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Aim: To explore the effects of second-line combination therapies with metformin on body weight, HbA1c and health-related quality of life, as well as the risks of hypoglycaemia and further treatment intensification in the DISCOVER study, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy., Materials and Methods: Adjusted changes from baseline in weight, HbA1c and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24 and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses., Results: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor (8.3%) or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8%-1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor or a GLP-1 receptor agonist was associated with greater weight loss (1.9, 2.9 and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < .0001). Proportions of further treatment intensification were similar across combinations (19.9%-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9%-6.4%, P < .0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU., Conclusions: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia and lower SF-36v2 scores., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

We report the prevalence and change in severity of chronic kidney disease (CKD) in DISCOVER, a global, 3-year, prospective, observational study of patients with type 2 diabetes (T2D) initiating second-line glucose-lowering therapy. CKD stages were defined according to estimated glomerular filtration rate (eGFR). Overall, 7843 patients from 35 countries had a baseline serum creatinine measurement. Of these (56.7% male; mean age: 58.1 years; mean eGFR: 87.5 mL/min/1.73 m 2 ), baseline prevalence estimates for stage 0-1, 2, 3 and 4-5 CKD were 51.4%, 37.7%, 9.4% and 1.4%, respectively. A total of 5819 patients (74.2%) also had at least one follow-up serum creatinine measurement (median time between measurements: 2.9 years, interquartile range: 1.9-3.0 years). Mean eGFR decreased slightly to 85.7 mL/min/1.73 m 2 over follow-up. CKD progression (increase of ≥1 stage) occurred in 15.7% of patients, and regression (decrease of ≥1 stage) in 12.0%. In summary, a substantial proportion of patients with T2D developed CKD or had CKD progression after the initiation of second-line therapy. Renal function should be regularly monitored in these patients, to ensure early CKD diagnosis and treatment., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus insulin degludec 100 U/mL (IDeg-100) in predefined (

Aims/hypothesis: In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881)., Methods: Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed., Results: A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were -16.2% (-23.9, -7.6) and 2.6 ml min -1 [1.73 m] -2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups., Conclusions/interpretation: Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR., Trial Registration: ClinicalTrials.gov NCT01986881.

Aims: Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow-up in patients with T2D [by presence and absence of co-existing coronary artery disease (CAD)]., Methods and Results: DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second-line glucose-lowering therapy. Among 14 057 patients with T2D from 36 countries, 289 (2.1%) had a diagnosis of HF at enrolment; median prevalence across countries was 2.0% (inter-quartile range 1.0-3.1%). Patients with HF at baseline were more likely to be older [HF vs. no HF: 67 ± 12 vs. 57 ± 12 years, standardized difference (StDiff) = 84%] and have longer duration of T2D (8.1 ± 7.2 vs. 5.6 ± 5.2 years, StDiff = 40%), CAD (44% vs. 6%, StDiff = 97%), atrial fibrillation (21% vs. 1%, StDiff = 66%), and kidney disease (23% vs. 4%, StDiff = 55%). Patients with HF were less likely to be on metformin (66% vs. 79%, StDiff = 28%) and thiazolidinediones (5.5% vs. 10.6%, StDiff = 19%) but had similar use of other glucose-lowering medications. Among 9313 patients with follow-up data, there were 70 incident cases of HF, which translates to an incidence of 2.6 cases per 1000 person years. Of these incident HF cases, 60% occurred in the absence of pre-existing or concomitant CAD, and 73% were diagnosed in the outpatient setting., Conclusions: In a large, global cohort of patients with T2D, the majority of incident cases of HF occurred in outpatients and in the absence of known CAD. These findings highlight the need for greater awareness of HF risk in patients with T2D., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain., Objective: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes., Data Sources: A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020., Study Selection: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials., Data Extraction and Synthesis: Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model., Main Outcomes and Measures: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials., Results: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction)., Conclusions and Relevance: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.

Aim: To investigate global patterns of cardiovascular risk factor control in patients with type 2 diabetes mellitus (T2D)., Methods: DISCOVER is an international, observational cohort study of patients with T2D beginning second-line glucose-lowering therapy. Risk factor management was examined among eligible patients (ie, those with the risk factor) at study baseline. Inter-country variability was estimated using median odds ratios (MORs)., Results: Among 14 343 patients with T2D from 34 countries, the mean age was 57.4 ± 12.0 years and the median (interquartile range) duration of T2D was 4.2 (2.0-8.0) years; 11.8% had documented atherosclerotic cardiovascular disease (ASCVD). Among eligible patients, blood pressure was controlled in 67.5% (9284/13756), statins were prescribed in 43.7% (5775/13208), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers were prescribed in 55.6% (5292/9512), aspirin was prescribed in 53.3% of those with established ASCVD (876/1645), and 84.4% (12 102/14343) were non-smoking. Only 21.5% of patients (3088/14343) had optimal risk factor management (defined as control of all eligible measures), with wide inter-country variability (10%-44%), even after adjusting for patient and site differences (MOR 1.47, 95% confidence interval 1.24-1.66)., Conclusion: Globally, comprehensive control of ASCVD risk factors is not being achieved in most patients, with wide variability among countries unaccounted for by patient and site differences. Better country-specific strategies are needed to implement comprehensive cardiovascular risk factor control consistently in patients with T2D to improve long-term outcomes., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes., Methods: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events., Results: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; P =0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, 0.54-1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30-0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58-1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min -1 ·1.73 m -2 , albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96])., Conclusions: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.

Aim: To assess the efficacy and safety of ertugliflozin in older patients with type 2 diabetes (T2D)., Materials and Methods: This is a post hoc analysis of patients with T2D aged less than 65 years and those aged 65 years or older who participated in randomized, double-blind, phase III studies of ertugliflozin. Efficacy was evaluated in a pooled analysis of three placebo-controlled studies (ertugliflozin monotherapy and add-on therapy). Safety was evaluated in a pooled analysis of seven placebo- and active-controlled studies (including those used for efficacy). Least-squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs)., Results: In participants aged less than 65 years, the placebo-adjusted mean changes from baseline in HbA1c, BW and SBP with ertugliflozin 5 and 15 mg at week 26 were -0.9% and -1.0%, -1.9 and -1.8 kg, and -3.7 and -3.6 mmHg, respectively; in participants aged 65 years or older they were -0.6% and -0.8%, -1.9 and -2.2 kg, and -2.7 and -3.4 mmHg, respectively. The incidences of AEs, serious AEs, discontinuations and deaths in participants aged less than 65 years and those aged 65 years or older were generally similar across the treatment groups. In patients aged 65 years or older the incidences of volume depletion AEs and genital mycotic infection were higher with ertugliflozin than with non-ertugliflozin., Conclusions: Ertugliflozin improved glycaemic control, BW and SBP in younger and older individuals with T2D and was generally well tolerated in both groups., (© 2020 John Wiley & Sons Ltd.)

Background: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established., Methods: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure., Results: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo., Conclusions: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.)., (Copyright © 2020 Massachusetts Medical Society.)

Introduction: A second-generation basal insulin analogue insulin glargine 300 U/mL (Gla-300) has been marketed in France since June 2016. This real-world study was designed to assess persistence with Gla-300 and the prevalence of related hypoglycemia requiring hospitalization as compared to first-generation basal insulins, in patients with type 2 diabetes mellitus (T2DM)., Methods: A retrospective study was conducted using data in the large French comprehensive national healthcare system claims databases. Patients with T2DM newly treated with insulin in 2016 and 2017 (2-year period) were included. Three basal insulins [Gla-300, glargine 100 U/mL (Gla-100; both branded and biosimilar) and insulin detemir (IDet)] were compared for (1) persistence until treatment discontinuation using adjusted Cox models and (2) hypoglycemia requiring hospitalization over the period of insulin exposure., Results: During the 2-year study period, in France, 181,263 patients initiated basal insulin therapy (in a basal scheme or a more complex insulin scheme), of whom 74% initiated Gla-100, 14.2% initiated IDet and 11.8% initiated Gla-300. Patient characteristics varied according to the insulin regimen in terms of age, gender, social coverage, insulin scheme, and Charlson Comorbidity Index. Overall, 72% of patients were still treated with any basal insulin after 1 year (75% in basal scheme). In all insulin treatment regimens, patients were less likely to discontinue Gla-300 as compared to Gla-100 [adjusted odds ratio (OR) 0.39, 95% confidence interval (CI) 0.37-0.41], with similar results when only the basal scheme was considered (adjusted OR 0.38, 95% CI 0.35-0.40). Persistence with IDet was similar to that with Gla-100. Patients treated with Gla-100 had higher crude hospitalization rates for hypoglycemia than those receiving Gla-300 (1.4 for 100 patients-years; OR 0.67, 95% CI 0.55-0.81); however, this difference was not statistically significant after adjustment for patient characteristics. Emergency Room (ER) visits were less frequent in patients treated with Gla-300 versus Gla-100 with or without adjustment for patient characteristics (p < 0.0001)., Conclusion: Real-world persistence for basal insulin therapy in patients with T2DM was significantly better in those on Gla-300 compared with those on Gla-100 and IDet. A trend to a lower frequency of hospitalization for hypoglycemia and ER visits, whatever the cause, was also observed in patients on Gla-300.

Aims: Using data from DISCOVER (NCT02322762; NCT02226822), a 3-year, global, observational study programme of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we assessed socioeconomic factors associated with hypoglycaemic events and fear of hypoglycaemia., Methods: Data were collected at baseline (second-line therapy initiation) and 6, 12 and 24 months. Factors associated with experiencing a hypoglycaemic event at baseline or during follow-up were determined using a hierarchical logistic regression model and an interval-censored survival analysis, respectively. Fear of hypoglycaemia was assessed using the hypoglycaemia fear survey-II (HFS-II)., Results: The overall proportion of patients reporting hypoglycaemic events during follow-up was 7.3%; this was higher in middle-income countries than in high-income countries (8.4% vs 5.8%, p < 0.001). Factors associated with an increased risk of hypoglycaemia during follow-up included living in a country with a low gross national income, use of glucose-monitoring equipment and second-line treatment with insulin, meglitinides or sulphonylureas (versus metformin). Experiencing hypoglycaemia was associated with increased HFS-II worry and overall scores., Conclusions: Our results highlight the global inequity in the treatment of type 2 diabetes. Increased risk of hypoglycaemia in middle-income countries may be explained by limited treatment options and may be underestimated because of limited access to glucose-monitoring equipment., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WR, BC, MBG, KK, MK, MVS, HW, IS and LJ are members of the DISCOVER Scientific Committee and received financial support from AstraZeneca to attend DISCOVER planning and update meetings. HC, PF and FS are employees of AstraZeneca. NH is a former employee of AstraZeneca. JC-R is an employee of Evidera. In addition, WR has received research support from Novo Nordisk; BC has received payment from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Takeda; MBG has received honoraria from Merck-Serono; KK has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda, Servier and Pfizer, research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi and Pfizer, and also acknowledges support from the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC-EM) and the NIHR Leicester Biomedical Research Centre; MK has received honoraria from Applied Therapeutics, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec Systems, Intarcia, Janssen, Novartis, Novo Nordisk, Merck (Diabetes) and Sanofi, and research support from AstraZeneca and Boehringer Ingelheim; MVS has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharpe & Dohme, Novo Nordisk, Sanofi and Servier, and research support from Novo Nordisk and Sanofi; HW has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Novartis, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho and Takeda, and research support from Abbott, Astellas Pharma, AstraZeneca, Bayer, Benefit One Health Care, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Johnson & Johnson, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nitto Boseki, Novartis, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Toyama Pharmaceutical, Takeda and Terumo Corp; IS has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Kowa, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho and Takeda Pharmaceutical, and research support from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Japan Foundation for Applied Enzymology, Japan Science and Technology Agency, Kowa, Kyowa Hakko Kirin, Midori Health Management Center, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanofi, Suzuken Memorial Foundation, and Takeda Pharmaceutical; FT is an employee of the Mid America Heart Institute and has received research support from AstraZeneca; and LJ has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Takeda, Sanofi and Roche, and research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Roche and Sanofi. OK has no disclosures to declare., (Copyright © 2020. Published by Elsevier B.V.)

Aim: Older people with type 2 diabetes (T2DM) are at an increased risk of hypoglycaemia and its consequences. However, efficacy and safety data for basal insulin therapy are limited in these individuals. This patient-level meta-analysis assessed the treatment effects of insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in people with T2DM ≥ 65 years old., Methods: Data were pooled for patients randomised to receive Gla-300 or Gla-100 in the Phase 3a, treat-to-target EDITION 1, 2 and 3 trials. Glycaemic efficacy, hypoglycaemia, changes in body weight and insulin dosage and adverse events were examined over 6 months' treatment with Gla-300 versus Gla-100 for participants aged ≥ 65 and < 65 years., Results: Of 2496 participants randomised, 662 were ≥ 65 years (Gla-300, n = 329; Gla-100, n = 333). Glycaemic control was comparable for Gla-300 and Gla-100 in participants ≥ 65 years (LS mean [95% CI] difference in HbA 1c change from baseline to month 6: 0.00 [-0.14 to 0.15] %; 0.00 [-1.53 to 1.64] mmol/mol) and < 65 years (0.00 [-0.09 to 0.08] %; 0.00 [-0.98 to 0.87] mmol/mol). Fewer participants receiving Gla-300 versus Gla-100 experienced nocturnal confirmed (≤ 3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycaemia (relative risk: ≥ 65 years: 0.70 [0.57 to 0.85]; < 65 years: 0.77 [0.68 to 0.87]). Annualised rates of nocturnal confirmed or severe hypoglycaemia were lower with Gla-300 than Gla-100 for both age groups., Conclusion: Gla-300 was associated with a reduced risk of nocturnal hypoglycaemia versus Gla-100, accompanied by comparable glycaemic improvement, for people aged ≥ 65 and < 65 years with T2DM., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Despite the availability of a large number of therapeutic options throughout the world, rates of optimal glycaemic control in adult patients with type 2 diabetes mellitus remain low. Delays in treatment intensification to insulin and low adherence to insulin regimes, which are well-documented contributors to poor glycaemic control, are in many cases driven by fear of hypoglycaemic events, weight gain and injections. Over the last 10 years, injectable glucagon-like peptide-1 receptor agonists (GLP1-RAs) have emerged as alternatives to basal insulin for treatment intensification in patients inadequately controlled with oral antidiabetic drugs. As a class, GLP1-RAs are associated with weight loss and fewer hypoglycaemic events than insulin. In addition, some of them are available in once-a-week formulations and therefore require fewer injections. However, as randomized controlled trials are not representative of everyday practice, physicians should consider the results of real-life studies to guide their treatment decisions. In this review, while significant variations in efficacy, tolerability and adherence data were noted from one study to another, rates of glycaemic control overall were low. Indeed, our present analysis has suggested that regular re-evaluations of treatment, including response, tolerability, adherence, cost and quality of life, are necessary., (Copyright © 2019. Published by Elsevier Masson SAS.)

Aim: To evaluate treatment data from DISCOVER (NCT02322762 and NCT02226822), a global, prospective, observational study programme of patients with type 2 diabetes initiating a second-line glucose-lowering therapy., Materials and Methods: Data were collected using a standardized case report form. First- and second-line treatments were assessed in 14 668 patients from 37 countries across six regions. Among patients prescribed first-line metformin monotherapy, Firth logistic regression models were used to assess factors associated with second-line treatment choices., Results: The most common first-line therapies were metformin monotherapy (57.9%) and combinations of metformin with a sulphonylurea (14.6%). The most common second-line therapies were combinations of metformin with other agents (72.2%), including dipeptidyl peptidase-4 (DPP-4) inhibitors (25.1%) or sulphonylureas (21.3%). Among patients prescribed first-line metformin monotherapy, the most common second-line therapies were combinations of metformin with a DPP-4 inhibitor [32.8%; across-region range (ARR): 2.4%-51.3%] or a sulphonylurea (30.0%; ARR: 18.3%-63.6%); only a few patients received combinations of metformin with sodium-glucose co-transporter-2 inhibitors (6.7%; ARR: 0.0%-10.8%) or glucagon-like peptide-1 receptor agonists (1.9%; ARR: 0.1%-4.5%). Both clinical and non-medical factors were associated with choice of second-line therapy after metformin monotherapy., Conclusions: Fewer patients than expected received metformin monotherapy at first line, and the use of newer therapies at second line was uncommon in some regions of the world. Patients' socioeconomic status was associated with treatment patterns, suggesting that therapy choices are influenced by cost and access., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To describe the characteristics and treatment of patients with type 2 diabetes mellitus initiating a second-line glucose-lowering therapy in the global DISCOVER study programme., Methods: DISCOVER comprises two similar 3-year prospective observational studies (NCT02322762 and NCT02226822), involving 15,992 patients initiating a second-line glucose-lowering therapy in 38 countries across six regions (Africa, Americas, South-East Asia, Eastern Mediterranean, Europe and Western Pacific)., Results: Overall, 54.2% of patients were male (across region range [ARR]: 37.7-58.6%). At baseline, mean age and time since diagnosis of type 2 diabetes mellitus were 57.2 (ARR: 53.1-61.9)and 5.6 (ARR: 4.6-6.9) years, respectively. Median glycated haemoglobin (HbA 1c ) was 63.9 mmol/mol (8.0%; ARR: 7.6-8.3%). Microvascular and macrovascular complications were reported in 18.9% (ARR: 14.5-23.5%) and 12.7% (ARR: 5.0-26.6%) of patients, respectively. First-line treatments were mostly metformin monotherapy (55.6%; ARR: 42.5-83.6%) and combinations of metformin with a sulfonylurea (14.4%; ARR: 5.8-31.1%). The most commonly prescribed second-line therapies were combinations of metformin with a dipeptidyl peptidase-4 inhibitor (23.5%; ARR: 2.2-29.6%) or a sulfonylurea (20.9%; ARR: 13.6-57.1%)., Conclusions: DISCOVER demonstrates considerable global variation in the treatment of type 2 diabetes mellitus, and a need for more aggressive risk factor control., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To evaluate the long-term efficacy and safety of ertugliflozin in adults with type 2 diabetes mellitus inadequately controlled on metformin., Materials and Methods: A 104-week Phase III, randomized double-blind study with a 26-week placebo-controlled period (Phase A) and a 78-week period (Phase B) where blinded glimepiride was added to non-rescued placebo participants with fasting fingerstick glucose ≥6.1 mmol/L. Results through week 104 are reported., Results: Mean (standard error) change in HbA1c from baseline was -0.7% (0.07) and -1.0% (0.07) at week 52; -0.6% (0.08) and -0.9% (0.08) at week 104 for ertugliflozin 5 and 15 mg. At week 52, 34.8% and 36.6% participants had HbA1c <7.0%, and 24.6% and 33.7% at week 104, for ertugliflozin 5 and 15 mg. Ertugliflozin reduced fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP) from baseline through week 104. The incidence of female genital mycotic infections (GMIs) was higher with ertugliflozin, and symptomatic hypoglycaemia was lower for ertugliflozin versus placebo/glimepiride. Minimal bone mineral density (BMD) changes were observed, similar to placebo/glimepiride, except at total hip where reduction in BMD was greater with ertugliflozin 15 mg versus placebo/glimepiride: difference in least squares means (95% CI) -0.50% (-0.95, -0.04) at week 52 and -0.84% (-1.44, -0.24) at week 104., Conclusions: Ertugliflozin maintained improvements from baseline in HbA1c, FPG, body weight and SBP through week 104. Ertugliflozin was well tolerated, with non-clinically relevant changes in BMD. Compared with placebo/glimepiride, ertugliflozin increased female GMIs, but reduced the incidence of symptomatic hypoglycaemia. ClinicalTrials.gov Identifier: NCT02033889., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Ertugliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). The VERTIS cardiovascular (CV) outcomes trial (NCT01986881) has a primary objective to demonstrate non-inferiority of ertugliflozin versus placebo on major adverse CV events: time to the first event of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to: 1) the composite outcome of CV death or hospitalization for heart failure (HF); 2) CV death; and 3) the composite outcome of renal death, dialysis/transplant, or doubling of serum creatinine from baseline., Methods: Patients ≥40 years old with T2DM (HbA1c 7.0-10.5%) and established atherosclerotic cardiovascular disease (ASCVD) of the coronary, cerebral, and/or peripheral arterial systems, were randomized 1:1:1 to once daily double-blind placebo, ertugliflozin 5 mg or 15 mg added to existing therapy., Results: 8246 patients were randomized and 8238 received at least 1 dose of investigational product. Mean age was 64.4 years, 11.0% were ≥75 years old, and mean diabetes duration was 12.9 years with screening HbA1c of 8.3%. At entry, coronary artery disease, cerebrovascular disease, and peripheral arterial disease were present in 76.3%, 23.1%, and 18.8% of patients, respectively. HF was present in 23.1%, and Stage 3 kidney disease in 21.6% of patients., Conclusion: The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD., (Copyright © 2018. Published by Elsevier Inc.)

Objectives: Our objects was to estimate the direct healthcare costs of type 2 diabetes mellitus (T2DM) in France in 2013., Methods: Data were drawn from a random sample of ≈600,000 patients registered in the French national health insurances database, which covers 90% of the French population. An algorithm was used to select patients with T2DM. Direct healthcare costs from a collective perspective were derived from the database and compared with those from a control group to estimate the cost of diabetes and related comorbidities. Overall direct costs were also compared according to the diabetes therapies used throughout the year 2013., Results: Cost analysis was available for a sample of 25,987 patients with T2DM (mean age 67.5 ± standard deviation 12.5; 53.9% male) matched with a control group of 76,406 individuals without diabetes. Overall per patient per year medical expenditures were €6506 ± 10,106 in the T2DM group as compared with €3668 ± 6954 in the control group. The cost difference between the two groups was €2838 per patient per year, mainly due to hospitalizations, medication and nursing care costs. Total per capita annual costs were lowest for patients receiving metformin monotherapy (€4153 ± 6170) and highest for those receiving insulin (€12,890). However, apart from patients receiving insulin, costs did not differ markedly across the different oral treatment patterns., Conclusion: Extrapolating these results to the whole T2DM population in France, total direct costs of diagnosed T2DM in 2013 was estimated at over €8.5 billion. This estimate highlights the substantial economic burden of this condition on society.

Aim: We evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%-10.5%) with metformin monotherapy (≥1500 mg/d for ≥8 weeks)., Methods: This was a double-blind, 26-week, multicentre study with ongoing 78-week extension (ClinicalTrials.gov identifier: NCT02033889). A total of 621 participants were randomized 1:1:1 to placebo, or ertugliflozin 5 or 15 mg/d. The primary endpoint was change from baseline at week 26 in HbA1c. Secondary efficacy endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight, systolic/diastolic blood pressure (SBP/DBP) and number of participants with HbA1c <7.0% (53 mmol/mol). Pre-specified adverse events (AEs) of special interest and percent change from baseline in bone mineral density (BMD) were also assessed at week 26., Results: At week 26, the placebo-adjusted least-squares mean change from baseline HbA1c (8.1%) was -0.7% and -0.9% for ertugliflozin 5 and 15 mg, respectively (both P < .001), to final means of 7.3% and 7.2%, respectively. The odds of HbA1c <7.0% were significantly greater in both ertugliflozin groups vs placebo. Ertugliflozin significantly reduced FPG, body weight, SBP and DBP vs placebo. The incidence of genital mycotic infections was higher in the ertugliflozin groups (female subjects: placebo, 0.9%; ertugliflozin 5 mg, 5.5%; ertugliflozin 15 mg, 6.3% [P = .032]; male subjects: 0%; 3.1%; 3.2%, respectively), as was the incidence of urinary tract infections and symptomatic hypoglycaemia. The incidence of hypovolaemia AEs was similar across groups. Ertugliflozin had no adverse impact on BMD at week 26., Conclusions: Ertugliflozin added to metformin in patients with inadequately controlled T2DM improved glycaemic control, reduced body weight and BP, but increased the incidence of genital mycotic infections., (© 2017 John Wiley & Sons Ltd.)

Aim: To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies., Materials and Methods: This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance., Results: Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was -1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, -0.45% per unit increase in HbA1c; HbA1c ≥9%, -0.87% per unit increase in HbA1c). Adjusted mean 6-month HbA1c reductions showed slight treatment differences (range, 0.92-1.09%; P < .001). Greater reductions in HbA1c were associated with second-line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P < .001])., Conclusions: Many patients with T2DM have very high HbA1c levels when initiating second-line therapy, indicating the need for earlier treatment intensification. Patient-specific factors merit consideration when making treatment decisions., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To analyse the effects of patient characteristics and different oral antidiabetes drug (OAD) use on standardised clinical outcomes in type 2 diabetes patients initiating insulin glargine 100 U/mL (Gla-100)., Materials and Methods: Patient-level data from 16 randomized, treat-to-target clinical trials that added Gla-100 to existing metformin (MET), sulfonylurea (SU) or metformin plus sulfonylurea (MET+SU) treatment in insulin-naïve patients inadequately controlled by oral therapy were analysed and patients were followed for ≥24 weeks. Change in glycated haemoglobin A1c (HbA1c) from baseline to week 24, other glycaemic endpoints and incidence of hypoglycaemia (overall, nocturnal, and severe) were analysed by age (<65 vs ≥65 years), gender (male vs female), body mass index (BMI; <25 vs ≥25 to <30 vs >30 kg/m 2 ) and concomitant OAD (MET vs SU vs MET+SU)., Results: At baseline, the overall population (N = 3188) had a mean age of 57.7 years, BMI of 30.5 kg/m 2 , HbA1c of 8.7%, fasting plasma glucose of 192 mg/dL, and 52.7% were male. Younger and older patients had similar HbA1c reductions with Gla-100 and a similar risk of hypoglycaemia. Females and patients with BMI <25 kg/m 2 were less likely to achieve HbA1c targets and more likely to experience hypoglycaemia, regardless of concomitant OAD. Adding Gla-100 to SU therapy (alone or in combination with MET) increased hypoglycaemia risk across all analyses., Conclusions: Our data suggest that female patients with type 2 diabetes and normal-weight patients treated with Gla-100 and MET ± SU are less likely to achieve glycaemic targets and, therefore, may require more clinical attention. Addition of Gla-100 to SU regimens may increase hypoglycaemia risk irrespective of age, gender, or BMI., (© 2017 John Wiley & Sons Ltd.)

Introduction: Saxagliptin is a potent, reversible inhibitor of dipeptidyl peptidase-4 that is indicated for the treatment of type 2 diabetes. The DIAPAZON study was a multicenter observational study intended to document the effectiveness, safety and patterns of saxagliptin use in France, including the saxagliptin retention rate, over 2 years of follow-up., Methods: A geographically representative sample of 304 French physicians (general practitioners and specialist endocrinologists or diabetologists) recruited 1131 adults with type 2 diabetes into an ambispective cohort; 1033 fulfilled the inclusion criteria. All had started saxagliptin during the previous 6 months or at study inclusion, and follow-up was for 24 ± 3 months after starting saxagliptin., Results: The mean age of the study population when starting saxagliptin was 61 years, and the mean HbA1c level was 8.0%; 79% had an HbA1c level ≥7%. Prior to starting saxagliptin treatment, most participants (91%) were receiving treatment with oral glucose-lowering drugs alone. The most commonly prescribed regimen at starting saxagliptin (53% of participants) was a combination of saxagliptin and metformin. The overall saxagliptin retention rate at 2 years was 79%, as estimated by the Kaplan-Meier method. The most common reasons for discontinuation were inadequate glycemic control (52%) and intolerance (22%). During the course of the study, the mean HbA1c level decreased to 7.0%, and the percentage of people with HbA1c <7% increased from 21% to 49%. The mean change in body weight was -1.8 kg. A total of 294 hypoglycemic episodes were reported in 70 participants (6.8%) during the follow-up period. Of these, 143 episodes in 41 participants (4.0%) occurred when saxagliptin was used in combination with agents associated with hypoglycemia, such as insulin, sulfonylureas or glinides., Conclusion: Saxagliptin is efficacious and well tolerated in a real-world practice setting, with almost 80% of participants remaining on treatment after 2 years., Funding: AstraZeneca, France.

Aim: Contemporary global real-world data on the management of type 2 diabetes are scarce. The global DISCOVER study program aims to describe the disease management patterns and a broad range of associated outcomes in patients with type 2 diabetes initiating a second-line glucose-lowering therapy in routine clinical practice., Methods: The DISCOVER program comprises two longitudinal observational studies involving more than 15,000 patients in 38 countries across six continents. Study sites have been selected to be representative of type 2 diabetes management in each country. Data will be collected at baseline (initiation of second-line therapy), at 6months, and yearly during a 3-year follow-up period., Results: The DISCOVER program will record patient, healthcare provider, and healthcare system characteristics, treatment patterns, and factors influencing changes in therapy. In addition, disease control (e.g. achievement of glycated hemoglobin target), management of associated risk factors (e.g. hypercholesterolemia and hypertension), and healthcare resource utilization will be recorded. Microvascular and macrovascular complications, incidence of hypoglycemic events, and patient-reported outcomes will also be captured., Conclusions: The DISCOVER program will provide insights into the current management of patients with type 2 diabetes worldwide, which will contribute to informing future clinical guidelines and improving patient care., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent cardiovascular outcome trials - the LEADER with liragutide and SUSTAIN-6 with semaglutide - have shown significant reductions of major cardiovascular (CV) events with these glucagon-like peptide (GLP)-1 receptor agonists. Progressive separation of the treatment and placebo curves, starting clearly between 12 and 18 months of the trial period, and significant reductions in the risk of myocardial infarction and stroke, indicate that the beneficial CV effects observed with GLP-1 receptor agonists could be due to an antiatherogenic effect. So far, the reasons for such an effect of GLP-1 receptor agonists have not been entirely clear, although several hypotheses may be proposed. As the reductions in glycated haemoglobin and systolic blood pressure (SBP) in these trials were modest, and both trials lasted only a short period of time, reductions in hyperglycaemia and SBP are unlikely to be involved in the beneficial CV effects of GLP-1 receptor agonists. On the other hand, their effect on lipids and, in particular, the dramatic decrease in postprandial hypertriglyceridaemia may explain their beneficial CV actions. Reduction of body weight, including a significant decrease in visceral fat in patients using GLP-1 receptor agonists, may also have beneficial CV effects by reducing chronic proatherogenic inflammation. In addition, there are in-vitro data showing a direct anti-inflammatory effect with these agents that could also be involved in their beneficial CV effects. Moreover, studies in humans have shown significant beneficial effects on ischaemic myocardium after a very short treatment period, suggesting a direct effect of GLP-1 receptor agonists on myocardium, although the precise mechanism remains unclear. Finally, as a reduction in insulin resistance has been associated with a decrease in CV risk, it cannot be ruled out that the lowering of insulin resistance induced by GLP-1 receptor agonists might also be involved in their beneficial CV actions., (© 2017 Elsevier Masson SAS. All rights reserved.)

Increased costs cannot be exclusively attributed to the consequences of insulin prescription. Any initiative designed to&#160;accelerate acquisition of patient autonomy would be likely to reduce the costs observed after switching to insulin, provided this initiative is adapted to the patient&#8217;s health profile, diabetes history and available medical resources..

Introduction: The objective of this study was to document the initiation of insulin therapy in patients with type 2 diabetes mellitus (T2DM) and its maintenance as a function of time after initiation in a French nationwide representative cohort., Methods: A retrospective cohort study was conducted on a random sample of ~600,000 beneficiaries registered in the French national health insurance database. Newly insulin treated T2DM patients were selected. Persistence was defined as remaining on insulin without discontinuation (defined over a 6 or a 12-month period)., Results: Among 1909 initiations identified in 2012/2013 (basal scheme: 61.8%, basal/rapid: 15%, other schemes: 23.2%) the average age (standard deviation) at initiation was, respectively, 67.5 (14.2), 61.8 (18.1) and 63.2 (18.4) years. Insulin was initiated by general practitioners in 39.3% and prescribed without other antidiabetic drugs in 32.0%. Persistence was studied in 1969 patients initiating insulin in 2011/2012. Among survivors, nearly 25% stopped insulin during the first year (18.4% for basal scheme). Patients discontinuing insulin were younger [64.7 years (18.5) vs 67.3 years (14.3) p = 0.0003] and less often male (45.8% vs 55.7%, p < 0.0001). A proportion of 20.2% did not receive any antidiabetic drug over 12 months after discontinuation. These high percentages were only partly explained by transient intensive insulin regimens in acutely ill patients identifiable in the database., Conclusion: We observed a high rate of early discontinuation of insulin in T2DM patients (but lower with basal insulin scheme). Further real world studies are warranted to identify factors associated with this poor persistence., Funding: This study was supported by Sanofi-France.

We conducted a pilot study to evaluate two therapeutic strategies at the time of insulin initiation in type 2 diabetic patients insufficiently controlled with metformin+insulin-secretagogues (IS, sulfonylureas or glinides). Patients were randomized to remain under the same dual therapy or to receive metformin+DPP4 inhibitors while starting insulin. Similar glycemic control was achieved in both groups. However less hypoglycemia was observed with DPP4 inhibitors despite higher doses of insulin., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aim: DIALOG assessed the prevalence and predictors of hypoglycaemia in patients with type 1 (T1DM) or insulin-treated type 2 diabetes mellitus (T2DM) in a real-life setting., Methods: In this observational study, insulin-treated patients (n=3048) completed prospective daily questionnaires reporting the frequency and consequences of severe/confirmed non-severe hypoglycaemia over 30 days. Patients (n=3743) also retrospectively reported severe hypoglycaemia over the preceding year., Results: In this prospective survey, 85.3% and 43.6% of patients with T1DM and T2DM, respectively, reported experiencing at least one confirmed hypoglycaemic event over 30 days, while 13.4% and 6.4%, respectively, reported at least one severe event. Hypoglycaemia frequency increased with longer duration of diabetes and insulin therapy. Strongly predictive factors for hypoglycaemia were previous hypoglycaemia, >2 injections/day, BMI<30kg/m(2) and duration of insulin therapy>10 years. HbA1c level was not predictive of hypoglycaemia in either T1DM or T2DM. The confirmed hypoglycaemia rate was increased in the lowest compared with the highest tertile of HbA1c in T1DM, but not T2DM. At the time of enrolment, physicians reported severe hypoglycaemia in 23.6% and 11.9% of T1DM and T2DM patients, respectively, during the preceding year; the retrospective survey yielded frequencies of 31.5% and 21.7%, respectively. Also, severe hypoglycaemia led to medical complications in 10.7% and 7.8% of events in T1DM and T2DM patients, respectively, over 30 days., Conclusion: Using a unique combined prospective and retrospective approach, the DIALOG study found a relatively high frequency of hypoglycaemia among insulin-treated patients. These findings emphasize the importance of a patient-centred approach for managing diabetes in which hypoglycaemia risk evaluation is critical., Trial Registration: ClinicalTrials.gov: NCT01628341., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Aim: To compare safety and efficacy of insulin glargine and liraglutide in patients with type 2 diabetes (T2DM)., Methods: This randomized, multinational, open-label trial included subjects treated for T2DM with metformin ± sulphonylurea, who had glycated haemoglobin (HbA1c) levels of 7.5-12%. Subjects were assigned to 24 weeks of insulin glargine, titrated to target fasting plasma glucose of 4.0-5.5 mmol/L or liraglutide, escalated to the highest approved clinical dose of 1.8 mg daily. The trial was powered to detect superiority of glargine over liraglutide in percentage of people reaching HbA1c <7%., Results: The mean [standard deviation (s.d.)] age of the participants was 57 (9) years, the duration of diabetes was 9 (6) years, body mass index was 31.9 (4.2) kg/m(2) and HbA1c level was 9.0 (1.1)%. Equal numbers (n = 489) were allocated to glargine and liraglutide. Similar numbers of subjects in both groups attained an HbA1c level of <7% (48.4 vs. 45.9%); therefore, superiority of glargine over liraglutide was not observed (p = 0.44). Subjects treated with glargine had greater reductions of HbA1c [-1.94% (0.05) and -1.79% (0.05); p = 0.019] and fasting plasma glucose [6.2 (1.6) and 7.9 (2.2) mmol/L; p < 0.001] than those receiving liraglutide. The liraglutide group reported a greater number of gastrointestinal treatment-emergent adverse events (p < 0.001). The mean (s.d.) weight change was +2.0 (4.0) kg for glargine and -3.0 (3.6) kg for liraglutide (p < 0.001). Symptomatic hypoglycaemia was more common with glargine (p < 0.001). A greater number of subjects in the liraglutide arm withdrew as a result of adverse events (p < 0.001)., Conclusion: Adding either insulin glargine or liraglutide to subjects with poorly controlled T2DM reduces HbA1c substantially, with nearly half of subjects reaching target levels of 7%., (© 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: SGLT1 is the primary transporter responsible for the absorption of glucose and galactose in the intestine, while SGLT2 and SGLT1 are both involved in the renal reabsorption of glucose. SGLT2 inhibitors are a new class of oral antidiabetic drugs, acting by increasing urinary glucose excretion (UGE). They offer the advantages of a reduced risk of hypoglycaemia, a decrease in body weight and blood pressure and an efficacy at all stages of type 2 diabetes (T2DM)., Areas Covered: Herein, the authors focus specifically on sotagliflozin (LX4211), the first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English were selected as the basis of this review. Clinical trials were identified using the Clinicaltrial.gov database., Expert Opinion: By a potential additional mechanism of action on intestinal glucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from SGLT2 inhibitors by reducing postprandial glucose excursion and insulin secretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on UGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 inhibitors on HbA1C reduction, with a similar safety profile in short-term studies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 development as an adjuvant treatment in patients with T1DM after positive results from a pilot study.

Objective: There is no clear consensus regarding treatment of patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. Recommended agents for triple combination therapy should have complementary mechanisms of action with minimal risk of added side effects such as weight gain and hypoglycemia. We discuss considerations in selecting triple oral therapy regimens in patients with T2DM, and review clinical trial data regarding triple oral therapy using dipeptidyl peptidase-4 (DPP-4) inhibitors., Methods: A search of the PubMed database was conducted to identify clinical trials of triple oral therapy incorporating a DPP-4 inhibitor (November 2013 to January 2015), using the following search terms: 'type 2 diabetes' AND 'alogliptin OR linagliptin OR saxagliptin OR sitagliptin OR vildagliptin' AND 'metformin'. Trials had to include adult patients with T2DM who received triple oral therapy with a DPP-4 inhibitor for ≥18 weeks. The bibliographies of retrieved articles were also searched to identify any other relevant trials., Results: A total of 17 clinical trials evaluating metformin and a DPP-4 inhibitor combined with a sulfonylurea (SU), thiazolidinedione (TZD), or sodium-glucose cotransporter 2 (SGLT2) inhibitor were identified and included in this review. Consistently, the addition of a DPP-4 inhibitor to metformin and SU, TZD, or SGLT2 inhibitor therapy improved glycemic measures, and these combinations were generally well tolerated. An increased incidence of hypoglycemia was reported for combinations that included an SU., Conclusions: Triple oral therapy that includes a DPP-4 inhibitor is a valid option for patients with T2DM not adequately controlled with dual combination therapy, and offers an alternative to insulin therapy. Triple oral therapy with a DPP-4 inhibitor, metformin, and a TZD or SGLT2 inhibitor should be considered when avoidance of hypoglycemia is a primary goal.

Aims: The efficacy of the once-daily prandial GLP-1 receptor agonist lixisenatide plus basal insulin in T2DM was assessed by pooling results of phase III trials., Methods: A meta-analysis was performed of results from three trials in the GetGoal clinical program concerning lixisenatide or placebo plus basal insulin with/without OADs. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints were change in PPG, FPG, insulin dose, and weight from baseline to week 24. Hypoglycemia rates and several composite endpoints were assessed., Results: Lixisenatide plus basal insulin was significantly more effective than basal insulin alone at reducing HbA1c at 24 weeks. Composite and secondary endpoints were improved significantly with lixisenatide plus basal insulin, with the exception of FPG, which showed no significant difference between the groups. Lixisenatide plus basal insulin was associated with an increased incidence of hypoglycemia versus basal insulin alone., Conclusions: Lixisenatide plus basal insulin resulted in significant improvement in glycemic control versus basal insulin alone, particularly in terms of controlling PPG. Prandial lixisenatide in combination with basal insulin is a suitable option for treatment intensification in patients with T2DM insufficiently controlled with basal insulin, as these agents have complementary effects on PPG and FPG, respectively., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Aims: T-emerge 2 was a randomized, open-label, 24-week trial comparing subcutaneous taspoglutide 10 mg weekly (Taspo10), taspoglutide 20 mg weekly (Taspo20; titrated after 4 weeks of Taspo10), with exenatide 10 mcg BID (Exe; after 4 weeks of Exe 5 mcg) in patients inadequately controlled on metformin, a thiazolidinedione, or both. T-emerge 2 showed that once-weekly Taspo provided better glycaemic control than Exe. This report focuses on a subset of T-emerge 2 participants undergoing a standardized liquid meal comparing Taspo to Exe, which has been previously shown to lower postprandial glucose., Methods: Meal tolerance tests (MTT) were performed at baseline and at week 24 in a subset of Taspo10, Taspo20 and Exe patients (n = 42, 39 and 67, respectively). Blood samples for glucose, insulin, glucagon and C-peptide were obtained before and after (30, 60, 90, 120 and 180 min) ingestion of a standardized liquid meal., Results: The 2-h postprandial, mean 0-3 h and iAUC0-3 h glucose during the MTT was reduced to a similar extent in all groups and the time profile of the postprandial glucose showed a similar pattern. Taspo10 and Taspo20, but not Exe, significantly increased insulin from baseline (both mean and iAUC0-3 h). Although changes from baseline in C-peptide were not significant within any treatment group, the mean change from baseline (both mean 0-3 h and iAUC0-3 h) was significantly increased in Taspo10 vs. Exe. Mean glucagon showed significant decreases in all groups., Conclusion: Taspoglutide and Exe improved postprandial glucose tolerance to a similar extent but possibly with different intimate mechanisms., (© 2013 John Wiley & Sons Ltd.)

OBJECTIVE Several studies have been published in 2009 suggesting a possible association between insulin glargine and increased risk of malignancies, including breast cancer. The objective of this study was to assess the relation between the individual insulins (glargine, aspart, lispro, and human insulin) and development of breast cancer. RESEARCH DESIGN AND METHODS Seven hundred seventy-five incident cases of primary invasive or in situ carcinoma breast cancer occurring in women with diabetes from 92 centers in the U.K., Canada, and France were matched to a mean of 3.9 diabetic community control subjects (n = 3,050; recruited from 580 general practices) by country, age, recruitment date, and diabetes type and management. The main risk model was a multivariate conditional logistic regression model with case/control status as the dependent variable and individual insulin use, 8 years preceding the index date, as the independent variable, controlling for past use of any insulin, oral antidiabetes drugs, reproductive factors, lifestyle, education, hormone replacement therapy and history of contraceptive use, BMI, comorbidities, diabetes duration, and annual number of physician visits. Glargine was also compared with every other insulin by computing all ratios using the variance-covariance matrix of logistic model parameters. RESULTS Adjusted odds ratios of breast cancer for each type of insulin versus no use of that insulin were 1.04 (95% CI 0.76-1.44) for glargine, 1.23 (0.79-1.92) for lispro, 0.95 (0.64-1.40) for aspart, and 0.81 (0.55-1.20) for human insulin. Two-by-two comparisons found no difference between glargine and the different types of insulins. Insulin dosage or duration of use and tumor stage did not change the results. CONCLUSIONS This international study found no difference in the risk of developing breast cancer in patients with diabetes among the different types of insulin with short- to mid-term duration of use. Longer-term studies would be of interest.

Objective: To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes., Design: Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial., Setting: NAVIGATOR trial., Participants: Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control., Main Outcome Measures: Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment., Results: During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively)., Conclusions: Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant., Trial Registration: ClinicalTrials.gov NCT00097786.

Background: Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM)., Objective: The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin., Methods: This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment. In contrast with the goal of maintaining a stable insulin dosage during the short-term phase, during the extension phase the insulin dosage was flexible and adjusted as deemed appropriate by the investigator. The study was conducted in a clinical practice setting, including family practice and hospital sites. Patients with T2DM aged 18-78 years with glycated hemoglobin (HbA1c) 7.5-11 % on a stable insulin regimen (30-150 U/day with or without metformin) for ≥8 weeks at screening were included in the study. Patients were stratified by metformin use and randomly assigned 2:1 to oral saxagliptin 5 mg (n = 304) or placebo (n = 151) once daily. All patients who completed the initial 24 weeks of treatment were eligible to participate in the 28-week extension, regardless of whether they had required rescue treatment. The main outcome measure was change in HbA1c from baseline to week 52., Results: In general, the outcomes achieved at week 24 were sustained to week 52. Adjusted mean change from baseline HbA1c at week 52 was greater with saxagliptin (-0.75 %) versus placebo (-0.38 %); the adjusted between-group difference was -0.37 % (95 % CI -0.55 to -0.19); between-group differences were similar in patients treated with metformin (-0.37 % [95 % CI -0.59 to -0.15]) and without metformin (-0.37 % [95 % CI -0.69 to -0.04]). At week 52, a greater proportion of patients receiving saxagliptin achieved HbA1c <7 % than those receiving placebo (21.3 vs. 8.7 %; between-group difference 12.6 % [95 % CI 6.1-19.1]). The increase from baseline in mean total daily insulin dose at week 52 was numerically smaller with saxagliptin (5.67 vs 6.67 U with placebo; difference, -1.01 U [95 % CI -3.24 to 1.22]). During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66.4 % with saxagliptin and 71.5 % with placebo, the majority being mild or moderate in intensity. The most common AEs (≥5 % with saxagliptin or placebo) were urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, influenza, and pain in extremity; the incidence of each AE was similar between treatment groups. In the saxagliptin and placebo groups, the incidence of reported hypoglycemia was 22.7 and 26.5 %, respectively; the incidence of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL [≤2.77 mmol/L] with characteristic symptoms) was 7.6 and 6.6 %, respectively. Adjusted mean change from baseline body weight was +0.8 kg with saxagliptin and +0.5 kg with placebo., Conclusion: Saxagliptin 5 mg once daily as add-on to insulin, with or without concomitant metformin, produced a durable improvement in glycemic control and was well tolerated over 52 weeks of treatment.

Aims/hypothesis: The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy., Methods: In a 26 week, open-label study, 653 patients (baseline HbA1c = 8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18-79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA1c  ≥ 7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA1c  ≥ 7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA1c change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%., Results: In the PP population (522 patients included: oral strategy, n = 269; injectable strategy, n = 253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA1c decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA1c at week 26 was -1.3% (95% CI -1.4, -1.2) in the oral strategy group and -1.4% (95% CI -1.5, -1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy., Conclusions/interpretation: An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA1c and had good overall tolerability. Trial registration ClinicalTrials.gov NCT01296412 Funding The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.

As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of β-cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin-treated T2DM populations.

Objective: Taspoglutide is a long-acting glucagon-like peptide 1 receptor agonist developed for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was compared with twice-daily exenatide., Research Design and Methods: Overweight adults with inadequately controlled type 2 diabetes on metformin ± a thiazolidinedione were randomized to subcutaneous taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 µg twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in HbA(1c) after 24 weeks., Results: Mean baseline HbA(1c) was 8.1%. Both doses of taspoglutide reduced HbA(1c) significantly more than exenatide (taspoglutide 10 mg: -1.24% [SE 0.09], difference -0.26, 95% CI -0.37 to -0.15, P < 0.0001; taspoglutide 20 mg: -1.31% [0.08], difference -0.33, -0.44 to -0.22, P < 0.0001; exenatide: -0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg, -1.6 kg; taspoglutide 20 mg, -2.3 kg) as did exenatide (-2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA(1c) and weight effects were maintained after 52 weeks. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients., Conclusions: Once-weekly taspoglutide demonstrated greater glycemic control than twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions.

Objective: The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose., Research Design and Methods: In this double-blind, 24-week study, metformin-tolerant patients with T2D on metformin monotherapy were randomised to receive fixed-dose metformin 1500 mg/day, plus either add-on saxagliptin 5 mg/day (SAXA-MET) or a two-step metformin uptitration (MET-UP) to a maximum dose (2500 mg/day)., Clinical Trial Registration: NCT01006590., Main Outcome Measures: Primary: absolute change from baseline in glycated haemoglobin A(1c) (HbA(1c)) (Week 24). Secondary: proportion of patients achieving a therapeutic glycaemic response (Week 24); change from baseline in fasting plasma glucose (Week 24); safety and tolerability. Exploratory analyses comprised three patient-related questionnaires, including the validated 5-dimension Digestive Health Status Index (DHSI)., Results: A total of 286 patients were randomised: (SAXA-MET: 147; MET-UP: 139). Baseline mean (SD) HbA(1c): 7.71 (0.85; SAXA-MET); 7.80 (0.82; MET-UP). Adjusted mean reductions from baseline in HbA(1c) (Week 24): -0.47% (SAXA-MET); -0.38% (MET-UP); mean (95% CI) difference in treatment effect, -0.10% (-0.26, 0.07); p = 0.260. The proportion of patients (95% CI) achieving a therapeutic glycaemic response (HbA(1c) < 7%): 43.8% (34.8, 49.6) (SAXA-MET) vs. 35.0% (29.0, 43.8) (MET-UP). Of the five DHSI domains, mean (95% CI) differences were observed for diarrhoea-predominant score (+0.8 [-2.5, 4.0] vs. +7.9 [4.6, 11.2]) and dysmotility score (-0.5 [-2.0, 1.0] vs. +1.9 [0.3, 3.4]), (SAXA-MET and MET-UP, respectively). The most common adverse event was diarrhoea: 6.1% (SAXA-MET) vs. 12.2% (MET-UP)., Conclusions: In metformin-tolerant patients with T2D (inadequately controlled on sub-maximal metformin monotherapy), saxagliptin was well tolerated. Although HbA(1c) reduction was not significantly different between treatment groups, the lower occurrence of gastrointestinal symptoms in the SAXA-MET group suggests that saxagliptin add-on treatment may be a suitable alternative treatment strategy to metformin uptitration.

Thiazolidinediones (TZDs) are anti-diabetic drugs that act as insulin sensitizers and are used in the management of type 2 diabetes mellitus. TZDs, which are ligands for the transcription factor peroxisome proliferator-activated receptor PPARγ, have a wide spectrum of action, including modulation of glucose and lipid homeostasis, inflammation, atherosclerosis, bone remodeling and cell proliferation. Randomized clinical trials have demonstrated the efficacy and durability of the anti-hyperglycemic action of TZDs, and have suggested that the TZD pioglitazone also exerts cardioprotective action. However, the clinical use of TZDs is limited by the occurrence of several adverse events, including body-weight gain, congestive heart failure, bone fractures and possibly bladder cancer. Therefore, there is an unmet need for the development of new safer PPARγ-modulating drugs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: To describe insulin therapy in patients with diabetes, to determine treatment costs and to compare costs among treatment regimens., Methods: This observational study was performed by 734 French pharmacists. Adult patients filling an insulin prescription were invited to participate. Participants provided information on their diabetes history and management. Levels of intensification of insulin therapy were determined by the number of injections in type 1 diabetes mellitus (T1DM) patients, and by the different schemes used in type 2 (T2DM) patients, such as basal/intermediate-acting insulin only, and regimens using both basal and rapid-acting insulin. Costs were evaluated according to official medication costs, nurse visits and glucose monitoring kits., Results: A total of 361 patients with T1DM and 1902 with T2DM were enrolled in the survey. Patients with T1DM more frequently took 1-2 injections per day (46.3% of patients) and used single-dose basal insulin together with ≥1 dose of rapid insulin (43.8%). Patients with T2DM used multiple treatment regimens, with 58 different combinations documented. Most took basal/intermediate insulin only (42.5%) or combinations of basal/intermediate and rapid insulins (52.7%). Mean cost of insulin therapy was €27.4/week for T1DM and €45.4/week for T2DM. In T1DM, insulin was the biggest cost component and increased with the number of injections/day. In T2DM, nurse visits were the most important cost contributors irrespective of treatment regimen. Overall, the cost of insulin therapy increased with the complexity of the insulin schemes., Conclusion: Considerable heterogeneity is found in insulin treatment regimens used in everyday diabetes care. Payers should consider the full costs associated with the use of insulin rather than the cost of insulin alone. Treatment algorithms to harmonize insulin therapy should help to improve care, while encouraging patients to self-inject insulin should help to reduce costs., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with metformin., Methods: Adults (n = 455) with HbA(1c) 7.5-11% on stable insulin therapy (30-150 U/day ± metformin) for at least 8 weeks were stratified by metformin use and randomly assigned 2:1 to receive saxagliptin 5 mg or placebo once daily for 24 weeks. Patients were to maintain stable insulin doses but these could be decreased to reduce risk of hypoglycemia. Patients with hyperglycemia or substantially increased insulin use were rescued with a flexible insulin regimen and remained in the study. Metformin doses were kept stable. The primary efficacy endpoint was change in HbA(1c) from baseline to week 24 (or rescue)., Results: Patients treated with saxagliptin versus placebo had significantly greater reductions in adjusted mean HbA(1c) (difference: -0.41%, p < 0.0001), postprandial glucose (PPG) 180-minute area under the curve (-3829.8 mg·min/dL, p = 0.0011), and 120-minute PPG (-23.0 mg/dL, p = 0.0016) at 24 weeks. Treatment with saxagliptin resulted in similar reductions in HBA(1c) relative to placebo, irrespective of metformin treatment. At 24 weeks, difference in adjusted mean fasting plasma glucose for saxagliptin versus placebo was -4.02 mg/dL (p = 0.3958); 17.3% and 6.7% of patients in the saxagliptin and placebo groups, respectively, achieved HbA(1c) < 7%. Mean change from baseline in body weight at week 24 was 0.39 kg for saxagliptin and 0.18 kg for placebo. Hypoglycemia was reported in 18.4% and 19.9% of patients in the saxagliptin and placebo groups, respectively (confirmed hypoglycemia: 5.3%, 3.3%). Other adverse events reported in at least 5% of patients were urinary tract infection (saxagliptin, placebo: 5.9%, 6.0%), influenza (3.0%, 6.6%), and pain in extremity (1.6%, 6.0%)., Conclusions: Saxagliptin 5-mg once-daily add-on therapy improves glycemic control in T2D patients on insulin alone or combined with metformin and is generally well-tolerated. NCT00757588.