Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes.

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glyburide 1 endocrinologydiseasesdrugs
metformin 76 endocrinologydiseasesdrugs
miglitol 1 endocrinologydiseasesdrugs
nateglinide 1 endocrinologydiseasesdrugs
rosiglitazone 2 endocrinologydiseasesdrugs

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glyburide 14505 (21.8 mmol/mol)Asp Ins, insulin aspart; FBG, fasting blood glucose; Glib, glibenclamide (known as glyburide in the USA and Canada); HF, heart failure (NYHA class 3–4); Ins, insulin; LFT, liver function test;
metformin 29 Title: DiabetologiaImpact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetesSimon
metformin 674 systematically identify and pool randomised trials reporting cardiovascular outcomes in which the effect of metformin was ‘isolated’ through comparison to diet, lifestyle or placebo.MethodsWe performed an electronic
metformin 934 Cochrane Library. We also manually screened the reference lists of previous meta-analyses of trials of metformin identified through a MEDLINE search. We included randomised controlled trials of adults with type 2
metformin 1096 randomised controlled trials of adults with type 2 diabetes comparing any dose and preparation of oral metformin with no intervention, placebo or a lifestyle intervention and reporting mortality or a cardiovascular
metformin 1341 articles reporting 13 trials (including a total of 2079 individuals with type 2 diabetes allocated to metformin and a similar number to comparison groups) of which only four compared metformin with placebo and collected
metformin 1422 diabetes allocated to metformin and a similar number to comparison groups) of which only four compared metformin with placebo and collected data on cardiovascular outcomes. Participants were mainly white, aged ≤65 years,
metformin 1992 for myocardial infarction to 70.5% for stroke. All outcomes, with the exception of stroke, favoured metformin , with limited heterogeneity between studies, but none achieved statistical significance. Effect sizes
metformin 2430 disease 0.81 (95% CI 0.50, 1.31).Conclusions/interpretationThere remains uncertainty about whether metformin reduces risk of cardiovascular disease among patients with type 2 diabetes, for whom it is the recommended
metformin 2889 uncertainty include the use of electronic health records in long-term pragmatic evaluations, inclusion of metformin in factorial trials, publication of cardiovascular outcome data from adverse event reporting in trials
metformin 3005 factorial trials, publication of cardiovascular outcome data from adverse event reporting in trials of metformin and a cardiovascular endpoint trial of metformin among people without diabetes.Electronic supplementary
metformin 3054 outcome data from adverse event reporting in trials of metformin and a cardiovascular endpoint trial of metformin among people without diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4337-9)
metformin 4576 blood glucose, even those with apparently similar pharmacological targets [[7]–[10]].The biguanide metformin has had an interesting history. After an inauspicious debut, a somewhat circuitous route (including
metformin 4990 UK Prospective Diabetes Study (UKPDS) results, showing evidence of cardiovascular benefits [[12]], metformin was introduced in the USA in 1995 and has emerged as the first-choice and most-prescribed oral medication
metformin 5228 worldwide [[13]]. However, recent systematic reviews have raised doubts about the effectiveness of metformin in reducing risk of complications [[14], [15]]. In these reviews, data were pooled from predominantly
metformin 5383 [15]]. In these reviews, data were pooled from predominantly small trials with short follow-up in which metformin was evaluated against a range of comparators that have heterogenous associations with risk of cardiovascular
metformin 5576 with risk of cardiovascular disease. This has constrained interpretation of the benefits and harms of metformin . Since 2008, the US Food and Drug Administration (FDA) have required demonstration of cardiovascular
metformin 6138 context, it therefore seems timely to review the evidence for cardiovascular disease prevention with metformin .As part of a series of papers to acknowledge the sixtieth anniversary of the first use of metformin
metformin 6238 metformin.As part of a series of papers to acknowledge the sixtieth anniversary of the first use of metformin for the treatment of type 2 diabetes in this issue of Diabetologia, we appraise the evidence concerning
metformin 6373 2 diabetes in this issue of Diabetologia, we appraise the evidence concerning the effectiveness of metformin in preventing cardiovascular disease in patients with type 2 diabetes by undertaking a meta-analysis.
metformin 6605 systematically identify and pool randomised trials reporting cardiovascular outcomes in which the effect of metformin was ‘isolated’ through comparison to diet, lifestyle or placebo, rather than alternative glucose-lowering
metformin 7462 literature search of MEDLINE, with no language or date limits, for papers with ‘meta-analysis’ and ‘ metformin ’ in the title. We manually screened the reference lists of identified meta-analyses. Finally, we manually
metformin 7899 randomised controlled trial among adults with type 2 diabetes comparing any dose and preparation of oral metformin with no intervention, or with placebo or a lifestyle intervention, and reporting mortality or a cardiovascular
metformin 8251 adverse event. There was no restriction based on duration of follow-up. We included studies in which metformin was combined with another drug as long as the comparator group was given the other drug at the same
metformin 8381 another drug as long as the comparator group was given the other drug at the same dose as used in the metformin combined therapy group, thereby controlling for the effects (either positive or negative) of the other
metformin 8533 controlling for the effects (either positive or negative) of the other drug and ‘isolating’ the impact of metformin . We excluded quasi-experimental studies, crossover and observational studies, and studies including
metformin 9420 size, interventions, inclusion criteria, duration of follow-up, participant characteristics (for the metformin group) and outcomes were extracted independently by at least two out of the three authors and any disagreement
metformin 10041 and ‘b’ in tables and figures). For factorial designs, we included overall comparisons between metformin and placebo groups. When data from one study were reported in more than one article we extracted the
metformin 10759 abstracts, we reviewed the full text of 98 articles and included ten articles reporting 13 trials of metformin . The commonest reasons for exclusion at the full text stage were the presence of an active comparator
metformin 11405 [[27]]. Three studies were open-label [[12], [21], [27]], one of which was a trial of cessation of metformin [[27]]. Of the ten placebo-controlled trials, six included other glucose-lowering drugs. We identified
metformin 11566 included other glucose-lowering drugs. We identified four trials including 417 patients allocated to metformin that simply compared metformin with placebo and collected data on cardiovascular outcomes [[19], [24]–[26]].
metformin 11597 drugs. We identified four trials including 417 patients allocated to metformin that simply compared metformin with placebo and collected data on cardiovascular outcomes [[19], [24]–[26]]. In total 2079 patients
metformin 11749 cardiovascular outcomes [[19], [24]–[26]]. In total 2079 patients with type 2 diabetes were allocated to metformin , and a similar number to comparison groups, in the included studies. Duration of follow-up ranged from
metformin 14622 USA and Canada); HF, heart failure (NYHA class 3–4); Ins, insulin; LFT, liver function test; Met, metformin ; Mig, miglitol; Nat, nateglinide; OW, overweight; Plac, placebo; Ros, rosiglitazone; Sul, sulfonylureaFig.
metformin 15052 unclear risk of bias; negative sign, high risk of bias; positive sign, low risk of biasThe effect of metformin on risk of all-cause mortality (Fig. 3), cardiovascular death (Fig. 4), myocardial infarction (Fig.
metformin 15294 peripheral vascular disease (Fig. 7) is shown. All outcomes, with the exception of risk of stroke, favoured metformin , with limited heterogeneity between studies, but none achieved statistical significance. Effect sizes
metformin 16116 published data [[12]]. This led to small changes in the pooled estimates that more strongly favoured metformin for risk of stroke but more strongly favoured comparison groups for risk of myocardial infarction and
metformin 16339 vascular disease. All of the pooled estimates in the sensitivity analysis remained non-significant ( metformin vs control). The funnel plot (Fig. 8) did not suggest that we had omitted trials demonstrating metformin-associated
metformin 16444 (metformin vs control). The funnel plot (Fig. 8) did not suggest that we had omitted trials demonstrating metformin -associated increased mortality.Fig. 3Forest plot showing the effect of metformin on risk of all-cause
metformin 16525 trials demonstrating metformin-associated increased mortality.Fig. 3Forest plot showing the effect of metformin on risk of all-cause mortalityFig. 4Forest plot showing the effect of metformin on risk of cardiovascular
metformin 16605 showing the effect of metformin on risk of all-cause mortalityFig. 4Forest plot showing the effect of metformin on risk of cardiovascular deathFig. 5Forest plot showing the effect of metformin on risk of myocardial
metformin 16686 showing the effect of metformin on risk of cardiovascular deathFig. 5Forest plot showing the effect of metformin on risk of myocardial infarctionFig. 6Forest plot showing the effect of metformin on risk of strokeFig.
metformin 16768 showing the effect of metformin on risk of myocardial infarctionFig. 6Forest plot showing the effect of metformin on risk of strokeFig. 7Forest plot showing the effect of metformin on risk of peripheral vascular diseaseFig.
metformin 16835 6Forest plot showing the effect of metformin on risk of strokeFig. 7Forest plot showing the effect of metformin on risk of peripheral vascular diseaseFig. 8Funnel plot of effect size estimates for all-cause mortality
metformin 17057 assess risk of publication bias. Circles represent M–H RR estimates for all-cause mortality comparing metformin vs control groupsDiscussionIn spite of its long history, we identified only 13 studies, including just
metformin 17223 we identified only 13 studies, including just over 2000 patients with type 2 diabetes allocated to metformin , that addressed our study question, and only four randomised-controlled cardiovascular endpoint trials
metformin 17353 study question, and only four randomised-controlled cardiovascular endpoint trials simply comparing metformin with placebo among patients with type 2 diabetes. Metformin monotherapy appears safe and, while there
metformin 17620 about whether it reduces risk of cardiovascular disease. According to our review it is possible that metformin reduces risk of all-cause mortality by up to 16% but it could increase risk of stroke by up to 48%.
metformin 17911 type 2 diabetes. However, in contrast to some newer treatments, cardiovascular endpoint trial data for metformin are largely derived from small studies among relatively young, overweight/obese, North American and
metformin 18568 there remains concern about the observed increased risk of mortality associated with the addition of metformin to sulfonylurea treatment [[14], [15]].The reports of all included trials either suggested the possibility
metformin 19282 influence its interpretation [[28]]. These include the small size (only 342 patients were allocated to metformin ), lack of placebo and double-blinding, ‘subgroup’ nature of the analysis with updated statistical
metformin 19863 to underestimation of effects, in particular the extent of any ‘legacy effect’ of treatment with metformin in the early part of the trial. However, a sensitivity analysis replacing the longer term follow-up
metformin 20449 on MEDLINE or EMBASE or are unpublished. We only included trials that ‘isolated’ the effects of metformin in order to distinguish between benefits of metformin and harms associated with comparator drugs. With
metformin 20503 included trials that ‘isolated’ the effects of metformin in order to distinguish between benefits of metformin and harms associated with comparator drugs. With the exception of screening of some of the full text
metformin 22200 published within the last 10 years [[14], [15], [29]]. In Selvin et al’s meta-analysis of trials of metformin vs any comparator, effect sizes for cardiovascular and all-cause mortality (M–H OR 0.74 [95% CI 0.62,
metformin 22396 0.74 [95% CI 0.62, 0.89] and M–H OR 0.81 [95% CI 0.60, 1.08], respectively) more strongly favoured metformin [[29]], mainly because of the inclusion of the open-label, active-comparator trial, the Comparative
metformin 22773 prevention and trials with active comparators (in particular rosiglitazone), reported no overall effect of metformin on cardiovascular events (M–H OR 0.94 [95% CI 0.82, 1.07]) [[15]]. When analysis was restricted to
metformin 22899 cardiovascular events (M–H OR 0.94 [95% CI 0.82, 1.07]) [[15]]. When analysis was restricted to comparisons of metformin with placebo or no drug treatment, metformin appeared to be beneficial (M–H OR 0.79 [95% CI 0.64,
metformin 22944 [[15]]. When analysis was restricted to comparisons of metformin with placebo or no drug treatment, metformin appeared to be beneficial (M–H OR 0.79 [95% CI 0.64, 0.98]). Our results most closely mirror those
metformin 23109 0.98]). Our results most closely mirror those of Boussageon et al [[14]], who reported no effect of metformin on all-cause mortality (M–H RR 0.99 [95% CI 0.75, 1.31]) or cardiovascular mortality (M–H RR 1.05
metformin 23709 meta-analysis of trials [[33]]. The number, size, quality, reporting and findings of randomised trials of metformin have resulted in continuing uncertainty regarding whether it reduces risk of diabetes-related complications,
metformin 24028 directly relevant to a significant proportion of the patients with type 2 diabetes worldwide for whom metformin is the recommended first-line medication. This contrasts with the evidence now available for newer and
metformin 24332 and of course for medications targeting different risk factors, for example statins. Nevertheless, metformin is included on the WHO model list of essential medicines, a list of ‘the most efficacious, safe and
metformin 24757 to equipoise to enable a large, double-blind, placebo-controlled, cardiovascular endpoint trial of metformin among patients with diabetes. It is also doubtful that a suitable industry, charity or government funder
metformin 24951 or government funder could be identified. While such a trial might reduce uncertainty about whether metformin is more effective than placebo, it would not inform common therapeutic dilemmas, such as which of the
metformin 25549 trials in which an industry-sponsored new medication can be evaluated alongside older drugs such as metformin . There has been considerable hope and hype concerning the potential for precision medicine to inform
metformin 25776 decisions [[35]], but progress is hampered by our lack of understanding about the mechanisms of action of metformin and a focus on intermediate endpoints. Publication of cardiovascular outcome data from adverse event
metformin 25910 intermediate endpoints. Publication of cardiovascular outcome data from adverse event reporting in trials of metformin would increase the data available for meta-analysis, thereby reducing the uncertainty of effect size
metformin 26446 these estimates were inflated because of participants undergoing outcome assessment while still taking metformin [[38]]. Proponents of a medical solution to what is essentially a societal problem are advocating the
metformin 26576 of a medical solution to what is essentially a societal problem are advocating the widespread use of metformin to ‘treat’ those at risk of diabetes. Indeed, metformin is now licensed in some countries for this
metformin 26636 problem are advocating the widespread use of metformin to ‘treat’ those at risk of diabetes. Indeed, metformin is now licensed in some countries for this indication. This effectively amounts to starting glucose-lowering
metformin 27046 risk of diabetes do not have symptoms attributable to hyperglycaemia, the rationale for recommending metformin would be considerably strengthened if trial evidence was available demonstrating that the use of metformin
metformin 27153 metformin would be considerably strengthened if trial evidence was available demonstrating that the use of metformin in people at risk of diabetes reduced risk of complications, such as cardiovascular disease. Perhaps,
metformin 27374 therefore, there is greater interest, opportunity and need for a cardiovascular endpoint trial evaluation of metformin among people without diabetes than among those already living with the condition. While acknowledging
metformin 27491 people without diabetes than among those already living with the condition. While acknowledging that metformin has pleiotropic effects, if it was shown to be effective in such a trial, the near-linear relationship
metformin 27772 and the somewhat arbitrary diagnostic threshold for diabetes, might also reinforce the reputation of metformin for treating diabetes. Metformin is cheap, widely available, safe, backed by pharmaco-epidemiological
metformin 28479 expensive and lack data on long-term use. Perhaps in spite of, rather than because of, the evidence, metformin is likely to remain the first-line treatment for the hyperglycaemia associated with type 2 diabetes
miglitol 14638 HF, heart failure (NYHA class 3–4); Ins, insulin; LFT, liver function test; Met, metformin; Mig, miglitol ; Nat, nateglinide; OW, overweight; Plac, placebo; Ros, rosiglitazone; Sul, sulfonylureaFig. 2Risk of
nateglinide 14653 failure (NYHA class 3–4); Ins, insulin; LFT, liver function test; Met, metformin; Mig, miglitol; Nat, nateglinide ; OW, overweight; Plac, placebo; Ros, rosiglitazone; Sul, sulfonylureaFig. 2Risk of bias summary. Review
rosiglitazone 14702 function test; Met, metformin; Mig, miglitol; Nat, nateglinide; OW, overweight; Plac, placebo; Ros, rosiglitazone ; Sul, sulfonylureaFig. 2Risk of bias summary. Review authors’ judgements about each risk of bias item
rosiglitazone 22727 meta-analysis, which included trials of diabetes prevention and trials with active comparators (in particular rosiglitazone ), reported no overall effect of metformin on cardiovascular events (M–H OR 0.94 [95% CI 0.82, 1.07])
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