INSULIN GLARGINE 300 U/ML IS ASSOCIATED WITH LESS WEIGHT GAIN, WHILE MAINTAINING GLYCEMIC CONTROL AND LOW RISK OF HYPOGLYCEMIA, COMPARED WITH INSULIN

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP OR INSULIN GLARGINE 300 U/ML IS ASSOCIATED WITH LESS WEIGHT GAIN, WHILE MAINTAINING GLYCEMIC CONTROL AND LOW RISK OF HYPOGLYCEMIA, COMPARED WITH INSULIN GLARGINE 100 U/ML IN AN AGING POPULATION WITH TYPE 2 DIABETES Medha N. Munshi, MD 1 3, Jasvinder Gill, PhD 4, Jason Chao, MSc 5, Elena V. Nikonova, MD 6, and Meenakshi Patel, MD 7 Running title: A1C control with lower hypoglycemia From the 1 Joslin Diabetes Center, Boston, Massachusetts; 2 Beth Israel Deaconess Medical Center, Boston, Massachusetts; 3 Harvard Medical School, Boston, Massachusetts; 4 Sanofi US, Inc., Bridgewater, New Jersey; 5 Xinyi, Inc., Bridgewater, New Jersey; 6 Artech Information Systems, LLC, Morristown, New Jersey; 7 Valley Medical Primary Care, Centerville, Ohio. Address correspondence: Dr. Medha Munshi; Director, Joslin Geriatric Diabetes Program BIDMC-Division of Gerontology; 110 Francis Street, Suite 1B; Boston, MA medha.munshi@joslin.harvard.edu

2 Funding sources This study was funded by Sanofi US, Inc. ABSTRACT OBJECTIVE: Assess efficacy, hypoglycemia and weight gain in patients with type 2 diabetes (T2D) treated with insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) across different age groups. METHODS: Pooled data were generated for patients randomized to Gla-300 or Gla-100 in the EDITION 2 (NCT ) and 3 (NCT ) studies. In four age groups (<55, 55 to <60, 60 to <65, 65 years), glycated hemoglobin A1C (A1C), percentage of patients reaching A1C <7.5% (58 mmol/mol), weight change, confirmed hypoglycemia (blood glucose 70 mg/dl) and/or severe hypoglycemia (events requiring third-party assistance) were analyzed with descriptive statistics and logistic, binomial, and ANCOVA regression modeling. RESULTS: A1C reductions from baseline and proportions of patients at target were similar for Gla-300 and Gla-100 across all age groups, at 6 and 12 months, but hypoglycemia incidence and event rate were lower with Gla-300 at 6 (both P<.001) and 12 months (P<.001 and P =.005, respectively). Patients on Gla-300 gained less weight than those on Gla-100 at 6 (P =.027) and 12 months (P=.021). Changes in weight and daily weight-adjusted insulin dose decreased with increasing age at 6 (P<.001 and P =.017, respectively) and 12 months (P<.001 and P =.011, respectively).

3 CONCLUSION: Older patients with T2D may benefit from treatment with Gla-300, which shows a lower hypoglycemia rate and less weight gain with similar efficacy compared with Gla-100. Abbreviations: AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association; ACCP = American College of Clinical Pharmacy; ANCOVA = Analysis of covariance; BL = Baseline; BMI = Body mass index; HEDIS = Healthcare Effectiveness Data and Information Set; Gla-100 = Insulin glargine 100 U/mL; Gla-300 = Insulin glargine 300 U/mL; A1C = Glycated hemoglobin A1C; mitt = Modified intention-to-treat; OADs = Oral antidiabetes drugs; SD = Standard deviation; SE = Standard error; T2D = Type 2 diabetes. INTRODUCTION In general, improvements in the management of type 2 diabetes (T2D) over the past decade have resulted in more patients achieving better glycemic control. The positive impact of tighter glycemic control is, however, counterbalanced by the negative impact of an increased incidence of hypoglycemia (1), which is now acknowledged to be a major limiting factor in the glycemic management of the disease (2). In individuals with T2D, hypoglycemia is associated with a reduction in quality of life, increased fear and anxiety, reduced productivity, and increased health-care costs (1). Older adults with T2D are at particular risk of the consequences of hypoglycemia (3,4), including arrhythmias (5), accidents and falls (and related fractures) (6,7), and neurological symptoms (e.g. dizziness, confusion) (8). Among older adults with T2D, hospital admissions for

4 hypoglycemia now exceed those for hyperglycemia (9). A recent US study, for example, showed nearly 2-fold higher rates of hospital admissions for hypoglycemia compared with hyperglycemia between 1999 and 2011 for patients aged 75 years, compared with patients aged years (9). Weight is also a factor in both the development and management of T2D (10). The goal of insulin use in T2D is to attain as normal a glycemic profile as possible without unacceptable weight gain or hypoglycemia (2). Basal insulins play an increasingly major role in the management of T2D and in the achievement of recommended glycemic targets. Despite the established efficacy of these agents in reducing glycated hemoglobin A1C (A1C) levels, glycemic control remains suboptimal in many patients. The American Diabetes Association (ADA)-recommended target for glycemic control for most patients is A1C <7.0% (53 mmol/mol), a target achieved by only 53% of patients (11). A higher A1C target may be acceptable for other patient groups, such as older individuals, to avoid the risk of hypoglycemia (3). Thus, there remains a need for therapies that are effective in achieving glycemic control but without unacceptable weight gain or hypoglycemia (1,2). The pharmacokinetic and pharmacodynamic profile of new insulin glargine 300 U/mL (Gla-300) results in a more prolonged duration of action compared with insulin glargine 100 U/mL (Gla-100) due to a more gradual release rate following subcutaneous injection, which provides a duration of action >24 hours (12,13). Data on the efficacy and safety of Gla-300 compared with Gla-100 are available from the treat-to-target EDITION program, aimed at

5 demonstrating non-inferiority for A1C in several phase 3 studies conducted in different populations of diabetes patients. These patient populations have included those receiving insulin as basal-bolus and basal only therapy, patients who are insulin naïve, and patients with type 1 diabetes and T2D. Published EDITION studies have shown that, overall, Gla-300 and Gla- 100 have similar glycemic efficacy, but that Gla-300 has lower hypoglycemia rates compared with Gla-100 (14 16). Analyses of data on the comparative effects of Gla-300 and Gla-100 in specific age groups, however, are lacking. The objective of the present analysis, therefore, was to assess the efficacy, hypoglycemia rates, and weight/body mass index (BMI) in patients with T2D across different age groups who were receiving treatment with Gla-300 and Gla-100 using data from the EDITION 2 and EDITION 3 studies. METHODS Study Design and Patients EDITION 2 (NCT ) and EDITION 3 (NCT ) were 6-month, open-label, efficacy and safety studies comparing Gla-300 and Gla-100 (both once daily) in patients with T2D; both studies had 6-month safety extensions providing 12 months of follow-up (15,16). In EDITION 2, Gla-300 was administered using a modified SoloSTAR pen injection device, and in EDITION 3 a modified TactiPen pen injector was used. Gla-100 was administered using a SoloSTAR pen in both studies.

6 In both studies, patients with T2D were eligible for inclusion if they were aged 18 years (17), were diagnosed with diabetes 1 year prior to screening, and had A1C 7.0% (53 mmol/mol). In EDITION 2, eligible patients were required to have been using basal insulin ( 42 U/day of either Gla-100 or neutral protamine Hagedorn insulin) plus oral antidiabetes drugs (OADs) for 6 months. In EDITION 3, eligible patients were required to have been using OADs for 6 months and be insulin naïve; use of sulfonylureas and glinides was discontinued, if applicable. Patients were excluded from EDITION 2 if they had A1C >10.0% (86 mmol/mol), and from EDITION 3 if they had A1C >11.0% (97 mmol/mol). Data were stratified for the analyses by patient age group (<55, 55 to <60, 60 to <65, and 65 years). Assessments The following outcomes were assessed at 6 and 12 months for pooled data from EDITION 2 and EDITION 3: A1C (%) change; percentage of patients achieving A1C <7.5% (58 mmol/mol) and <7.0% (53 mmol/mol); the incidence (% of patients with 1 hypoglycemic event) and event rates of confirmed hypoglycemia (defined as blood glucose 70 mg/dl) and/or severe hypoglycemia (defined as events requiring assistance by another person to administer carbohydrate, glucagon, or other therapy); change in weight (kg) and BMI (kg/m 2 ); and change in basal insulin dose (U/day and U/kg/day). Statistical Analysis

7 A modified intention-to-treat (mitt) population was used for efficacy assessment, defined as all randomized patients in EDITION 2 and EDITION 3 with T2D who received 1 dose of study insulin, and who had baseline and 1 post-baseline assessments. Descriptive statistics, trending analysis, and regression modeling analyses were conducted. The adjusted rate of patients achieving A1C target was derived from a generalized linear model. This analysis included age group, treatment, region (US or non-us), and their interaction as fixed effects; baseline A1C was included as a covariate, and the study (EDITION 2 or EDITION 3) was also included as a factor for modeling. The adjusted hypoglycemia incidence (percentage of patients with 1 event) and event rates (events/patient-year) were derived from a generalized linear model. This analysis included age group, treatment, region, and their interaction as fixed effects; baseline BMI and duration of diabetes were included as covariates, and the study (EDITION 2 or EDITION 3) was also included as a factor for modeling. The adjusted hypoglycemia incidence by A1C levels was also derived from a generalized linear model that included A1C response, treatment, and their interaction as fixed effects; baseline BMI and duration of diabetes were included as covariates. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC, USA). RESULTS Baseline Demographics and Clinical Characteristics A total of 1,670 patients were included in this mitt analysis, split into the following age groups: <55 years (n = 553), 55 to <60 years (n = 343), 60 to <65 years (n = 364), 65 years (n

8 = 410). Patient demographics and characteristics at baseline for the EDITION 2 and EDITION 3 studies and the pooled data are shown (Table 1); these data were reported previously for the EDITION 2 and EDITION 3 studies (15,16). Overall, mean (standard deviation [SD]) patient age was 58.0 (9.63) years, ranging from 24.0 to 87.0 years, mean (SD) A1C was 8.4% (68 mmol/mol) (1.0%), and mean (SD) duration of T2D was 11.2 (6.8) years. Mean (SD) BMI was 33.8 (6.59) kg/m 2, indicating that this population was obese. Efficacy At both 6 and 12 months of follow-up, A1C reductions from baseline were similar for Gla-300 and Gla-100 across all age groups, as were the proportions of patients achieving A1C <7.5% (58 mmol/mol) and <7.0% (53 mmol/mol) (Tables 2 3). Hypoglycemia Generalized linear model analysis showed that the incidence of confirmed and/or severe hypoglycemia at 6 months was lower with Gla-300 than with Gla-100 across all age groups (P<.001), as was the hypoglycemia event rate (P<.001) (Table 2). The incidence of hypoglycemia at 6 months ranged from % with Gla-300 versus % with Gla-100, and the hypoglycemia event rate at 6 months ranged from events/patient-year with Gla-300 versus events/patient-year with Gla-100. The incidence of hypoglycemia was also lower for Gla-300 than with Gla-100 when patients were stratified by achieved A1C levels. At 6

9 months, the hypoglycemia incidence in patients with final A1C <7.0% (53 mmol/mol) was 65.8% for Gla-300 and 73.6% for Gla-100, versus 56.5% for Gla-300 and 65.4% for Gla-100 in patients with final A1C 7.0% (53 mmol/mol) (P<.001 for treatment comparison [logistic regression, after adjusting for A1C responder status (<7.0% [53 mmol/mol] or 7.0% [53 mmol/mol]), baseline BMI, and duration of diabetes]). Similarly, the hypoglycemia event rates at 6 months for patients who achieved A1C <7% (53 mmol/mol) were 10.5 for Gla-300 versus 15.7 for Gla- 100, and, for patients with final A1C 7.0% (53 mmol/mol), 8.3 for Gla-300 and 10.6 for Gla-100 (P<.001 for treatment comparison [negative binomial regression, after adjusting for A1C responder status, baseline BMI, and duration of diabetes]). The incidence of hypoglycemia at 12 months was also significantly lower with Gla-300 than with Gla-100 across all age groups (P<.001), as was the hypoglycemia event rate (P = 0.005) (Table 3). The incidence of hypoglycemia at 12 months ranged from % with Gla-300 versus % with Gla-100, and the hypoglycemia event rate at 12 months ranged from events/patient-year with Gla-300 versus events/patient-year with Gla The generalized linear model analysis also showed trends towards a higher incidence and an increased event rate of hypoglycemia with increasing age at 6 months (P =.105 and P =.057, respectively) and 12 months (P =.208 and P =.080, respectively). At 12 months, for patients achieving A1C <7.0% (53 mmol/mol), hypoglycemia incidence was 67.3% for Gla-300 and 76.9% for Gla-100, versus 61.4% for Gla-300 and 68.3% for Gla-100 for patients with final A1C 7.0% (53 mmol/mol) (P<.001 for treatment comparison [logistic regression, after adjusting for A1C responder status, baseline BMI, and duration of diabetes]). The hypoglycemia event rates at 12

10 months were 14.0 events/patient-year for Gla-300 and 18.7 events/patient-year for Gla-100, for patients with final A1C <7.0% (53 mmol/mol), versus 10.5 events/patient-year for Gla-300 and 12.8 events/patient-year for Gla-100 for patients with final A1C 7.0% (53 mmol/mol) (P =.006 for treatment comparison [negative binomial regression, after adjusting for A1C responder status, baseline BMI, and duration of diabetes]). As expected, the incidence and rate of severe hypoglycemia events were quite low in both arms, given patients were on OADs only or OADs with basal insulin, and under stringent constraints of randomized controlled trial settings. Weight and Insulin Dose There was less weight gain in patients on Gla-300 than in those on Gla-100 at 6 months (P =.027) and 12 months (P =.021), as shown by generalized linear model analysis (Table 2 and Table 3). At 6 months, mean weight change from baseline ranged from 0.18 kg to kg with Gla-300, and kg to kg with Gla-100. At 12 months, mean weight change from baseline ranged from kg to kg with Gla-300, and kg to kg with Gla-100. Generalized linear model analysis also showed that weight change was smaller with increasing age at both 6 and 12 months (both, P<.001) (Table 2 and Table 3). There was a slight increase in the mean insulin dose and weight-adjusted mean insulin dose with both Gla-300 and Gla-100 from 6 months to 12 months (Tables 2 3). At 6 months, mean change in dose ranged from 30.7 U/day to 43.1 U/day with Gla-300, and from 20.5 U/day to 33.0 U/day with Gla-100. At 12 months, mean change in dose ranged from 34.2 U/day to

11 48.0 U/day with Gla-300, and from 22.2 U/day to 37.0 U/day with Gla-100. At both time points, the change in dose decreased with increasing age. At 6 and 12 months, smaller changes in dose were seen with increasing age (P =.002 and P =.003, respectively). Regarding weight-adjusted insulin dose, at 6 months, mean change ranged from 0.33 U/kg/day to 0.42 U/kg/day with Gla-300, and from 0.21 U/kg/day to 0.32 U/kg/day with Gla At 12 months, mean change in weight-adjusted insulin dose ranged from 0.36 U/kg/day to 0.46 U/kg/day with Gla-300, and from 0.22 U/kg/day to 0.35 U/kg/day with Gla-100. Weightcorrected insulin dose changes were significantly different between treatment arms, both at 6 and 12 months (P<.001 for both), after adjusting for study, age group, baseline A1C, dose/kg, BMI, and duration (Table 2 and Table 3). Further, this analysis demonstrated that changes in insulin dose/kg/day decreased with increasing age, both at 6 and 12 months (P =.017 and P =.011, respectively), after adjusting for study, treatment arm, baseline A1C, dose/kg, BMI, and duration (Table 2 and Table 3). DISCUSSION This analysis of data from open-label, efficacy and safety studies in patients with T2D revealed that Gla-300 and Gla-100 had similar efficacy in reducing A1C in younger and older age groups, and that there was less hypoglycemia with Gla-300 at both 6 and 12 months. Specifically, A1C reductions from baseline were similar for Gla-300 and Gla-100 across all age groups, as was the proportion of patients achieving A1C <7.5% (58 mmol/mol) and <7.0% (53

12 mmol/mol). These findings confirm that the efficacy of the pharmacokinetic/pharmacodynamic profile of Gla-300 is maintained in an aging T2D population. The incidence of hypoglycemia and the hypoglycemia event rate were lower with Gla- 300 than with Gla-100 across all age groups, which is noteworthy given the tight glycemic control required for both trials (14,15). The improved pharmacokinetic/pharmacodynamic profile of Gla-300 compared with Gla-100 specifically a more constant and prolonged duration of action (12,13) most likely accounts for its reduced risk of hypoglycemia. These data support those seen in another study by Lingvay et al, which also used data from the EDITION 2 and EDITION 3 (18). The study compared Gla-300 with Gla-100 in patients with T2D stratified according to whether they were considered high risk ( 65 years or had 1 Healthcare Effectiveness Data and Information Set [HEDIS]-defined comborbidity), or low-risk (<65 years with no HEDIS-derived comorbidities) for hypoglycemia. It showed consistent, although statistically non-significant, trends favouring Gla-300 with regards to burden of hypoglycemia regardless of prior insulin experience. While for our analysis we pooled EDITION 2 and EDITION 3 data, Lingvay et al decided against this, keeping the analyses separate. This may have resulted in reduced power and therefore their results being non-significant (18). Weight is an important factor in both the development and management of T2D (10). The prevalence of T2D is closely linked to excess weight, and it has been estimated that up to 90% of patients with T2D are overweight (19). Insulin therapy may result in weight gain (20), making it an issue of concern among patients with T2D and their physicians and possibly

13 creating a psychological barrier to the initiation of insulin and negatively affecting adherence with therapy (10,21). It has become increasingly clear, therefore, that equal attention should be given to weight management and glycemic control in T2D patients (22); potential weight gain should be considered when tailoring therapy for individual patients, and therapy-related weight gain should be minimized. The T2D patient population investigated in the present analysis were obese, with a mean BMI of 33.8 kg/m 2 at baseline (23). It is likely that such a patient population and their physicians would be concerned about insulin-related weight gain. Positive findings from the present analysis were that despite greater increases in insulin dose, Gla-300 did not cause any more, and in fact was associated with significantly less, weight gain than Gla-100 across all age groups. Weight change was shown to decrease significantly with increasing age. In general, weight loss is not recommended in many older and frailer patients with diabetes. However, less weight gain following insulin therapy is beneficial for both old and young adults. Taken together, these findings suggest that Gla-300 may be an appropriate choice when tailoring insulin therapy for aging, overweight T2D patients. Limitations that should be taken into account when considering the findings of this analysis include the open-label design of the study, the relatively short duration of follow-up, and the limited generalizability of the results to other patient populations. In addition, some hypoglycemic events may have been missed if patients self-treated without documenting the glucose level for confirmation of the hypoglycemic event. The age limit of approximately 75 years in the EDITION studies means that any findings from this analysis may not be directly

14 applicable to the very elderly. It is expected that several ongoing or recently completed clinical trials with Gla-300 will provide additional data for the older population. A phase 3 clinical trial (SENIOR [NCT ]), assessing the safety and efficacy of Gla-300 in older patients ( 65 years) with T2D has recently been completed, and three real-world phase 4 clinical trials with Gla-300 (ACHIEVE CONTROL [NCT ], REACH CONTROL [NCT ], and REGAIN CONTROL [NCT ]) involving more than 4,500 patients with T2D are currently being conducted. CONCLUSION We observed sustained efficacy with lower risk of hypoglycemia after 12 months among patients with T2D receiving Gla-300 compared with those receiving Gla-100. The aging diabetes population may benefit from treatment with Gla-300, which shows a lower rate of hypoglycemia and less weight gain, while maintaining similar efficacy compared with Gla-100.

15 ACKNOWLEDGMENTS The authors received writing/editorial support in the preparation of this manuscript provided by Pim Dekker, PhD, and Lisa Longato, PhD, of Excerpta Medica, funded by Sanofi US, Inc. A prior iteration of this work was presented in poster form at the American Association of Clinical Endocrinologists (AACE) 25 th Annual Meeting & Clinical Congress May 25-29, 2016 in Orlando, Florida; the 2016 American College of Clinical Pharmacy (ACCP) Annual Meeting October 23-26, 2016 in Hollywood, Florida; and at the AACE 24 th Annual Meeting & Clinical Congress May 13-17, 2015 in Nashville, Tennessee. DISCLOSURE Dr. Munshi reports that she is a consultant for Sanofi. Dr. Gill reports that she is an employee of Sanofi US, Inc. Mr. Chao reports that he is an employee of Xinyi, Inc., under contract with Sanofi US, Inc. Dr. Nikonova reports that she is an employee of Artech Information Systems, LLC, under contract with Sanofi US, Inc. Dr. Patel reports that she participates in the speakers bureau for Sanofi US, Inc. and has received funding from Sanofi Pasteur.

16 REFERENCES 1. Fidler C, Elmelund Christensen T, Gillard S. Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs. J Med Econ. 2011;14: Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia. 2002;45: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38: Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M. Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions. Acta Diabetol. 2015;52: Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J. Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab. 2012;14:

17 7. Kachroo S, Kawabata H, Colilla S, et al. Association between hypoglycemia and fallrelated events in type 2 diabetes mellitus: analysis of a U.S. commercial database. J Manag Care Spec Pharm. 2015;21: Jaap AJ, Jones GC, McCrimmon RJ, Deary IJ, Frier BM. Perceived symptoms of hypoglycaemia in elderly type 2 diabetic patients treated with insulin. Diabet Med. 1998;15: Lipska KJ, Ross JS, Wang Y, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to JAMA Intern Med. 2014;174: Hollander PA. Insulin detemir for the treatment of obese patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2012;5: Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, Diabetes Care. 2013;36: Becker RH, Dahmen R, Bergmann K, Lehmann A, Jax T, Heise T. New insulin glargine 300 Units ml-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units ml-1. Diabetes Care. 2015;38: Shiramoto M, Eto T, Irie S, et al. Single-dose new insulin glargine 300U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes. Diabetes Obes Metab. 2015;17:

18 14. Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care. 2014;37: Yki-Järvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37: Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17: World Health Organization (WHO). Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation. Available at: Accessed October 1, Lingvay I, Chao J, Dalal MR, Meneghini LF. Efficacy and Safety of Insulin Glargine 300 U/mL Versus Insulin Glargine 100 U/mL in High-Risk and Low-Risk Patients with Type 2 Diabetes Stratified Using Common Clinical Performance Measures. Diabetes Technology & Therapeutics May 19. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world a growing challenge. N Engl J Med. 2007;356:

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20 Table 1 Baseline Demographics and Clinical Characteristics (mitt Population) for EDITION 2, EDITION 3 and Pooled Data 15,16 EDITION 2 EDITION 3 Pooled data Gla-300 Gla-100 Gla-300 Gla-100 Gla-300 Gla-100 (n = 403) (n = 405) (n = 432) (n = 430) (n = 835) (n = 835) Age, years 58 (9.1) 59 (9.2) 58 (9.8) 57 (10.3) 58 (9.5) 58 (9.8) Age groups, n (%) <55 years 135 (33.5) 121 (29.9) 138 (31.9) 159 (37.0) 273 (32.7) 280 (33.5) 55 to <60 years 75 (18.6) 100 (24.7) 87 (20.1) 81 (18.8) 162 (19.4) 181 (21.7) 60 to <65 years 107 (26.6) 82 (20.2) 94 (21.8) 81 (18.8) 201 (24.1) 163 (19.5) 65 years 86 (21.3) 102 (25.2) 113 (26.2) 109 (25.3) 199 (23.8) 211 (25.3) A1C, % 8.3 (0.86) 8.2 (0.77) 8.5 (1.05) 8.6 (1.07) 8.4 (0.97) 8.4 (0.95) Weight, kg 98.7 (22.36) 98.1 (20.69) 94.9 (23.15) 95.4 (22.63) 96.8 (22.84) 96.7 (21.74) BMI, kg/m (6.63) 34.8 (6.05) 32.8 (6.82) 33.1 (6.55) 33.7 (6.80) 34.0 (6.36) Duration of diabetes, years 12.7 (7.03) 12.5 (7.04) 10.1 (6.50) 9.5 (6.11) 11.4 (6.88) 11.0 (6.75) Starting insulin dose, U/day 62.1 (26.41) 63.9 (25.96) 18.3 (5.19) 18.6 (5.20) 39.5 (28.80) 40.6 (29.24) Abbreviations: A1C = hemoglobin A1C; BMI = body mass index; Gla-100 = insulin glargine 100 U/mL; Gla-300 = insulin glargine 300 U/mL; mitt = modified intention to treat; U = units. Values are mean (standard deviation [SD]) unless stated otherwise.

21 Table 2 Clinical Outcomes by Age Groups After 6 Months of Follow-Up (mitt Population) Using Pooled Data from EDITION 2 and EDITION 3 15,16 6 months of Gla-300 (n = 835) Gla-100 (n = 835) P P follow-up Age group, years Age group, years Gla-300 Age <55 55 to <60 60 to <65 65 <55 55 to 60 to 65 vs (n = 273) (n = 162) (n = 201) (n = 199) (n = 280) <60 <65 (n = 211) Gla-100 (n = 181) (n = 163) A1C change from BL, % 0.94 (0.060) 1.07 (0.077) 1.06 (0.069) 1.01 (0.071) 1.01 (0.060) 0.99 (0.073) 1.10 (0.077) 1.02 (0.069) Patients achieving A1C <7.5%*, % Patients achieving A1C <7.0%, % Hypoglycemia incidence, % < Hypoglycemia rate < Weight change from BL, kg 0.96 (0.210) 0.20 (0.274) 0.18 (0.243) 0.02 (0.249) 1.37 (0.209) 0.67 (0.257) 0.24 (0.270) 0.25 (0.240).027 <.00 1 Dose change from BL, U/day < (unadjusted) (2.01) (2.48) (1.93) (1.80) (1.67) (1.97) (1.93) (1.67)

22 Dose change from BL, < U/kg/day (unadjusted) (0.28) (0.26) (0.27) (0.24) (0.24) (0.23) (0.24) (0.20) Abbreviations: A1C = hemoglobin A1C; BL = baseline ; Gla-100 = insulin glargine 100 U/mL; Gla-300 = insulin glargine 300 U/mL; mitt = modified intention to treat; U = units. * 58 mmol/mol, 53 mmol/mol, events/patient-year P values were generated by generalized linear model analysis: values are mean (standard error [SE]), unless stated otherwise. Estimates defined from analyses are adjusted as described in the statistical analysis section.

23 12 months of Table 3 Clinical Outcomes by Age Groups After 12 Months of Follow-Up (mitt Population) Using Pooled Data from EDITION 2 and EDITION 3 15,16 Gla-300 (n = 796) Gla-100 (n = 799) P P follow-up Age group, years Age group, years Gla-300 Age <55 55 to <60 60 to <65 65 <55 55 to <60 60 to <65 65 vs (n = 258) (n = 156) (n = 195) (n = 187) (n = 265) (n = 175) (n = 159) (n = 200) Gla-100 A1C change from BL, % 0.77 (0.004) 0.99 (0.007) 0.86 (0.005) 0.96 (0.006) 0.81 (0.004) 0.74 (0.006) 0.84 (0.007) 0.95 (0.005) Patients achieving A1C <7.5%*, % Patients achieving A1C <7.0%, % Hypoglycemia incidence, % < Hypoglycemia rate Weight change from BL, kg 1.31 (0.015) 0.25 (0.026) 0.29 (0.020) 0.64 (0.021) 1.83 (0.015) 1.05 (0.022) 0.77 (0.025) 0.70 (0.020).021 <.001 Dose change from BL, U/day < (unadjusted) (2.48) (2.99) (2.22) (2.18) (2.01) (2.29) (2.27) (1.99) Dose change from BL, U/kg/day < (unadjusted) (0.31) (0.30) (0.3) (0.27) (0.28) (0.25) (0.28) (0.23) Abbreviations: A1C = hemoglobin A1C; BL = baseline ; Gla-100 = insulin glargine 100 U/mL; Gla-300 = insulin glargine 300 U/mL; mitt = modified intention to treat; U = units. *58 mmol/mol, 53 mmol/mol, events/patient-year

24 P values were generated by generalized linear model analysis: Values are mean (standard error [SE]), unless stated otherwise. Estimates defined from analyses are adjusted as described in the statistical analysis section.