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Original Investigation |

Metformin Use and Mortality Among Patients With Diabetes and Atherothrombosis FREE

Ronan Roussel, MD, PhD; Florence Travert, MD, PhD; Blandine Pasquet, MSc; Peter W. F. Wilson, MD; Sidney C. Smith Jr, MD; Shinya Goto, MD, PhD; Philippe Ravaud, MD, PhD; Michel Marre, MD, PhD; Avi Porath, MD, MPH; Deepak L. Bhatt, MD, MPH; P. Gabriel Steg, MD; Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators
[+] Author Affiliations

Author Affiliations: Institut National de la Santé et de la Récherche Médicale (INSERM), Unité 695 (Drs Roussel, Travert, and Marre) and Unité 698 (Dr Steg), Université Paris 7, and Departments of Diabetology, Endocrinology, and Nutrition and Epidemiology, Biostatistics, and Clinical Research (Ms Pasquet and Dr Ravaud), Bichat Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France; Atlanta Veterans Affairs Medical Center and Emory University School of Medicine, Atlanta, Georgia (Dr Wilson); Center for Cardiovascular Science and Medicine, University of North Carolina School of Medicine, Chapel Hill (Dr Smith); Tokai University School of Medicine, Isehara, Kanagawa, Japan (Dr Goto); Department of Health Care Policy, Clalit Health Services and Faculty of Health Sciences, Ben-Gurion University of Negev, Beer-Sheva, Israel (Dr Porath); and Department of Cardiology, Veterans Affairs Boston Healthcare System, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Bhatt).Group Information: A list of the REACH Registry Investigators was published in JAMA (2006;295[2]:188) and can be found at http://jama.ama-assn.org/cgi/content/full/295/2/180AUTHINFO.


Arch Intern Med. 2010;170(21):1892-1899. doi:10.1001/archinternmed.2010.409.
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Published online

Background  Metformin is recommended in type 2 diabetes mellitus because it reduced mortality among overweight participants in the United Kingdom Prospective Diabetes Study when used mainly as a means of primary prevention. However, metformin is often not considered in patients with cardiovascular conditions because of concerns about its safety.

Methods  We assessed whether metformin use was associated with a difference in mortality among patients with atherothrombosis. The study sample comprised 19 691 patients having diabetes with established atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry between December 1, 2003, and December 31, 2004, treated with or without metformin. Multivariable adjustment and propensity score were used to account for baseline differences. The main outcome measure was 2-year mortality.

Results  The mortality rates were 6.3% (95% confidence interval [CI], 5.2%-7.4%) with metformin and 9.8% 8.4%-11.2%) without metformin; the adjusted hazard ratio (HR) was 0.76 (0.65-0.89; P < .001). Association with lower mortality was consistent among subgroups, noticeably in patients with a history of congestive heart failure (HR, 0.69; 95% CI, 0.54-0.90; P = .006), patients older than 65 years (0.77; 0.62-0.95; P = .02), and patients with an estimated creatinine clearance of 30 to 60 mL/min/1.73 m2 (0.64; 95% CI, 0.48-0.86; P = .003) (to convert creatinine clearance to mL/s/m2, multiply by 0.0167).

Conclusions  Metformin use may decrease mortality among patients with diabetes when used as a means of secondary prevention, including subsets of patients in whom metformin use is not now recommended. Metformin use should be tested prospectively in this population to confirm its effect on survival.

Figures in this Article

Cardiovascular diseases are frequent in patients with type 2 diabetes mellitus and are the most common cause of death. Notable progress has been made in preventive care among the population with diabetes, but the excess of deaths associated with diabetes remains important.1 Recently, large-scale trials failed to demonstrate a clear benefit of intensive glycemic control in patients with type 2 diabetes mellitus at high risk of cardiovascular outcomes or with established diabetic complications.2 In the United Kingdom Prospective Diabetes Study,3 metformin was the first-line therapeutic agent among newly diagnosed overweight patients with diabetes, and the regimen reduced mortality at 11 years and at long-term follow-up. Therefore, it is now believed that metformin can bring some benefit in primary prevention of cardiovascular complications.4 Metformin has been on the market for decades in Europe but only since 1995 in the United States because of concern about metformin-associated lactic acidosis. This concern led to conservative recommendations for the use of metformin in patients with chronic conditions, such as cardiac diseases or renal failure, that predispose them to lactic acidosis.5 These limitations drastically reduced the number of patients who could be treated with and who may benefit from metformin.6 Findings from previous studies5,7 suggest that metformin therapy may be associated with a better prognosis in older patients with diabetes discharged after hospitalization for heart failure, which was a contraindication to the use of metformin in the international recommendations5,8 until 2009.

Evaluation of the potential risks and benefits associated with metformin use as a secondary means of prevention of cardiovascular disorders has not yet been performed, to our knowledge. Herein, we studied the baseline characteristics and 2-year outcomes of 19 691 patients with diabetes undergoing a secondary prevention strategy in the international Reduction of Atherothrombosis for Continued Health (REACH) Registry. Our aim was to assess whether metformin use was associated with a difference in mortality after adjustment for baseline differences and for the propensity to receive metformin among patients with established coronary artery disease, cerebrovascular disease, or peripheral arterial disease.

The study design has been published previously, including the strategy for selecting physicians, collecting follow-up data, and ensuring data quality, as well as the baseline description of the REACH Registry.911 Briefly, consecutive outpatients 45 years and older with established coronary artery disease, cerebrovascular disease, or peripheral arterial disease or patients with at least 3 atherothrombotic risk factors were enrolled by 5587 physician practices in 44 countries between December 1, 2003, and December 31, 2004. This protocol was submitted to the institutional review boards in each country according to local requirements, and signed informed consent was required for all patients.

Data were collected centrally via the use of a standardized international case report form, which was completed at the study visit. Body mass index was calculated as weight in kilograms divided by height in meters squared. Patients were considered overweight if their body mass index was 25 to 29 or obese if it was 30 or higher. Diabetes was defined by antidiabetic medication use. Creatinine clearance was calculated according to the Modification of Diet in Renal Disease formula,12 and stages of kidney function were defined according to the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines (http://www.kidney.org/professionals/KDOQI/guideline_diabetes/guide1.htm). Current smoking was defined as a mean of at least 5 cigarettes per day in the month before enrollment, and former smoking was defined as cessation more than 1 month before enrollment. A prior investigation11 showed ethnic-related differences in the medical treatment and outcomes of high-risk patients. Ethnicity was self-reported, and in instances of mixed ethnic origin, subjects were asked to choose the single ethnicity that had the strongest personal influence. In some countries, local rules did not allow ethnicity recording, so the data for those patients were considered missing.

At follow-up visits until 24 months after enrollment, data were collected from participating physicians regarding patients' clinical outcomes, vascular procedures, employment status, weight, and current smoking status, as well as any medications used. If appropriate, dates of the outcomes were collected.

In the present study, only baseline and 2-year follow-up data of patients having diabetes with a history of arterial disease were analyzed. Patients with only baseline data were not included in the analysis. Events were not adjudicated; therefore, our analysis focuses on all-cause mortality. However, we also provide the hazard ratios (HRs) associated with metformin use for cardiovascular death and for first-occurring event among death, myocardial infarction (MI), or stroke based on investigator reports. Cardiovascular death included fatal stroke, fatal MI, and other cardiovascular death. Other cardiovascular death was defined as the following: death related to pulmonary embolism; death attributed to heart failure; death following a visceral or limb infarction; any sudden death, including unobserved and unexpected death (eg, while sleeping) unless proven otherwise by autopsy; death following a vascular operation, vascular procedure, or amputation (except for trauma or malignant neoplasm); and any other death that could not be definitely attributed to a nonvascular cause or hemorrhage. Any MI or stroke that was followed by death in the subsequent 28 days, regardless of the cause, was considered a fatal MI or fatal stroke. To ensure data quality in each country, 10% of all sites (ie, physicians) that enrolled at least 1 patient underwent quality control by means of a site visit. These sites were chosen randomly 6% of the time, and an additional 4% were chosen because of the number of queries and missing data from the sites. For each site undergoing monitoring, 100% of case report forms for patients enrolled at that site were monitored for source documentation and accuracy.

Data analyses were conducted independent of the registry sponsors by 2 of us (B.P. and P.R.), who planned the data analysis and received the entire raw data set. The results of the independent analysis are those presented herein. Confounding factors were taken into account using the propensity score method.13 This score represents the probability of receiving metformin given an individual's characteristics. The list of covariables was built in a 2-step process. First, bivariate analyses were conducted to determine the variables associated with metformin prescription among all available data variables. For the purpose of the preliminary selection, the P value limit was arbitrarily set at .20. Second, the selected variables were then introduced to construct a multivariable logistic regression model. To ensure the robustness of the score, the variables with more than 5% missing data were excluded from the logistic regression. Finally, the propensity score was calculated for every patient using the individual data in this model. The quality of the model was assessed using global evaluation (Wald test) and calculating the area under the corresponding receiver operating characteristic curve. A minimal value of 0.7 was expected to validate the score.

Patient characteristics are given as the mean (SD) or median (first through third quartiles) and were compared using the t test or χ2 test, when appropriate. Hazard ratios for death, cardiovascular death, and first-occurring event among death, MI, or stroke were calculated using a Cox proportional hazards model that included survival time in any individual patient, with metformin use and propensity scores as covariables, as well as other specified factors. Survival time was calculated according to the date of the outcome as collected by the enrolling physicians. For patients who did not experience the adverse outcome studied, data were censored at the time of the last visit with available information. Mortality rates are presented based on total sample sizes. The homogeneity of treatment effects across subgroups was tested by adding interaction terms to the relevant models. P < .05 was considered significant. All analyses were performed using commercially available statistical software (SAS, version 9.1; SAS Institute, Cary, North Carolina).

BASELINE CHARACTERISTICS, RISK FACTORS, AND DRUG PRESCRIPTIONS

Of 68 375 patients enrolled in the REACH Registry, 20 768 had diabetes mellitus and were symptomatic (established arterial disease at baseline). Among these, 19 691 (94.9%) had follow-up data and represent our study population; 1069 were excluded because no site visit was performed or because their enrolling physician had withdrawn from the registry. The characteristics of the population at baseline according to metformin use are given in Table 1. The mean follow-up times were 20.8 (4.0) and 20.9 (4.0) months for metformin users and nonusers, respectively (P = .09).

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Population by Metformin Use a

Patients prescribed metformin tended to be younger (67.1 [9.3] vs 69.2 [9.5] years, P < .001) and were more frequently overweight or obese (79.2% vs 72.4%, P < .001) (Table 1). Based on their fasting glycemia index, their glycemic control was slightly worse (138 [114-171] vs 131 [109-163] mg/dL, P < .001) (to convert glucose level to millimoles per liter, multiply by 0.0555). Their mean renal function was better (estimated glomerular filtration rate [eGFR], 76.0 [37.5] vs 78.3 [61.1] mL/min/1.73 m2; P = .003), which may be related to application of current prescription guidelines14 and to avoidance of the drug among patients with renal failure. Regarding classical risk factors, metformin users had a slightly lower fasting total cholesterol concentration (180 [153-213] vs 184 [157-215] mg/dL, P = .02), higher triglycerides concentration (157 [111-221] vs 145 [102-207] mg/dL, P < .001), and more frequent hypertension (87.7% vs 86.6%, P = .03) (to convert cholesterol concentration to millimoles per liter, multiply by 0.0259; triglycerides concentration to millimoles per liter, multiply by 0.0113). Overall, cardiovascular risk was lower among patients treated with metformin. Metformin users were more frequently prescribed cardioprotective drugs such as antiplatelet agents (85.0% vs 82.3%), statins (75.2% vs 68.5%), and angiotensin-converting enzyme inhibitors (54.3% vs 48.5%) (P < .001 for all).

PROPENSITY SCORE

The covariables used to calculate the propensity score were age, geographic region, body mass index, smoking status, hypercholesterolemia, carotid surgery, atrial fibrillation or flutter, and use of aspirin, lipid-lowering agents, statins, angiotensin II receptor blockers, calcium channel blockers, diuretics, angiotensin-converting enzyme inhibitors, other antihypertensive agents, sulfonylureas, insulin, and other antidiabetic agents. Factors excluded because of an excessive rate of missing data (>5%) were ethnicity, history of aortic valve stenosis or abdominal aortic aneurysm, serum creatinine and fasting blood glucose levels, and fasting total cholesterol and triglycerides concentrations. However, they were included as covariables in the Cox proportional hazards models because they were associated with mortality in univariate analysis.

The propensity scores reached the quality requirements because the likelihood associated with the model was strong (P < .001, Wald test) and because the area under the receiver operating characteristic curve of 0.72 exceeded the 0.7 threshold.

METFORMIN USE AS SECONDARY PREVENTION AND MORTALITY AMONG PATIENTS WITH DIABETES

At the 2-year follow-up visit, 1270 deaths (6.4%) and 823 cardiovascular deaths (4.2%) were recorded. Mortality rates were 6.3% (95% confidence interval [CI], 5.2%-7.4%) and 9.8% (8.4%-11.2%) among metformin users and nonusers, respectively (Figure 1). The assumption for proportionality was met for the Cox proportional hazards analysis. Metformin use was associated with lower all-cause mortality after adjustment for propensity score and for factors associated with mortality in univariate analyses (HR, 0.76; 95% CI, 0.65-0.89; P < .001) (Table 2). Metformin use was also associated with lower cardiovascular mortality (HR, 0.79; 95% CI, 0.65-0.96; P = .02) and with reduced rates of death, MI, or stroke (HR, 0.88; 95% CI, 0.79-0.99; P = .04).

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Figure 1.

Event curves for all-cause mortality from enrollment to 2 years by metformin use as recorded at baseline. Hazard ratio, 0.67; 95% confidence interval, 0.59-0.75; and adjusted hazard ratio, 0.76; 95% confidence interval, 0.65-0.89 (P < .001 for both, log-rank test). Hazard ratios are adjusted for age and sex. Adjusted hazard ratios are adjusted for significant risk factors in univariate analysis and for propensity score. Number of patients is slightly different from those of Table 1 (in which all cohort individuals at baseline were included in the descriptive statistics). For the Figures and outcomes analysis, cohort individuals with at least 1 follow-up datum on vital status were included.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Hazard Ratios (HRs) Associated With Metformin Use in the Study Populationa

Of 4585 patients with a history of congestive heart failure, 1428 were prescribed metformin. Metformin use was associated with lower all-cause mortality after adjusting for prognostic factors and propensity score (HR, 0.69; 95% CI, 0.54-0.90; P = .006) (Figure 2). Cardiovascular mortality was also decreased among metformin users but not significantly (HR, 0.80; 95% CI, 0.61-1.04; P = .10).

Place holder to copy figure label and caption
Figure 2.

Hazard ratios (HRs) for mortality associated with metformin use as recorded at baseline adjusted for significant risk factors in univariate analysis and for propensity score and stratified by relevant clinical categories. Black boxes indicate hazard ratios, and their sizes are representative of patient numbers. Horizontal lines indicate 95% confidence intervals (CIs). CHF indicates congestive heart failure; eGFR, estimated glomerular filtration rate; and TZDs, thiazolidinediones. Number of patients is slightly different from those of Table 1 (in which all cohort individuals at baseline were included in the descriptive statistics). For the Figures and outcomes analysis, cohort individuals with at least 1 follow-up datum on vital status were included.

Graphic Jump Location

According to available baseline characteristics, 10 914 patients had normal or only slightly reduced kidney function (eGFR, ≥60 mL/min [KDOQI stages 1 and 2]), 5031 patients had moderately reduced kidney function (30 to <60 mL/min), and 590 patients had severely reduced kidney function (<30 mL/min [KDOQI stage 3]); among them, 4442 (40.7%), 1572 (31.2%), and 118 (20.0%), respectively, had metformin treatment. Mortality was lower among patients taking metformin with KDOQI stages 1 and 2 and with KDOQI stage 3, although statistical significance was reached only for the latter patients (Figure 2). Further substaging (KDOQI stage 3a and 3b, with a cutoff value of 45 mL/min) showed an even greater mortality reduction among these groups with the most severe disease (HR, 0.75; 95% CI, 0.52-1.10; P = .15 for KDOQI stage 3a; 0.57; 0.35-0.92; P = .02 for KDOQI stage 3b). No effect of metformin use was shown for an eGFR of less than 30 mL/min, although this may be related to the few patients receiving metformin in this subgroup, as suggested by the large CI for their HR.

Metformin use was associated with improved survival among patients younger than 65 years (HR for death, 0.63; 95% CI, 0.45-0.89; P = .008) or those aged 65 to 80 years (0.77; 0.62-0.95; P = .02) (Figure 2). Mortality was also decreased among metformin users older than 80 years but not significantly (HR, 0.92; 95% CI, 0.66-1.28; P = .61).

Metformin use was consistently associated with reduced mortality across various geographic regions and ethnic origins of patients enrolled in the REACH Registry. These data are not shown.

The proportion of patients having a single arterial bed with established atherosclerosis was 77.3% (15 115 of 19 553). No interaction effect on mortality was shown between metformin use and the number of diseased arterial beds (P = .23 for interaction) (Figure 2).

These data from the observational REACH Registry indicate that the use of metformin as a means of secondary prevention was associated with a significant 24.0% reduction in all-cause mortality after 2-year follow-up. Such a reduction of mortality among patients with diabetes when used as secondary prevention has not to our knowledge been observed with any glucose-lowering drug. After controlling for potential confounding factors in multivariable propensity score–based models, these associations remained strong and consistent among some clinically important subgroups.

The lower mortality among the metformin-treated group may result from a specific drug-related effect; metformin addresses mainly hepatic insulin resistance, and insulin resistance has been suggested to be an independent cardiovascular risk factor.15,16 Metformin use has been associated with a small improvement in lipoprotein levels, especially low-density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor type 1.1720 It is also associated with a modest reduction of body weight, another well-established risk factor of cardiovascular death and of noncardiovascular death. Metformin is a powerful glucose-lowering drug. Because the glycemic control did not demonstrate a clinically relevant difference between users and nonusers of metformin, the latter group received different combinations of antidiabetic agents, which might have had a deleterious role that we cannot rule out. We have not studied the types of drug combinations used and how metformin use was associated or unassociated with thiazolidinediones, sulfonylureas, or insulin, nor do we know the therapeutic strategies in the patients not treated with metformin.

The finding of lower mortality associated with metformin use in the REACH Registry is consistent with results of the United Kingdom Prospective Diabetes Study and its 10-year follow-up3,21 and with a Cochrane systematic review of trials of metformin as monotherapy for type 2 diabetes mellitus compared with other antidiabetic agents, which found that metformin therapy resulted in decreased all-cause mortality.22 Our data are also consistent with 2 other observational studies7,23 focusing on patients having diabetes with congestive heart failure, both of which found that metformin use was associated with lower mortality, although these investigations were limited because of their observational design.

According to our results, metformin was prescribed worldwide in 1572 patients with moderate renal failure (KDOQI stage 3) in contraindication to guidelines for its use.14 Among this subgroup, metformin use was associated with at least a similar reduction in mortality as among the overall population we studied.

Lactic acidosis is the most severe adverse effect of metformin use; hence, it is contraindicated because classical risk factors for lactic acidosis among patients treated with metformin are older age and cardiac diseases, including decompensated congestive heart failure, hypoperfusion, renal insufficiency, and chronic pulmonary disease.5,24 However, one investigator has reported that lactic acidosis is not more frequent among patients treated with metformin when these predisposing conditions are present.25 Unfortunately, cases of lactic acidosis were not specifically recorded in the REACH Registry, which is a limitation of our study. However, the apparent mortality benefit from metformin-based treatment in the REACH Registry suggests that the benefits of metformin use probably outweigh its risks not only in symptomatic high-risk patients with diabetes but also in those with congestive heart failure, moderate renal failure, and older age, at least in those younger than 80 years.

We are aware of the limitations inherent to any observational study. Among these, we should underline that the durations of diabetes and metformin use or exposure were not recorded in the registry. We also acknowledge that the lack of information on glycated hemoglobin level may be detrimental to the analysis. This variable is the criterion standard for estimation of glucose control, and it is less variable than fasting glycemia. However, it is not routinely available worldwide, especially in developing countries, and, when available, it is often not well standardized because of various techniques of measurement. Because fasting glycemia and glycated hemoglobin level have been reported to be well correlated in large studies,26 the REACH Registry limited its data collection to fasting glycemia. Finally, the mean fasting glycemia did not differ dramatically between metformin users and nonusers. Events were not adjudicated but only recorded; therefore, we focused mainly on all-cause death (the most robust and relevant outcome). When addressing causal questions from nonrandomized studies, it is crucial to adjust optimally for observed confounding variables. Owing to major differences in clinical characteristics between metformin users and nonusers, our analyses may be subject to allocation bias. By design, the REACH Registry recorded a large set of individual characteristics related to cardiovascular risk, offering an ideal database to test our hypothesis regarding metformin safety and benefits among high-risk patients with diabetes using propensity scores, a validated method to adjust for confounding variables. Moreover, the magnitude of the observed effect on mortality reduces the chance that the effect is related to unmeasured confounding factors, although this cannot be excluded with certainty.

As with any study, caution is required in extrapolating our results to other populations. However, the diversity of countries, geographic regions, practice settings, and types of physicians and patients participating in the REACH Registry, as well as the well-balanced recruitment between specialists and primary care providers, makes the conclusions broadly relevant.

In conclusion, a randomized controlled trial would be the next natural step to assess definitively the benefits and risks of metformin use as a means of prevention of secondary cardiovascular disorders among patients having diabetes with a history of coronary artery disease, cerebrovascular disease, or peripheral arterial disease. Factors now regarded as contraindications should not be limiting factors for eligibility because, as in this study, the apparent benefit of metformin use was consistent across these patient subsets; results from this study and other studies7,27 suggest no apparent harm with frequent use. Our findings provide data sufficiently pertinent and consistent to initiate a properly defined and powered randomized controlled trial to confirm the effect of metformin use on survival.

Correspondence: Ronan Roussel, MD, PhD, Department of Diabetology, Endocrinology, and Nutrition, Bichat Hospital, 46 rue Henri Huchard, 75018 Paris, France (ronan.roussel@bch.aphp.fr).

Accepted for Publication: April 9, 2010.

Author Contributions: Dr Roussel had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Roussel, Travert, Bhatt, and Steg. Acquisition of data: Goto and Steg. Analysis and interpretation of data: Roussel, Travert, Marre, Bhatt, and Steg. Drafting of the manuscript: Roussel, Travert, Porath, Bhatt, and Steg. Critical revision of the manuscript for important intellectual content: Roussel, Travert, Wilson, Smith, Goto, Marre, Porath, Bhatt, and Steg. Statistical analysis: Roussel, Pasquet, Ravaud, and Steg. Obtained funding: Goto and Steg. Administrative, technical, and material support: Goto and Steg. Study supervision: Bhatt and Steg.

REACH Registry Executive Committee: Deepak L. Bhatt, MD, MPH, Veterans Affairs Boston Healthcare System and Brigham and Women's Hospital, Boston, Massachusetts (cochair); Gabriel Steg, MD, INSERM Unité 698, Université Paris 7, Assistance Publique–Hôpitaux de Paris, Paris, France (cochair); E. Magnus Ohman, MD, Duke University Medical Center, Durham, North Carolina; Joachim Röther, MD, Johannes Wesling Klinikum Minden, Minden, Germany; Peter W. F. Wilson, MD, Emory University School of Medicine, Atlanta, Georgia.

REACH Registry Global Publication Committee: Mark J. Alberts, MD, Northwestern University Medical School, Chicago, Illinois; Deepak L. Bhatt, MD, MPH, Veterans Affairs Boston Healthcare System and Brigham and Women's Hospital, Boston (cochair); Ralph D’Agostino, PhD, Boston University, Boston; Kim Eagle, MD, University of Michigan, Ann Arbor; Shinya Goto, MD, PhD, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Alan T. Hirsch, MD, Minneapolis Heart Institute Foundation and University of Minnesota School of Public Health, Minneapolis; Chiau-Suong Liau, MD, PhD, Taiwan University Hospital and College of Medicine, Taipei; Jean-Louis Mas, MD, Centre Raymond Garcin, Paris; E. Magnus Ohman, MD, Duke University Medical Center, Durham; Joachim Röther, MD, Johannes Wesling Klinikum Minden, Minden; Sidney C. Smith Jr, MD, University of North Carolina, Chapel Hill; Gabriel Steg, MD, INSERM Unité 698, Université Paris 7, Assistance Publique–Hôpitaux de Paris (cochair); Peter W. F. Wilson, MD, Emory University School of Medicine, Atlanta.

Financial Disclosure: Dr Roussel has received research grants, honoraria, or consulting fees from sanofi-aventis, Merck Sharp et Dohme (MSD)–Chibret, Servier Laboratories, F. Hoffman–La Roche Ltd, Eli Lilly and Company, Novo Nordisk A/S, Medtronic Inc, and Lifescan Inc. Dr Travert lectures for Servier Laboratories and MSD-Chibret. Dr Wilson has received research grants from sanofi-aventis within the past 3 years. Dr Goto has received honoraria and consulting fees from Eisai Pharmaceuticals, sanofi-aventis, Daiichi-Sankyo Co Ltd, GlaxoSmithKline plc, Bristol-Myers Scribb, Otsuka Pharmaceutical Group, Bayer AG, Schering-Plough, Takeda Pharmaceutical Co Ltd, Astellas Pharma Inc, AstraZeneca, Novartis Pharmaceuticals Corporation, and Kowa Company Ltd; Dr Goto also received research grants from Pfizer Inc, Ono Pharmaceutical, Eisai Pharmaceuticals, Otsuka Pharmaceutical Group, Daiichi-Sankyo Co Ltd, sanofi-aventis, Takeda Pharmaceutical Co Ltd, and Astellas Pharma Inc within the past 3 years. Dr Ravaud has received research grants, honoraria, or consulting fees from sanofi-aventis, MSD-Chibret, Servier Laboratories, Novartis Pharmaceuticals Corporation, and Pfizer Inc within the past 3 years. Dr Marre has received honoraria as an adviser and for lectures from Novo-Nordisk A/S, sanofi-aventis, Merck & Co Inc, Servier Laboratories, and Eli Lilly and Company. Dr Bhatt has received research grants from AstraZeneca, Bristol-Myers Squibb, Eisai Pharmaceuticals, Ethicon Inc, Heartscape Technologies Inc, sanofi-aventis, and The Medicines Company; received honoraria (donated to nonprofit organizations for >4 years) from AstraZeneca, Bristol-Myers Squibb, Centocor Ortho Biotech Inc, Daiichi-Sankyo Co Ltd, Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Millennium Pharmaceuticals Inc, ParinGenix Inc, PDL BioPharma Inc, sanofi-aventis, Schering-Plough, and The Medicines Company; served on the speakers' bureau (>4 years ago) for Bristol-Myers Squibb, sanofi-aventis, and The Medicines Company; served as a consultant or on the advisory board (honoraria donated to nonprofit organizations) for Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Cardax Pharmaceuticals, Centocor Ortho Biotech Inc, Cogentus Pharmaceuticals Inc, Daiichi-Sankyo Co Ltd, Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson Services Inc, McNeil-PPC Inc, Medtronic Inc, Millennium Pharmaceuticals Inc, Otsuka Pharmaceutical Group, ParinGenix Inc, PDL BioPharma Inc, Philips Healthcare, Portola Pharmaceuticals Inc, sanofi-aventis, Schering-Plough, The Medicines Company, and Vertex Pharmaceuticals; and provided expert testimony regarding clopidogrel bisulfate (compensation donated to a nonprofit organization). Dr Steg has received research grants from sanofi-aventis (1999-2008); is on the speakers' bureau for B oehringer Ingelheim GmbH, Bristol-Myers Squibb, GlaxoSmithKline, The Menarini Group, Medtronic Inc, Nycomed International Management GmbH, Pierre Fabre Laboratories, sanofi-aventis, Servier Laboratories, and The Medicines Company; is on the consulting or advisory boards for Astellas Pharma Inc, AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Daiichi-Sankyo Co Ltd, Endotis Pharma, GlaxoSmithKline, Medtronic Inc, MSD-Chibret, Nycomed International Management GmbH, sanofi-aventis, Servier Laboratories, and The Medicines Company; and is a stockholder for Aterovax.

Funding/Support: The REACH Registry is sponsored by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation of Japan, Inc, which assisted with the design and conduct of the study and with data collection. Editorial assistance was funded by sanofi-aventis and Bristol-Myers Squibb.

Role of the Sponsors: The REACH Registry is supported by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation of Japan, Inc. All analyses from the REACH Registry are prepared by independent authors who are not governed by the funding sponsors and are prioritized and reviewed by an academic publications committee before submission for publication. The statistical analyses were conducted solely by an academic team (Ms Pasquet and Dr Ravaud). The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript.

Previous Presentation: This study was presented as an abstract at the Late-Breaking Clinical Studies session of the American Diabetes Association's 70th Scientific Sessions; June 29, 2010; Orlando, Florida.

Additional Contributions: Rachel Spice and Sophie Rushton-Smith, PhD, assisted with coordinating revisions and provided other editorial help in preparing the manuscript.

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American Diabetes Association, Standards of medical care in diabetes—2009. Diabetes Care 2009;32 ((suppl 1)) S13- S61
PubMed
Sulkin  TVBosman  DKrentz  AJ Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997;20 (6) 925- 928
PubMed
Masoudi  FAInzucchi  SEWang  YHavranek  EPFoody  JMKrumholz  HM Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005;111 (5) 583- 590
PubMed
American Diabetes Association, Standards of medical care in diabetes—2008. Diabetes Care 2008;31 ((suppl 1)) S12- S54
PubMed
Ohman  EMBhatt  DLSteg  PG  et al. REACH Registry Investigators, The REduction of Atherothrombosis for Continued Health (REACH) Registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events—study design. Am Heart J 2006;151 (4) 786- e1-e10
PubMed10.1016/j.ahj.2005.11.004
Steg  PGBhatt  DLWilson  PW  et al. REACH Registry Investigators, One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297 (11) 1197- 1206
PubMed
Bhatt  DLSteg  PGOhman  EM  et al. REACH Registry Investigators, International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295 (2) 180- 189
PubMed
Levey  ASBosch  JPLewis  JBGreene  TRogers  NRoth  DModification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130 (6) 461- 470
PubMed
Rubin  DB Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127 (8, pt 2) 757- 763
PubMed
American Diabetes Association, Standards of medical care in diabetes—2010. Diabetes Care 2010;33 ((suppl 1)) S11- S61
PubMed
Tenenbaum  AAdler  YBoyko  V  et al.  Insulin resistance is associated with increased risk of major cardiovascular events in patients with preexisting coronary artery disease. Am Heart J 2007;153 (4) 559- 565
PubMed
DeFronzo  RAFerrannini  E Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14 (3) 173- 194
PubMed
DeFronzo  RAGoodman  AMThe Multicenter Metformin Study Group, Efficacy of metformin in patients with non–insulin-dependent diabetes mellitus. N Engl J Med 1995;333 (9) 541- 549
PubMed
Wu  MSJohnston  PSheu  WH  et al.  Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13 (1) 1- 8
PubMed
Grant  PJ The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996;19 (1) 64- 66
PubMed
Haukeland  JWKonopski  ZEggesbø  HB  et al.  Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44 (7) 853- 860
PubMed
UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352 (9131) 854- 865
PubMed
Saenz  AFernandez-Esteban  IMataix  AAusejo  MRoque  MMoher  D Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005; (3) CD002966
PubMed10.1002/14651858.CD002966.pub3
Eurich  DTMcAlister  FABlackburn  DF  et al.  Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335 (7618) 497.10.1136/bmj.39314.620174.80
PubMed
Misbin  RIGreen  LStadel  BVGueriguian  JLGubbi  AFleming  GA Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998;338 (4) 265- 266
PubMed
Misbin  RI The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27 (7) 1791- 1793
PubMed
Bonora  ECalcaterra  FLombardi  S  et al.  Plasma glucose levels throughout the day and HbA(1c) interrelationships in type 2 diabetes: implications for treatment and monitoring of metabolic control. Diabetes Care 2001;24 (12) 2023- 2029
PubMed
Calabrese  ATColey  KCDaPos  SVSwanson  DRao  RH Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med 2002;162 (4) 434- 437
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Event curves for all-cause mortality from enrollment to 2 years by metformin use as recorded at baseline. Hazard ratio, 0.67; 95% confidence interval, 0.59-0.75; and adjusted hazard ratio, 0.76; 95% confidence interval, 0.65-0.89 (P < .001 for both, log-rank test). Hazard ratios are adjusted for age and sex. Adjusted hazard ratios are adjusted for significant risk factors in univariate analysis and for propensity score. Number of patients is slightly different from those of Table 1 (in which all cohort individuals at baseline were included in the descriptive statistics). For the Figures and outcomes analysis, cohort individuals with at least 1 follow-up datum on vital status were included.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Hazard ratios (HRs) for mortality associated with metformin use as recorded at baseline adjusted for significant risk factors in univariate analysis and for propensity score and stratified by relevant clinical categories. Black boxes indicate hazard ratios, and their sizes are representative of patient numbers. Horizontal lines indicate 95% confidence intervals (CIs). CHF indicates congestive heart failure; eGFR, estimated glomerular filtration rate; and TZDs, thiazolidinediones. Number of patients is slightly different from those of Table 1 (in which all cohort individuals at baseline were included in the descriptive statistics). For the Figures and outcomes analysis, cohort individuals with at least 1 follow-up datum on vital status were included.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Population by Metformin Use a
Table Graphic Jump LocationTable 2. Hazard Ratios (HRs) Associated With Metformin Use in the Study Populationa

References

Gaede  PLund-Andersen  HParving  HHPedersen  O Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358 (6) 580- 591
PubMed
Turnbull  FMAbraira  CAnderson  RJ  et al. Control Group, Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52 (11) 2288- 2298
PubMed
Holman  RRPaul  SKBethel  MAMatthews  DRNeil  HA 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359 (15) 1577- 1589
PubMed
Nathan  DMBuse  JBDavidson  MB  et al. American Diabetes Association; European Association for Study of Diabetes, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32 (1) 193- 203
PubMed
American Diabetes Association, Standards of medical care in diabetes—2009. Diabetes Care 2009;32 ((suppl 1)) S13- S61
PubMed
Sulkin  TVBosman  DKrentz  AJ Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997;20 (6) 925- 928
PubMed
Masoudi  FAInzucchi  SEWang  YHavranek  EPFoody  JMKrumholz  HM Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005;111 (5) 583- 590
PubMed
American Diabetes Association, Standards of medical care in diabetes—2008. Diabetes Care 2008;31 ((suppl 1)) S12- S54
PubMed
Ohman  EMBhatt  DLSteg  PG  et al. REACH Registry Investigators, The REduction of Atherothrombosis for Continued Health (REACH) Registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events—study design. Am Heart J 2006;151 (4) 786- e1-e10
PubMed10.1016/j.ahj.2005.11.004
Steg  PGBhatt  DLWilson  PW  et al. REACH Registry Investigators, One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297 (11) 1197- 1206
PubMed
Bhatt  DLSteg  PGOhman  EM  et al. REACH Registry Investigators, International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295 (2) 180- 189
PubMed
Levey  ASBosch  JPLewis  JBGreene  TRogers  NRoth  DModification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130 (6) 461- 470
PubMed
Rubin  DB Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127 (8, pt 2) 757- 763
PubMed
American Diabetes Association, Standards of medical care in diabetes—2010. Diabetes Care 2010;33 ((suppl 1)) S11- S61
PubMed
Tenenbaum  AAdler  YBoyko  V  et al.  Insulin resistance is associated with increased risk of major cardiovascular events in patients with preexisting coronary artery disease. Am Heart J 2007;153 (4) 559- 565
PubMed
DeFronzo  RAFerrannini  E Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14 (3) 173- 194
PubMed
DeFronzo  RAGoodman  AMThe Multicenter Metformin Study Group, Efficacy of metformin in patients with non–insulin-dependent diabetes mellitus. N Engl J Med 1995;333 (9) 541- 549
PubMed
Wu  MSJohnston  PSheu  WH  et al.  Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13 (1) 1- 8
PubMed
Grant  PJ The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996;19 (1) 64- 66
PubMed
Haukeland  JWKonopski  ZEggesbø  HB  et al.  Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44 (7) 853- 860
PubMed
UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352 (9131) 854- 865
PubMed
Saenz  AFernandez-Esteban  IMataix  AAusejo  MRoque  MMoher  D Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005; (3) CD002966
PubMed10.1002/14651858.CD002966.pub3
Eurich  DTMcAlister  FABlackburn  DF  et al.  Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335 (7618) 497.10.1136/bmj.39314.620174.80
PubMed
Misbin  RIGreen  LStadel  BVGueriguian  JLGubbi  AFleming  GA Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998;338 (4) 265- 266
PubMed
Misbin  RI The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27 (7) 1791- 1793
PubMed
Bonora  ECalcaterra  FLombardi  S  et al.  Plasma glucose levels throughout the day and HbA(1c) interrelationships in type 2 diabetes: implications for treatment and monitoring of metabolic control. Diabetes Care 2001;24 (12) 2023- 2029
PubMed
Calabrese  ATColey  KCDaPos  SVSwanson  DRao  RH Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med 2002;162 (4) 434- 437
PubMed

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