence and metformin remains controversial. Our aim was to quantitatively estimate the relationship between incidences of lung cancer and metformin in patients with diabetes in this meta-analysis. Methods:We performed a search in PubMed, Embase, ISI Web of Science, and Cochrane Library until September 20, 2017. The odds ratio (OR), relative risk (RR) or hazard ratio (HR), and 95% confidence interval (95% CI) were estimated using the random-effect model. The Newcastle-Ottawa Scale (NOS) was used to assess the study quality. Results:A total of 13 studies (10 cohort studies and 3 case-control studies) were included in the meta-analysis. Compared to nonmetformin users, metformin probably decreased lung cancer incidence in diabetic patients (RR = 0.89; 95% CI, 0.83-0.96; P = 0.002) with significant heterogeneity (Q = 35.47, I 2 = 66%, P = 0.0004). Subgroup analysis showed that cohort studies (RR = 0.91; 95% CI, 0.85-0.98; P = 0.008), location in Europe (RR = 0.90; 95% CI, 0.86-0.94; P < 0.0001), the control drug of the sulfonylurea group (RR = 0.91; 95% CI, 0.86-0.96; P = 0.001), and adjusting for smoking (RR = 0.86; 95% CI, 0.75-1.00; P = 0.05) may be related to lower lung cancer risk. No significant publication bias was detected using a funnel plot. Conclusion:Metformin use was related to a lower lung cancer risk in diabetic patients compared to nonusers, but this result was retrieved from observational studies and our findings need more well-designed RCTs to confirm the association.
Project description:<h4>Background</h4>The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality.<h4>Methods and findings</h4>This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I(2)=41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p=0.10 and 0.02, respectively).<h4>Conclusions</h4>Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation.
Project description:This meta-analysis aims to update the evidence for the effects of intensive glucose control (IGC) on the outcomes among critically ill patients. We performed a systematic literature review from inception through December, 2017 by two independent authors by searching PubMed, EMBASE and Cochrane Library. Randomized clinical trials of the effects of IGC compared with conventional glucose control were selected. Random-effect models were applied to calculate summary relative risks (RRs) for the related outcomes. Of 4247 records identified, we abstracted data from 27 relevant trials for meta-analysis. Compared with patients receiving conventional glucose control (controls), patients with IGC did not have significantly decreased risk of short-term mortality (in-hospital mortality or intensive care unit (ICU) mortality) (RR 0.99, 95% CI 0.92-1.06) or 3- to 6-month mortality (RR 1.02, 95% CI 0.97-1.08). These results remained constant among different study settings including surgical ICUs, medical ICUs or mixed ICUs. Similarly, we also found that patients with IGC did not have significantly lower risk of sepsis (RR 1.00, 95% CI 0.89-1.11) or new need for dialysis (RR 0.97, 95% CI 0.84-1.11). However, patients with IGC had almost 4-fold increase in risk of hypoglycemia (RR 4.86, 95% CI 3.16-7.46). In conclusion, in this updated meta-analysis of published trials, critically ill patients receiving IGC were found to be at neutral risk for short-term or 3- 6-month mortality, risk of sepsis or new need for dialysis, but at higher risk of hypoglycemia.