Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials
Background:
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.
Methods and Findings:
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 (I2 = 41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p = 0.10 and 0.02, respectively).
Conclusions:
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.
: Please see later in the article for the Editors' Summary
Vyšlo v časopise:
Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials. PLoS Med 9(4): e32767. doi:10.1371/journal.pmed.1001204
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.1001204
Souhrn
Background:
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.
Methods and Findings:
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 (I2 = 41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p = 0.10 and 0.02, respectively).
Conclusions:
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.
: Please see later in the article for the Editors' Summary
Zdroje
1. WildSGreenASicreeRKingH 2004 Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27 1047 1053
2. The Emerging Risk Factors Collaboration 2010 Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375 2215 2222
3. UK Prospective Diabetes Study (UKPDS) Group 1998 Effect of Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352 854 865
4. NathanDMBuseJBDavidsonMBFerranniniEHolmanRR 2009 Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 32 193 203
5. National Institute for Health and Clinical Excellence 2008 May Type 2 diabetes: the management of type 2 diabetes. Available: http://www.nice.org.uk/CG66. Accessed 18 May 2011
6. SaenzAFernandez-EstebanIMataixAAusejo SeguraMRoqué i FigulsM 2005 Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005 CD002966
7. SelvinEBolenSYehHCWileyCWilsonLM 2008 Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 168 2070 2080
8. BennettWLMaruthurNMSinghSSegalJBWilsonLM 2011 Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 154 602 613
9. LamannaCMonamiMMarchionniNMannucciE 2011 Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomised clinical trials. Diabetes Obes Metab 13 221 228
10. RachmaniRSlavachevskiILeviZZadokBKedarY 2002 Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 13 428 433
11. CryerDMillsDNicholasSPStadelBVHenryDH 2005 Comparative outcomes study of metformin intervention versus conventional approach. Diabetes Care 28 539 543
12. The University Group Diabetes Program 1975 A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of phenformin therapy. Diabetes 24 Suppl 1 65 184
13. JadadARMooreRACarrollDJenkinsonCReynoldsDJ 1996 Assessing the quality of reports on randomised clinical trials: Is blinding necessary? Control Clin Trials 17 1 12
14. HigginsJPThompsonSG 2002 Quantifying heterogeneity in a meta-analysis. Stat Med 21 1539 1558
15. RückerGSchwarzerGCarpenterJRSchumacherM 2008 Undue reliance on I(2) in assessing heterogeneity may mislead. BMC Med Res Methodol 27 79 Available: http://www.biomedcentral.com/1471-2288/8/79. Accessed 5 March 2012
16. KooyADe JagerJLehertPBetsDWulffeléMG 2009 Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 169 616 625
17. TeupeBBergisK 1991 Prospective randomised two-years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes. Diabete Metab 17 213 217
18. HermannLSSchersténBBitzénPOKjellströmTLindgärdeF 1994 Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care 17 1100 1109
19. HortonEFoleyJClinkingbeardCMallowsSGatlinM 2000 Nateglinide alone and in combination with Metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 23 1660 1665
20. HermannLSKalénJKatzmanPLagerINilssonA 2001 Long-term glycaemic improvement after addition of metformin to insulin in insulin-treated obese type 2 diabetes patients. Diabetes Obes Metab 3 428 434
21. HällstenKVirtanenKALönnqvistFSipiläHOksanenA 2002 Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes 51 3479 3485
22. GarberAJDonovanDSDandonaPBruceSParkJS 2003 Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes. J Clin Endocrinol Metab 88 3598 3604
23. BlondeLRosenstockJMooradianADPiperBAHenryD 2002 Glyburide/metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylureas therapy. Diabetes Obes Metab 4 368 375
24. DeFronzoRAGoodmanAM 1995 Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 333 541 549
25. ChiassonJLNadtichL for the Miglitol Canadian University Investigator Group 2001 The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care 24 989 994
26. GreenbergSA 2009 How citation distortions create unfounded authority: analysis of a citation network. BMJ 339 b2680 doi:10.1136/bmj.b2680
27. ADVANCE Collaborative Group 2008 Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358 2560 2572
28. HomePDPocockSJBeck-NielsenHCurtisPSGomisR 2009 Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373 2125 2135
29. AzoulayLSchneider-LindnerVDell'anielloSSchiffrinASuissaS 2010 Combination therapy with sulphonylureas and metformin and the prevention of death in type 2 diabetes: a nested case-control study. Pharmacoepidemiol Drug Saf 19 335 342
30. AnderssonCOlesenJBHansenPRWeekePNorgaardML 2010 Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. Diabetologia 53 2546 2553
31. SillarsBDavisWAHirschIBDavisTM 2010 Sulphonylureas-metformin combination therapy, cardiovascular disease and all-cause mortality: the Fremantle Diabetes Study. Diabetes Obes Metab 9 757 765
32. RaoADKuhadiyaNReynoldsKFonsecaVA 2008 Is the combination of sufonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality. Diabetes Care 31 1672 1678
33. NathanDM 1998 Some answers, more controversy, from UKPDS. Lancet 352 832 833
34. EwartRM 2001 The case against agressive treatment of type 2 diabetes: critique of the UK prospective diabetes study. BMJ 323 854 858
35. McCormackJGreenhalghT 2000 Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data. BMJ 320 1720 1723
36. UK Prospective Diabetes Study (UKPDS) Group 1998 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352 837 853
37. SchulzKFChalmersIHayesRJAltmanDG 1995 Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 273 408 412
38. MoherDPhamBJonesACookDJJadadAR 1998 Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 352 609 613
39. HolmanRRMatthewsDRNeilHA 2009 Follow-up of intensive glucose control in type 2 diabetes. The authors reply. N Engl J Med 360 416 418
40. BaileyC 1996 Metformin. N Engl J Med 334 574 579
41. HirstJAFarmerAJAliRRobertsNWStevensRJ 2012 Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care 35 446 454
42. ShaughnessyAFSlawsonDC 2003 What happened to the valid POEMs? A survey of review articles on the treatment of type 2 diabetes. BMJ 327 266 273
43. GandhiGYMuradMHFujiyoshiAMullanRJFlynnDN 2008 Patient-important outcomes in registered diabetes trials. JAMA 299 2543 2549
44. PrenticeRL 1989 Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8 431 440
45. FitzgeraldEMathieuSBallA 2009 Metformin associated lactic acidosis. BMJ 339 b3660 doi:10.1136/bmj.b3660
46. De JagerJKooyALehertPWulffeléMGvan der KolkJ 2010 Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 340 c2181 doi:10.1136/bmj.c2181
47. TzoulakiIMolokhiaMCurcinVLittleMPMillettCJ 2009 Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 339 b4731 doi:10.1136/bmj.b4731
48. GambleJMSimpsonSHEurichDTMajumdarSRJohnsonJA 2010 Insulin use and increased risk of mortality in type 2 diabetes: a cohort study. Diabetes Obes Metab 12 47 53
49. EurichDTMcAlisterFABlackburnDFMajumdarSRTsuyukiRT 2007 Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 335 497
50. BowkerSLMajumdarSRVeugelersPJohnsonJA 2006 Increased cancer-related mortality for patients with type 2 diabetes who use sulphonylureas or insulin. Diabetes Care 29 254 258
51. CurrieCJPooleCDGaleEA 2009 The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52 1766 1777
52. NissenSEWolskiK 2007 Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Eng J Med 356 2457 2471
53. RichterBBandeira-EchtlerEBergerhoffKClarCEbrahimSH 2006 Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006 CD006060
54. RousselRTravertFPasquetBWilsonPWFSmithSCJr 2010 Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 170 1892 1899
Štítky
Interné lekárstvoČlánok vyšiel v časopise
PLOS Medicine
2012 Číslo 4
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Pleiotropní účinky statinů na kardiovaskulární systém
- Statiny indukovaná myopatie: Jak na diferenciální diagnostiku?
- DESATORO PRE PRAX: Aktuálne odporúčanie ESPEN pre nutričný manažment u pacientov s COVID-19
- Význam hydratace při hojení ran
Najčítanejšie v tomto čísle
- Induction of Labor versus Expectant Management in Women with Preterm Prelabor Rupture of Membranes between 34 and 37 Weeks: A Randomized Controlled Trial
- The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience
- Long-Term Exposure to Silica Dust and Risk of Total and Cause-Specific Mortality in Chinese Workers: A Cohort Study
- Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification