Metformin Use and Mortality Among Patients With Diabetes and Atherothrombosis FREE

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 studies^5,7 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 recommendations^5,8 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.^9- 11 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).

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).

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).

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.

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).

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).

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.^17- 20 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-up^3,21 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 studies^7,23 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 studies^7,27 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.