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Aims To characterize the incidence of diabetes-associated complications and assess the safety of sitagliptin in participants with chronic kidney disease ( CKD) in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin ( TECOS). Materials and methods For participants with baseline eGFR measurements (n = 14 528), baseline characteristics and safety outcomes were compared for the CKD cohort ( eGFR < 60 mL/min per 1.73 m2) vs those without CKD. Within the CKD cohort, the same analyses were performed, comparing sitagliptin- and placebo-assigned participants. Baseline characteristics were summarized for all participants, and serious adverse events were analysed in those who received at least 1 dose of study medication. Adverse events of interest and diabetes complications were summarized for the intention-to-treat population. Results CKD was present in 3324 (23%) participants at entry into TECOS. The mean ( SD) age for this CKD cohort was 68.8 (7.9) years, mean diabetes duration was 13.7 (9.0) years, and 62% were men. Incidences of serious adverse events, malignancy, bone fracture, severe hypoglycaemia and most categories of diabetes complications were higher in the CKD cohort compared with those without CKD. Over ~2.8 median years of follow-up, CKD participants assigned to sitagliptin had rates of diabetic eye disease, diabetic neuropathy, renal failure, malignancy, bone fracture, pancreatitis and severe hypoglycaemia similar to those of placebo-assigned participants. Conclusions Participants in TECOS with CKD had higher incidences of serious adverse events and diabetes complications than those without CKD. Treatment with sitagliptin was generally well tolerated, with no meaningful differences in safety outcomes observed between those with CKD assigned to sitagliptin or placebo. [ABSTRACT FROM AUTHOR]

Objective: Limited data exist regarding safety and efficacy of antihyperglycemic drugs in older patients with type 2 diabetes. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized, double-blind, placebo-controlled trial assessing the impact of sitagliptin on a primary composite outcome of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or unstable angina hospitalizations in patients with type 2 diabetes (HbA1c ≥6.5% [48 mmol/mol] and ≤8.0% [64 mmol/mol]) and cardiovascular disease. We analyzed baseline characteristics and clinical outcomes for TECOS participants aged ≥75 years.Research Design and Methods: Clinical and safety event summaries are presented for older versus younger participants and for the treatment groups within the older cohort.Results: Of 14,351 participants with age recorded, 2,004 (14%) were ≥75 years old (mean age 78.3 years [SD 3.1]), with 68% men and type 2 diabetes duration median 12.0 years (IQR 7, 21). During 2.9 years median follow-up, older participants had higher rates of the primary outcome (6.46 vs. 3.67 events per 100 person-years; hazard ratio 1.72 [95% CI 1.52-1.94]), death (2.52 [2.20-2.89]), severe hypoglycemia (1.53 [1.15-2.03]), and fractures (1.84 [1.44-2.35]). In the older cohort, sitagliptin did not significantly impact the primary composite (1.10 [0.89-1.36]), death (1.05 [0.83-1.32]), heart failure hospitalization (0.99 [0.65-1.49]), severe hypoglycemia (1.03 [0.62-1.71]), rates of acute pancreatitis and pancreatic cancer, or serious adverse events.Conclusions: Among older patients with well-controlled type 2 diabetes and cardiovascular disease, sitagliptin had neutral effects on cardiovascular risk and raised no significant safety concerns. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i).Research Design and Methods: In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, a cardiovascular safety study of sitagliptin, all suspected cases of acute pancreatitis and pancreatic cancer were collected prospectively for 14,671 participants during a median follow-up time of 3 years, and were adjudicated blindly.Results: Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96-3.88], P = 0.065; 0.107 vs. 0.056/100 patient-years), with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28-1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient-years). Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78 [95% CI 1.13-2.81], P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54 [95% CI 0.28-1.04], P = 0.07).Conclusions: Pancreatitis and pancreatic cancer were uncommon events with rates that were not statistically significantly different between the sitagliptin and placebo groups, although numerically more sitagliptin participants developed pancreatitis and fewer developed pancreatic cancer. Meta-analysis suggests a small absolute increased risk for pancreatitis with DPP-4i therapy. [ABSTRACT FROM AUTHOR]

Objective: To compare the incidence of cardiovascular events and mortality in patients with type 2 diabetes mellitus treated with sitagliptin or non-sitagliptin comparators. Methods: A post hoc assessment of cardiovascular safety in 14,611 patients was performed by pooling data from 25 double-blind studies, which randomised patients at baseline to sitagliptin 100 mg/day or a non-sitagliptin comparator (i.e., non-exposed). Included studies were limited to those at least 12 weeks in duration (range: 12 to 104 weeks). Patient-level data were used in this analysis of major adverse cardiovascular events (MACE) including ischaemic events and cardiovascular deaths. Analyses were performed in three cohorts: the entire 25-study cohort, the cohort from placebo-controlled portions of studies (n=19), and the cohort from studies comparing sitagliptin to a sulphonylurea (n=3). Results: In the entire cohort analysis, 78 patients had at least 1 reported MACE-related event, with 40 in the sitagliptin group and 38 in the non-exposed group. The exposure-adjusted incidence rate was 0.65 per 100 patient-years in the sitagliptin group and 0.74 in the non-exposed group (incidence rate ratio = 0.83 [95% confidence interval (CI): 0.53, 1.30]). In the analysis comparing sitagliptin to placebo, the exposure-adjusted incidence rate was 0.80 per 100-patient-years with sitagliptin and 0.76 with placebo (incidence rate ratio = 1.01 [95% CI: 0.55, 1.86]). In the analysis comparing sitagliptin to sulphonylurea, the exposure-adjusted incidence rate was 0.00 per 100 patient-years with sitagliptin and 0.86 with sulphonylurea (incidence rate ratio = 0.00 [95% CI: 0.00, 0.31]). Conclusion: A pooled analysis of 25 randomised clinical trials does not indicate that treatment with sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus. In a subanalysis, a higher rate of cardiovascular-related events was associated with sulphonylurea relative to sitagliptin. [ABSTRACT FROM AUTHOR]

Background: In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies. Methods: The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events. Results: Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events. Conclusions: In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to describe the pattern of comorbidities in patients with type 2 diabetes mellitus with and without atherosclerotic cardiovascular disease.Methods: This was a retrospective, cross-sectional analysis of the IQVIA Commercial Data Delivery database. Patients were ≥18 years on their last encounter between 1 October 2014 and 30 September 2015 and had either a type 2 diabetes mellitus diagnosis or a prescription for an oral diabetes medication. Atherosclerotic cardiovascular disease was confirmed by diagnosis codes. Comorbidities were identified using diagnosis codes, clinical measurements, and/or medication use.Results: A total of 1,522,526 type 2 diabetes mellitus patients were included in the analysis, 25% of whom had atherosclerotic cardiovascular disease. The most common comorbidities were hypertension, hyperlipidemia, overweight/obesity, chronic kidney disease, congestive heart failure, and neuropathy. These were present, respectively, in the following percentages of patients with and without cardiovascular disease: 98.3 and 91.0%, 94.8 and 78.5%, 80.5 and 80.6%, 38.5 and 18.9, 20.2, and 4.3%, and 13.7 and 8.6%. Thus, the frequencies of hyperlipidemia, chronic kidney disease, and congestive heart failure were notably higher in patients with cardiovascular disease. This trend held true for patients grouped by sex, age, and race.Conclusions: Patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease have different rates of certain comorbidities compared to those without atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD). This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to efinopegdutide 10 mg or semaglutide 1 mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. Among 145 randomized participants (efinopegdutide n = 72, semaglutide n = 73), 33.1% had T2DM. At baseline, mean BMI was 34.3 kg/m2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8–78.7]) than with semaglutide (42.3% [90% CI 36.5–48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p = 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events. In patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. EudraCT: 2020-005136-30; NCT: 04944992. Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10 mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1 mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH. [Display omitted] • There are no approved therapies for fatty liver disease. • Dual glucagon/glucagon-like peptide-1 receptor agonism may be beneficial. • Efinopegdutide (dual agonist) improved liver fat content compared with semaglutide. • Efinopegdutide's tolerability profile was similar to that of semaglutide. • Efinopegdutide may be an effective treatment for fatty liver disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Marked Expansion of Exocrine and Endocrine Pancreas With Incretin Therapy in Humans With Increased Exocrine Pancreas Dysplasia and the Potential for Glucagon-Producing Neuroendocrine Tumors," by A. E. Butler et al. in the 2013 issue of "Diabetes."

Abstract: Sitagliptin and glipizide added to metformin provided similar degrees of glycemic efficacy in patients with type 2 diabetes with inadequate glycemic control on metformin monotherapy at 1 year; however, significantly more patients in the sitagliptin group achieved an A1C reduction of >0.5% without hypoglycemia and without an increase in body weight. [Copyright &y& Elsevier]

Objective: To better manage type 2 diabetes mellitus (T2DM), the tradeoff between improved glycemic control and hypoglycemia should be evaluated. The purpose of this study was to assess the relationship between hypoglycemia and hemoglobin A1c (HbA1c) in a real-world population.Research Design and Methods: Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) was a multi-center, observational study. Patients ≥30 years old using any oral anti-hyperglycemic agent were recruited from seven European and five Asian countries between 2006 and 2007. Hypoglycemia events were collected through patient-reported questionnaires. HbA1c data was collected through chart review. Logistic regression was performed to assess the relationship between hypoglycemia and the most proximate HbA1c levels adjusting for potential confounders (demographics, clinical variables, other medication use, and comorbid conditions).Results: A total of 4399 patients were recruited and analyzed. Mean age was 60 years, 52% were male, and 75% were on sulfonylureas (S.U.s). Respectively, 37% or 42% of patients reported hypoglycemia in the past 6 (Asia) or 12 months (Europe) before recruitment. Prevalence of hypoglycemia increased significantly (33% to 40%) as HbA1c decreased (p = 0.035). The same trend was also observed among S.U.-treated patients (p < 0.01). After adjusting for confounders, hypoglycemia prevalence was significantly higher for HbA1c <7.0% (odds ratio [O.R.] = 1.66 [95% C.I. 1.21, 2.28]; p = 0.002) vs. HbA1c ≥10.0%.Limitations: Our analyses pooled data from Asia and Europe, which differed in terms of the recall period for ascertaining hypoglycemia symptoms and the timing of latest HbA1c measure.Conclusions: Lower HbA1c level was associated with higher hypoglycemia prevalence among S.U.-treated patients. HbA1c level should be taken into consideration when reporting hypoglycemia prevalence. [ABSTRACT FROM AUTHOR]

Background: Patients with type 2 diabetes on metformin monotherapy frequently require treatment intensification with another anti-hyperglycemic medication over time. Previous studies have indicated that a high proportion of patients with diabetes have a significant delay in the initiation of oral add-on therapy after metformin alone fails to achieve targeted glycemic control. In this study, we evaluated the impact of the timing of treatment intensification with oral add-on drug on glycemic goal attainment among diabetic patients failing metformin monotherapy. Research design and methods: Using the General Electric (GE) Centricity Electronic Medical Record database (January 2004 through December 2009), we identified 5,870 patients with type 2 diabetes with treatment failure on metformin monotherapy - defined by a glycosylated hemoglobin (HbA1c) of ≥7.5% (index date). This cut-off of ≥ 7.5% (trigger HbA1c) was chosen rather than that of > 7.0% to ensure that selected patients were more likely to be indicated for treatment intensification with add-on drug. Continuous enrollment of one year prior and two years after index date was required to be included in the study. Add-on treatment was defined as prescription of second oral agent from any available therapeutic classes while continuing metformin. Early treatment intensification was defined as initiation of oral add-on therapy within 3 months (n = 1,012) of index date while late intensification was defined as add-on initiation between 10 and 15 months after index date (n = 461). The study outcome was defined as glycemic goal attainment (HbA1c < 7%), which was evaluated between 18 and 24 months after index date. Results: Our results suggested that at the end of the follow-up period, 47.2% of patients in the early add-on group were at glycemic goal compared to 41.7% in the late add-on group (p = 0.039). In a multivariable logistic regression model that accounted for age, gender, trigger HbA1c level, Charlson comorbidity index, anti-hypertensive and anti-hyperlipidemic drug use and history of cardiovascular disease, the adjusted odds ratio (OR) for glycemic goal attainment was 1.36 (95% confidence intervals [CI]: 1.09-1.72) comparing early add-on to late add-on treatment. This association was stronger among patients with higher trigger HbA1c at baseline; ORs of 1.53 (95% CI: 1.08-2.19) for HbA1c ≥8% and 2.63 (95% CI: 1.40-5.27) for HbA1c ≥9%. Conclusion: These results suggest that earlier use of oral add-on drug in treatment regimen helps better achieve glycemic goal attainment in patients with metformin failure. Future studies should evaluate whether earlier treatment intensification is also associated with longer term health outcomes such as risk of microvascular and macrovascular complications. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). Study Design: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10--17 years, had HbA1c 6.5%--10% (7.0%--10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. Results: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. Conclusions: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42) [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. Study Design: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%--10% (7.0%--10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. Results: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m², age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. Conclusions: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23). [ABSTRACT FROM AUTHOR]

Aims: To assess the efficacy, safety and tolerability of ipragliflozin 50 mg once daily added to sitagliptin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). Materials and Methods: The results of two clinical trials are reported. In both trials, patients had glycated haemoglobin (HbA1c) levels of 7.0% to 10.0% on sitagliptin 50 mg once daily 2 weeks prior to addition of ipragliflozin or placebo. In one trial (Trial 843), patients were randomized 1:1 to addition of blinded ipragliflozin 50 mg once daily (n = 73) or placebo (n = 70) for 24 weeks; the primary endpoint was efficacy (change in HbA1c at Week 24). In the other trial (Trial 849), open‐label ipragliflozin 50 mg once daily was added for 52 weeks (n = 77); the primary objective was to assess safety/tolerability. Results: In Trial 843, baseline characteristics were similar between groups (mean age 60.5 years, HbA1c 8.0%); after 24 weeks, adding ipragliflozin provided significantly greater reduction in HbA1c compared to placebo: least squares mean difference −0.77% (95% confidence interval −0.98, −0.57; P <0.001). In Trial 843, the incidences of adverse events (AEs) overall and prespecified AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia, and polyuria/pollakiuria) were similar between groups. In Trial 849, specific AEs with incidence ≥5% were nasopharyngitis, pollakiuria, back pain, thirst, constipation, influenza and arthralgia; drug‐related AEs reported in ≥2 patients were pollakiuria, thirst and constipation. Conclusions: Ipragliflozin 50 mg once daily added on to sitagliptin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated in Japanese patients with T2D. ClinicalTrials.gov: NCT02577003, NCT02564211. [ABSTRACT FROM AUTHOR]

Aims: To investigate the efficacy, safety and tolerability of sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). Materials and Methods: Japanese patients with T2D and glycated haemoglobin (HbA1c) 7.0% to 10.0% while treated with ipragliflozin 50 mg once daily were randomized 1:1 to additional treatment with sitagliptin 50 mg once daily (N = 70) or matching placebo (N = 71) for 24 weeks. The primary efficacy endpoint was change in HbA1c at Week 24. Secondary efficacy endpoints were changes in 2‐hour post‐meal glucose (PMG), total PMG 0‐ to 2‐hour area under the curve (AUC0‐2h), and fasting plasma glucose (FPG). Results: Baseline characteristics were similar in the two groups (mean age 55.5 years, mean baseline HbA1c 8.0%). After 24 weeks, the addition of sitagliptin provided significantly greater reduction in HbA1c compared to placebo (least squares [LS] mean difference −0.83% [95% confidence interval −1.05, −0.62]; P <0.001). Significant reductions were also observed in all secondary endpoints: LS mean differences from placebo in changes in 2‐hour PMG, total PMG AUC0‐2h, and FPG were −42.5 mg/dL, −67.0 mg·h/dL and −11.2 mg/dL, respectively (all P <0.001). The incidence of adverse events (AEs) overall and incidence of predefined AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia and polyuria/pollakiuria) were similar in the two groups. Conclusions: In Japanese patients with T2D, sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated. ClinicalTrials.gov: NCT02577016. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of adding the once‐weekly oral dipeptidyl peptidase‐4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycaemic control on insulin monotherapy. Materials and Methods: In a 52‐week clinical trial, Japanese patients on insulin monotherapy were randomized to once‐weekly omarigliptin 25 mg (N = 123) or placebo (N = 61) for a 16‐week, double‐blind, placebo‐controlled period. After Week 16, patients continued or switched to omarigliptin for a 36‐week open‐label period. Results: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were −0.61% (omarigliptin) and 0.29% (placebo); the between‐group difference was −0.90% (p <.001). At Week 52, the mean change from baseline in HbA1c was −0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug‐related AEs and discontinuation from trial medication because of an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n = 13 [10.6%]) compared with placebo (n = 4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52. Conclusion: The addition of once‐weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycaemic control throughout the trial period. ClinicalTrials.gov: NCT02906709 [ABSTRACT FROM AUTHOR]

Aims/Introduction: To assess the efficacy and safety of metformin/sitagliptin‐based dual/triple therapy in elderly Chinese patients with type 2 diabetes mellitus. Materials and Methods: This subgroup analysis included individuals aged ≥65 years from the STRATEGY study, a two‐stage study in which type 2 diabetes mellitus patients with unsatisfactory glycemic control on metformin were first treated with the dual combination of metformin and sitagliptin for 16 weeks (n = 681), and then, if glycemic control had not been achieved, were treated with a third add‐on oral antihyperglycemic drug for another 24 weeks (n = 291). The efficacy end‐point was change in glycated hemoglobin (HbA1c) in each stage, and the safety end‐point was adverse events with a focus on hypoglycemia. Results: At week 16, the change in HbA1c was −0.81% from baseline, and the percentages of patients who achieved HbA1c targets of <7% and <7.5% were 44.9 and 67.2%, respectively. After 24 weeks, a further average HbA1c reduction of −0.60% was observed with specific reductions of −0.70% with glimepiride, −0.63% with gliclazide, −0.51% with repaglinide and −0.45% with acarbose. The proportions of patients who achieved HbA1c targets of <7% and <7.5% were 65.4 and 81.3%, respectively, over the entire study. The rates of drug‐related adverse events and hypoglycemia were, respectively, 4.1 and 4.3% in the dual therapy stage, and 5.2% and 7.1% in the triple therapy stage, without occurrence of severe hypoglycemia. Conclusions: In elderly Chinese type 2 diabetes mellitus patients, metformin/sitagliptin‐based dual and triple oral therapy can provide clinically meaningful glycemic control and is generally well tolerated with a low incidence of hypoglycemia. [ABSTRACT FROM AUTHOR]

Introduction: Older patients with type 2 diabetes (T2D) are at increased risk of diabetic nephropathy and mild renal insufficiency. This analysis compared the anti-hyperglycemic efficacy and safety of sitagliptin with dapagliflozin in patients ≥ 65 years of age with T2D and mild renal insufficiency. Methods: This was a post hoc analysis of data from 410 patients ≥ 65 years old who participated in a 24-week, randomized, double-blind clinical trial (CompoSIT-R [comparison of sitagliptin with dapagliflozin in mild renal impairment]; NCT02532855) in T2D patients with mild renal insufficiency and on metformin ± a sulfonylurea; the primary efficacy end point was change in HbA1c at week 24. Results: Treatment groups were well balanced at baseline (mean HbA1c = 7.7/7.7% and eGFR = 79/76 ml/min/1.73 m2 for sitagliptin/dapagliflozin). At week 24, LS mean (95% CI) change in HbA1c and percentage of patients with HbA1c < 7% were greater with sitagliptin, − 0.48% and 41%, respectively, compared with dapagliflozin, − 0.36% and 28%; between-group differences = − 0.12% (− 0.36, 0.01) and 12.8% (3.3, 22.2) for change in HbA1c and percentage with HbA1c < 7%, respectively. The sitagliptin group had greater reductions in PPG end points, while the dapagliflozin group had greater reductions in FPG. Treatments were generally well tolerated. There were fewer drug-related adverse events (AEs) with sitagliptin than with dapagliflozin but AE profiles were otherwise similar. Conclusions: In patients ≥ 65 years of age with T2D and mild renal insufficiency with inadequate glycemic control on metformin ± sulfonylurea, treatment with sitagliptin for 24 weeks resulted in improvement in HbA1c relative to treatment with dapagliflozin that is consistent with that previously observed in the overall population. Both treatments were generally well tolerated. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To explore the factors associated with the glucose‐lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes mellitus. Materials and Methods: This was a post‐hoc analysis of pooled data from seven sitagliptin phase II and III clinical studies carried out in Japan. All studies were double‐blind, randomized, placebo‐controlled, parallel‐group and of 12‐week duration. The analysis population consisted of 1,075 type 2 diabetes mellitus patients. In two of the trials, sitagliptin 50 mg and/or 100 mg daily were used as monotherapy; in five others, sitagliptin 50 mg daily was used as add‐on treatment to ongoing pioglitazone, glimepiride, metformin, voglibose or glinides. Efficacy (reduction in hemoglobin A1c [HbA1c]) was evaluated in 12 sets of subgroups defined by demographic, glycemic, pancreatic β‐cell function and insulin resistance parameters. An analysis of covariance model was used to evaluate the interaction between each parameter and efficacy. Results: Sitagliptin consistently provided a clinically meaningful reduction in HbA1c relative to placebo across all subgroups. Within subgroups, a greater absolute HbA1c reduction was associated with higher baseline HbA1c, fasting plasma glucose and 2‐h post‐meal glucose. Lower β‐cell function, represented by homeostatic model assessment of β‐cell function and insulinogenic index, was also associated with greater HbA1c reduction. In contrast, age, sex, body mass index, duration of type 2 diabetes mellitus and insulin resistance‐related parameters did not interact with HbA1c changes. Conclusions: Sitagliptin treatment was associated with clinically meaningful improvement in glycemic control in all subgroups of Japanese patients with type 2 diabetes mellitus that were evaluated. Higher baseline glycemic status and lower baseline β‐cell function were identified as factors associated with greater HbA1c reduction after sitagliptin treatment. [ABSTRACT FROM AUTHOR]

Objective: Hypoglycemia (HG) occurs in up to 60% of patients with diabetes mellitus (DM) each year. We assessed a HG alert tool in an electronic health record system, and determined its effect on clinical practice and outcomes.Methods: The tool applied a statistical model, yielding patient-specific information about HG risk. We randomized outpatient primary-care providers (PCPs) to see or not see the alerts. Patients were assigned to study group according to the first PCP seen during four months. We assessed prescriptions, testing, and HG. Variables were compared by multinomial, logistic, or linear model. ClinicalTrials.gov ID: NCT04177147 (registered on 22 November 2019).Results: Patients (N = 3350) visited 123 intervention PCPs; 3395 patients visited 220 control PCPs. Intervention PCPs were shown 18,645 alerts (mean of 152 per PCP). Patients' mean age was 55 years, with 61% female, 49% black, and 49% Medicaid recipients. Mean baseline A1c and body mass index were similar between groups. During follow-up, the number of A1c and glucose tests, and number of new, refilled, changed, or discontinued insulin prescriptions, were highest for patients with highest risk. Per 100 patients on average, the intervention group had fewer sulfonylurea refills (6 vs. 8; p < .05) and outpatient encounters (470 vs. 502; p < .05), though the change in encounters was not significant. Frequency of HG events was unchanged.Conclusions: Informing PCPs about risk of HG led to fewer sulfonylurea refills and visits. Longer-term studies are needed to assess potential for long-term benefits. [ABSTRACT FROM AUTHOR]

Objective: Hypoglycemia occurs in 20–60% of patients with diabetes mellitus. Identifying at-risk patients can facilitate interventions to lower risk. We sought to develop a hypoglycemia prediction model. Methods: In this retrospective cohort study, urban adults prescribed a diabetes drug between 2004 and 2013 were identified. Demographic and clinical data were extracted from an electronic medical record (EMR). Laboratory tests, diagnostic codes and natural language processing (NLP) identified hypoglycemia. We compared multiple logistic regression, classification and regression trees (CART), and random forest. Models were evaluated on an independent test set or through cross-validation. Results: The 38,780 patients had mean age 57 years; 56% were female, 40% African-American and 39% uninsured. Hypoglycemia occurred in 8128 (539 identified only by NLP). In logistic regression, factors positively associated with hypoglycemia included infection, non-long-acting insulin, dementia and recent hypoglycemia. Negatively associated factors included long-acting insulin plus sulfonylurea, and age 75 or older. The models' area under curve was similar (logistic regression, 89%; CART, 88%; random forest, 90%, with ten-fold cross-validation). Conclusions: NLP improved identification of hypoglycemia. Non-long-acting insulin was an important risk factor. Decreased risk with age may reflect treatment or diminished awareness of hypoglycemia. More complex models did not improve prediction. [ABSTRACT FROM AUTHOR]

The efficacy/safety of sitagliptin (SITA) has been studied in global populations. This post hoc pooled analysis of 20 placebo (PBO)-controlled studies reports data collected specifically in East Asian populations (EAP). Results were summarized for overall EAP and subgroups defined by geography. Change from baseline in A1C was analyzed at week 12 using ANCOVA model with treatment, study, and baseline A1C terms. A1C values following initiation of rescue medication were excluded. Missing A1C values were imputed using LOCF method. Baseline characteristics were generally balanced across treatments (mean A1C 8.5%, age 55-56 years, BMI 25 kg/m2, FPG 177-179 mg/dL, duration T2D 7-8 years). After 12 weeks of SITA, all populations showed significant A1C reductions vs. PBO (Table) and the largest PBO-adjusted reduction was seen in the Japan subgroup. PBO treatment was associated with reductions in A1C in China Mainland (CM), but with increases in Japan. The percentages of SITA-treated pts with A1C <7% were 18.9%, 14.2%, 37.4% and 30.4% for overall EAP, CM, Japan and Other East Asian subgroups, respectively (all p<0.001 vs. PBO). The incidences of hypoglycemia (i.e., symptomatic/asymptomatic) were 13/981 [1.3%] and 5/816 [0.6%] for SITA and PBO, respectively. These results are consistent with previous findings in global populations. Disclosure: J.M. Conceicao: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Merck Sharp & Dohme Corp. C.D. Gonzalez: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. J. Ahn: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Merck Sharp & Dohme Corp. S. Tokita: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Merck Sharp & Dohme Corp. Y. Zhang: Employee; Self; Merck Sharp & Dohme Corp. R. Zhang: Employee; Self; Merck Sharp & Dohme Corp. R.L. Lam: Employee; Self; Merck & Co., Inc. A. Pong: None. Funding: Merck & Co., Inc. [ABSTRACT FROM AUTHOR]

Objective: Hypoglycemia occurs in 20-60% of patients with diabetes mellitus. Identifying at-risk patients can facilitate interventions to lower risk. We sought to develop a hypoglycemia prediction model. Methods: In this retrospective cohort study, urban adults prescribed a diabetes drug between 2004 and 2013 were identified. Demographic and clinical data were extracted from an electronic medical record (EMR). Laboratory tests, diagnostic codes and natural language processing (NLP) identified hypoglycemia. We compared multiple logistic regression, classification and regression trees (CART), and random forest. Models were evaluated on an independent test set or through cross-validation. Results: The 38,780 patients had mean age 57 years; 56% were female, 40% African-American and 39% uninsured. Hypoglycemia occurred in 8128 (539 identified only by NLP). In logistic regression, factors positively associated with hypoglycemia included infection, non-long-acting insulin, dementia and recent hypoglycemia. Negatively associated factors included long-acting insulin plus sulfonylurea, and age 75 or older. The models' area under curve was similar (logistic regression, 89%; CART, 88%; random forest, 90%, with ten-fold cross-validation). Conclusions: NLP improved identification of hypoglycemia. Non-long-acting insulin was an important risk factor. Decreased risk with age may reflect treatment or diminished awareness of hypoglycemia. More complex models did not improve prediction. [ABSTRACT FROM AUTHOR]

Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0-9.0% on metformin ≥1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104. Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were -0.3% (-0.4, -0.2), -0.4% (-0.5, -0.3) and -0.4% (-0.5, -0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups. Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks. [ABSTRACT FROM AUTHOR]

Aims: To characterize the glycaemic efficacy and safety of initiation of the dipeptidyl peptidase‐4 inhibitor sitagliptin during metformin dose escalation in people with type 2 diabetes (T2D) not at glycated haemoglobin (HbA1c) goal on a sub‐maximal dose of metformin. Materials and methods: Study participants with HbA1c ≥58 mmol/mol and ≤97 mmol/mol (≥7.5% and ≤11.0%) while on 1000 mg/d metformin were randomized to sitagliptin 100 mg once daily or placebo. All were to uptitrate metformin to 2000 mg/d. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is superior to placebo when initiated during uptitration of metformin in reducing HbA1c at week 20. [ClinicalTrials.gov Identifier: NCT02791490, EudraCT: 2015‐004224‐59] Results: A total of 458 participants (mean HbA1c 71.1 mmol/mol [8.7%], T2D duration 6.3 years) were treated. After 20 weeks, the least squares (LS) mean changes from baseline in HbA1c were −12.1 mmol/mol (−14.0, −10.1) (−1.10% [−1.28, −0.93]) and −7.6 mmol/mol (−9.6, −5.6) (−0.69% [−0.88, −0.51]) with sitagliptin and placebo, respectively; the between‐group difference in LS mean changes from baseline HbA1c was −4.5 mmol/mol (−6.5, −2.5) (−0.41% [−0.59, −0.23]); P < 0.001. The likelihood of having HbA1c <53 mmol/mol (<7.0%) at week 20 was higher in the sitagliptin group than in the placebo group in the overall population (relative risk 1.7, P = 0.002) and in those with a baseline HbA1c ≥69 mmol/mol (≥8.5%) (relative risk 2.4, P = 0.026). There were no notable differences between groups with regard to adverse events overall, hypoglycaemia events, changes in body weight or other safety variables. Conclusion: In participants not at HbA1c goal on a sub‐maximal dose of metformin, addition of sitagliptin at the time of metformin dose uptitration improved glycaemic response and HbA1c goal attainment, with similar safety and tolerability, compared to metformin uptitration alone. [ABSTRACT FROM AUTHOR]

Aims: To compare the effects of continuing versus discontinuing sitagliptin when initiating and intensively titrating insulin glargine. Materials and methods: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/d) in combination with a dipeptidyl peptidase‐4 (DPP‐4) inhibitor and/or a sulphonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP‐4 inhibitors and sulphonylureas) and stabilized during a run‐in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0 to 5.6 mmol/L. Results: A total of 743 participants (mean glycated haemoglobin [HbA1c] 72.6 mmol/mol [8.8%], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 51.4 mmol/mol (6.85%) and −20.5 mmol/mol (−1.88%) in the sitagliptin group and 56.4 mmol/mol (7.31%) and −15.5 mmol/mol (−1.42%) in the placebo group; the difference in LS mean changes from baseline HbA1c was −5.0 mmol/mol (−0.46%; P < 0.001). The percentage of participants with HbA1c <53 mmol/mol (<7.0%) was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycaemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups. Conclusion: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycaemia. ClinicalTrials.gov Identifier: NCT02738879. [ABSTRACT FROM AUTHOR]

To improve understanding of the safety and efficacy of adding sitagliptin to treatment of patients with type 2 diabetes taking premixed insulin, data from patients using premixed insulin ± metformin (screening HbA1c ≥7.5% and ≤11%) in either of two clinical trials in which sitagliptin 100 mg once‐daily or placebo was added to various formulations of insulin treatment, were analysed. In both trials, insulin doses were to remain stable throughout the 24‐week trial period. At week 24, the between‐group difference (sitagliptin ‐ placebo) in the least squares mean (95% confidence intervals) change from baseline in HbA1c in patients using premixed insulin was −0.43% (−0.58, −0.28), P <0.001. Adverse events were generally similar between the treatment groups. The incidence of symptomatic hypoglycaemia was slightly higher with sitagliptin, and the incidence of hypoglycaemia requiring medical attention was slightly higher with placebo; in both cases the difference was not statistically significant. The data from this pooled analysis confirm the utility of sitagliptin used in combination with premixed insulin in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor sitagliptin with the sodium‐glucose transporter‐2 inhibitor dapagliflozin in patients with type 2 diabetes and mild renal insufficiency. Materials and Methods: Patients with HbA1c ≥7.0 to ≤9.5% (≥53 to ≤80 mmol/mol) and estimated glomerular filtration rate ≥60 to <90 mL/min/1.73m2 on metformin (≥1500 mg/d) ± sulfonylurea were randomized to sitagliptin 100 mg (n = 307) or dapagliflozin 5 mg titrated to 10 mg (n = 306) once daily for 24 weeks. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is non‐inferior to dapagliflozin in reducing HbA1c at Week 24, with superiority to be tested if non‐inferiority is met. ClinicalTrials.gov NCT02532855. Results: Baseline mean HbA1c (% [mmol/mol]) was 7.7 (60.9) and 7.8 (61.2), and mean eGFR (mL/min/1.73m2) was 79.4 and 76.9 for the sitagliptin and dapagliflozin groups, respectively. After 24 weeks, the between‐group difference in least squares mean (95% CI) changes from baseline in HbA1c was −0.15% (−0.26, −0.04) (−1.67 mmol/mol [−2.86, −0.48]), P = 0.006, meeting the prespecified criteria for declaring both non‐inferiority and superiority of sitagliptin versus dapagliflozin. The HbA1c goal of <7% (<53 mmol/mol) was met by 43% (sitagliptin) and 27% (dapagliflozin) of patients. No meaningful between‐group difference was observed in a pre‐specified analysis of 2‐hour incremental postprandial glucose excursion. A review of adverse events (AEs) was notable for a lower incidence of drug‐related AEs with sitagliptin compared with dapagliflozin. Conclusions: In patients with type 2 diabetes, mild renal insufficiency and inadequate glycaemic control on metformin ± sulfonylurea, sitagliptin treatment resulted in greater improvement in glycaemic control compared with dapagliflozin and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Introduction: The use of antihyperglycemic agents (AHA), especially insulin and sulfonylureas (SU), is a risk factor for hypoglycemia. Despite the significant clinical and economic burdens associated with hypoglycemia and the decreasing use of SU in favor of other oral AHA, relatively little is known about hypoglycemia trends specific to the use of non-insulin AHA. We sought to estimate annual hypoglycemia event rates and costs among patients with type 2 diabetes mellitus (T2DM) who started either SU or dipeptidyl peptidase-4 inhibitors (DPP-4i) and to predict rates and costs in the absence of DPP-4i.Methods: Truven’s MarketScan Commercial Claims database was used to estimate hypoglycemia event rates and costs from 2007 to 2013. Hypoglycemia, defined using diagnosis codes, was assessed during the 12 months following SU (n = 245,201) or DPP-4i (n = 176,786) initiation by adults with T2DM. Coefficients from a Poisson regression model used to estimate the impact of patient characteristics on hypoglycemia rates for patients who started SU were used to predict rates for patients who started DPP-4i had they started SU instead.Results: Hypoglycemia events per 100 patient-years (costs per event) ranged from 5.4 ($565) in 2007 to 10.4 ($1154) in 2013 for patients starting SU; rates (costs) for patients starting DPP-4i ranged from 3.2 ($308) in 2007 to 6.4 ($482) in 2013. Predicted hypoglycemia rates would have been 5.3-9.9 per 100 person-years for patients who started DPP-4i had they started SU instead. Starting DPP-4i, rather than SU, would have resulted in national savings of $750.3 million in healthcare costs due to avoided hypoglycemia events during this period.Conclusions: Hypoglycemia rates and costs were consistently higher for patients who started SU rather than DPP-4i. The overall burden of hypoglycemia could be lowered substantially in the USA if, when feasible, patients with T2DM initiate DPP-4i instead of SU.Funding: Merck & Co., Inc., Kenilworth, NJ USA. [ABSTRACT FROM AUTHOR]

Aim: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Materials and methods: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo‐controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Results: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant‐years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71‐0.89, adjusted HR 0.64, 95% CI 0.55‐0.74; P < .0001). Women also had a significantly lower risk of secondary CV outcomes and all‐cause death. Conclusions: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: To assess the efficacy and safety profile of the dipeptidyl-peptidase-4 inhibitor sitagliptin in a population of self-identified Hispanic/Latino patients with type 2 diabetes.Methods: Data were pooled from ten randomized, double-blind studies in which subjects were treated with sitagliptin 100 mg/day (as mono- or combination therapy) or placebo, and used to evaluate the glycemic efficacy, safety, and tolerability of sitagliptin compared with placebo after 24 weeks of treatment.Results: A total of 804 Hispanic/Latino patients were included in the analysis. Baseline characteristics in the treatment groups were similar (mean baseline HbA1c of approximately 8.5%). The LS mean HbA1c changes from baseline were − 0.94% with sitagliptin and − 0.32% with placebo, and the between-group difference was − 0.62%, p < 0.001. After 24 weeks of treatment, 35% and 18% of subjects were at the HbA1c goal of < 7% in the sitagliptin and placebo groups, respectively. Body weight increased slightly in both treatment groups. Incidences of adverse events of hypoglycemia were similar and low (1.9% and 1.4% for sitagliptin and placebo, respectively) in both groups in studies in which insulin or sulfonylurea were not used and were similar (9% and 11% for sitagliptin and placebo, respectively) when all studies were included. Overall safety and tolerability of treatment with sitagliptin and placebo were similar. No clinically meaningful differences between the safety profile of sitagliptin in the Hispanic/Latino population analyzed here and broader populations previously evaluated were observed.Conclusion: In this pooled analysis of sitagliptin therapy vs placebo in Hispanic/Latino patients, sitagliptin provided significant improvement in glycemic control and was generally well tolerated.Funding: Merck & Co., Inc., Kenilworth, NJ, USA. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. Methods: In this study ( Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. Results: At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (−1.5%) and E15/S100 (−1.5%) than with individual agents (−1.0%, −1.1% and −1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin‐treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups. Conclusions: In patients with uncontrolled type 2 diabetes while using metformin, co‐administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents. [ABSTRACT FROM AUTHOR]

Aims: To explore the association between hypoglycemia severity and health-related quality of life (HRQoL), productivity, health care resource utilization (HCRU), and costs among patients with type 2 diabetes mellitus (T2DM).Methods: Data were from the 2013 US National Health and Wellness Survey. This analysis included adults with treated T2DM. Participants were categorized based upon their self-reported experience in the previous 3 months: no hypoglycemia, non-severe hypoglycemia, or severe hypoglycemia. Validated instruments were used to measure HRQoL and productivity; HCRU was based on participant-reported health care provider (HCP) and emergency department (ED) visits and hospitalizations. Multivariable models tested for trends across the severity groups.Results: The analysis included 3630 participants-1729 (47.6%) with non-severe hypoglycemia and 172 (4.7%) with severe hypoglycemia. Mental and physical component scores and utility scores were significantly associated with hypoglycemia severity (P < 0.001 for each). Similar trends were observed for absenteeism (P < 0.001), presenteeism (P = 0.005), HCP and ED visits (P ≤ 0.002), and hospitalizations (P < 0.001). Annual HCRU costs associated with increasingly severe hypoglycemia were $6908, $7132, and $15,410, respectively (P < 0.001), and productivity costs were $7248, $7493, and $12,167, respectively (P = 0.008).Conclusion: Hypoglycemia severity appears to be related to reduced HRQoL and productivity, which are mirrored by increased direct and indirect costs. [ABSTRACT FROM AUTHOR]

Aims: To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose‐lowering regimens with differing risks of hypoglycaemia. Methods: Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose‐lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all‐cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time‐dependent covariable. Results: There were 6646 deaths in a total follow‐up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95‐1.12); sulphonylurea, aHR 1.11 (95% CI 0.99‐1.25); insulin, aHR 1.47 (95% CI 1.25‐1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94‐1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13‐1.35) and including insulin, aHR 1.28 (95% CI 1.18‐1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all‐cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. Conclusions: The pattern of mortality risk across the range of HbA1c differed by glucose‐lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk. [ABSTRACT FROM AUTHOR]

Aims: To assess the efficacy and safety of once-weekly omarigliptin as monotherapy in people with type 2 diabetes mellitus (T2DM).Methods: People with T2DM not on glucose-lowering medications, or who were washed off monotherapy or low-dose dual therapy, were randomized double-blind to omarigliptin 25 mg (n=165) or matching omarigliptin placebo (n=164) for 24 weeks, followed by a 30-week period to assess continuing efficacy and safety longer-term of omarigliptin during which metformin was added to the placebo group and metformin placebo to the omarigliptin group.Results: From a mean baseline HbA1c of 8.0-8.1%, the least squares mean (95% CI) change from baseline in HbA1c at week 24 (primary endpoint) was -0.49% (-0.73, -0.24) in the omarigliptin group and -0.10% (-0.34, 0.14) in the placebo group, for a between-group difference of -0.39% (-0.59, -0.19) (p<.001). Protocol deviation in use of metformin by 38 of 252 (15%) people whose samples were available for evaluation probably attenuated glycemic efficacy results, as suggested by the LS mean difference -0.53% (-0.75, -0.32) after censoring of such participants. At 24 and 54 weeks, the incidences of adverse events (AEs) were similar in the omarigliptin and placebo groups. During 54 weeks there were no AEs of symptomatic hypoglycemia in the omarigliptin group and 5 AEs in the placebo group. Over 54 weeks, a majority of the omarigliptin treatment had a persistent reduction in HbA1c, remaining rescue-free.Conclusions: In people with T2DM, omarigliptin monotherapy improved glycemic control over 54 weeks and was generally well tolerated with a low risk of hypoglycemia. ClinicalTrials.gov Identifier: NCT01717313. EudraCT Number: 2012-003626-24. [ABSTRACT FROM AUTHOR]

Aims: To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin. Materials and Methods: In this double‐blind randomized study ( Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53‐91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) were randomized to ertugliflozin 5 mg once‐daily, 15 mg once‐daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52. Results: A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2). After 26 weeks, placebo‐adjusted least squares (LS) mean changes in HbA1c from baseline were −0.7% (−7.5 mmol/mol) and −0.8% (−8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%‐14.1%) vs placebo (0%‐1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups. Conclusions: Ertugliflozin added to metformin and sitagliptin was well‐tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks. [ABSTRACT FROM AUTHOR]

Introduction: Previous analyses concluded that patients initiating treatment with sitagliptin are older and have more comorbidities than patients initiating treatment with other oral antihyperglycemic agents (OAHAs). However, these studies focused on the general population or subjects ≤ 65 years of age. We sought to compare differences in baseline characteristics of elderly patients (≥ 65 years of age) with T2DM initiating sitagliptin vs. non-DPP-4 inhibitor (non-DPP-4i) OAHA in the MarketScan® Medicare Supplemental Database.Methods: Relevant patients were identified in the MarketScan® Medicare Supplemental Database and categorized according to the complexity of their antihyperglycemic treatment: initiating monotherapy, escalating to dual combination therapy, or escalating to triple combination therapy. Within each category, the comparison between patients initiating use of sitagliptin or non-DPP-4i OAHA was made within three age groups: 65–74, 75–84, and ≥ 85 years. Gender and comorbidity recorded within the 12 months prior to the index date (date of initiation/escalation of treatment) were assessed as baseline characteristics in each group. Between-treatment group differences in each covariate were compared using standardized differences.Results: Patients with T2DM who initiated treatment with sitagliptin tended to be older and were more likely to have a pre-treatment history of arrhythmia, congestive heart failure, peripheral vascular disease, renal failure, and stroke than those initiating non-DPP-4i OAHAs, with the most pronounced differences observed between patients initiating monotherapy in all three age groups. As treatment complexity advanced to dual combination therapy, the differences were attenuated and mostly observed in the 75–84 and ≥ 85 age groups. In patients aged 65–74 years initiating triple therapy, no differences were observed between groups.Conclusion: Patients ≥ 65 years with T2DM initiating sitagliptin tend to be older and have more comorbidities than those prescribed other classes of OAHA. Appropriate adjustment is required to minimize the impact of potential confounding and channeling bias in any comparative analyses including users of sitagliptin.Funding: Merck & Co., Inc., Kenilworth, NJ, USA. [ABSTRACT FROM AUTHOR]

Introduction: This study assessed the safety and efficacy of ertugliflozin (an oral sodium-glucose cotransporter 2 inhibitor) vs. glimepiride in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.Methods: This phase III, double-blind, non-inferiority study (NCT01999218) randomized patients with HbA1c ≥ 7.0% and ≤ 9.0% on stable metformin ≥ 1500 mg/day 1:1:1 to ertugliflozin 15 or 5 mg once-daily (QD), or glimepiride (titrated from 1 mg QD). The primary hypothesis was that ertugliflozin 15 mg was non-inferior to glimepiride on HbA1c (non-inferiority criterion: upper bound of the 95% confidence interval [CI] about the treatment difference < 0.3%).Results: Mean baseline HbA1c of randomized patients (N = 1326) was 7.8%. Mean and median doses of glimepiride were 3.0 mg/day throughout the study. At week 52, the least squares mean change (95% CI) from baseline in HbA1c was − 0.6% (− 0.7, − 0.5), − 0.6% (− 0.6, − 0.5), and − 0.7% (− 0.8, − 0.7) in the ertugliflozin 15 mg, ertugliflozin 5 mg, and glimepiride groups, respectively. The between-group difference for ertugliflozin 15 mg and glimepiride of 0.1% (− 0.0, 0.2) met the pre-specified non-inferiority criterion. Relative to glimepiride, greater body weight and systolic blood pressure (SBP) reductions were observed with ertugliflozin. The overall incidence of adverse events (AEs) was similar across groups. The incidence of symptomatic hypoglycemia and genital mycotic infection (GMI) were, respectively, lower and higher with ertugliflozin relative to glimepiride. The incidences of urinary tract infection and hypovolemia AEs were not meaningfully different among the groups.Conclusions: Ertugliflozin 15 mg was non-inferior to glimepiride in reducing HbA1c when added to metformin in patients with T2DM. Ertugliflozin had an acceptable safety profile and resulted in less hypoglycemia and more GMIs than glimepiride.Clinical Trial Registration: Clinicaltrials.gov NCT01999218. [ABSTRACT FROM AUTHOR]

Introduction: Ertugliflozin is an oral sodium-glucose cotransporter 2 inhibitor that is being developed to treat type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of co-initiation of ertugliflozin and sitagliptin compared with placebo in patients with T2DM inadequately controlled on diet and exercise.Methods: In this phase III, randomized, double-blind, multicenter, placebo-controlled 26-week study (NCT02226003), patients with T2DM and glycated hemoglobin (HbA1c) 8.0–10.5% on diet/exercise were randomized 1:1:1 to ertugliflozin 5 mg once daily (QD) and sitagliptin 100 mg QD (E5/S100), ertugliflozin 15 mg QD and sitagliptin 100 mg QD (E15/S100), or placebo. The primary efficacy endpoint was the change from baseline in HbA1c at week 26.Results: The mean baseline HbA1c of the randomized patients (n = 291) was 8.9%. At week 26, both ertugliflozin/sitagliptin treatments provided significant reductions from baseline in HbA1c compared with placebo [least squares mean HbA1c change (95% confidence intervals) from baseline was − 0.4% (− 0.7, − 0.2), − 1.6% (− 1.8, − 1.4), and − 1.7% (− 1.9, − 1.5) for placebo, E5/S100, and E15/S100, respectively]. At week 26, 8.3%, 35.7%, and 31.3% of patients receiving placebo, E5/S100, and E15/S100, respectively, had HbA1c < 7.0%. Significant reductions in fasting plasma glucose, 2-h post-prandial glucose, body weight, and systolic blood pressure were observed with both ertugliflozin/sitagliptin groups compared with placebo. The incidence of adverse events (AEs) was similar across the groups. The incidences of the pre-specified AEs of urinary tract infection, genital mycotic infection, symptomatic hypoglycemia, and hypovolemia were low and not meaningfully different across groups.Conclusion: Co-initiation of ertugliflozin with sitagliptin in patients with T2DM inadequately controlled on diet and exercise provided a clinically meaningful improvement in glycemic control over 26 weeks.Clinical Trial Registration: Clinicaltrials.gov NCT02226003. [ABSTRACT FROM AUTHOR]

Introduction: Ertugliflozin is a sodium-glucose cotransporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The safety and efficacy of ertugliflozin were evaluated over 52 weeks in patients with chronic kidney disease (CKD).Methods: In this double-blind randomized study (NCT01986855), patients with glycated hemoglobin (A1C) 7.0–10.5% and stage 3 CKD [estimated glomerular filtration rate (eGFR) ≥ 30 to < 60 mL/min/1.73 m2] who were undergoing treatment with standard diabetes therapy (or therapies) including insulin and/or sulfonylureas were randomized to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Patients on metformin underwent a pre-randomization ≥ 10-week wash-off period. The primary endpoint was change from baseline in A1C at week 26 in the overall cohort. Secondary efficacy endpoints were assessed in the stage 3A CKD cohort (eGFR ≥ 45 to < 60 mL/min/1.73 m2) at weeks 26 and 52. Safety was assessed in the overall cohort.Results: 468 patients were randomized (baseline mean A1C 8.2%). At week 26, reductions from baseline in A1C were observed across groups in the overall cohort [least squares mean changes (95% confidence interval) – 0.3% (– 0.4, – 0.1), – 0.3% (– 0.4, – 0.1), and – 0.4% (– 0.6, – 0.3) for placebo and for ertugliflozin 5 mg and 15 mg, respectively]. Prohibited use of metformin was identified in ~ 17% of patients and impacted evaluation of the primary endpoint. Greater reductions from baseline in body weight, fasting plasma glucose, and systolic blood pressure were observed with ertugliflozin versus placebo at week 26 (stage 3A CKD cohort). The incidences of urinary tract infections, genital mycotic infections, and hypoglycemia adverse events were not meaningfully different between groups. The incidence of hypovolemia-related adverse events was higher with ertugliflozin relative to placebo.Conclusion: Although surreptitious metformin use impacted the primary analysis, reductions in blood glucose and body weight were observed with ertugliflozin in patients with T2DM and stage 3 CKD; ertugliflozin had an acceptable safety profile.Funding: Merck Sharp & Dohme Corp. a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Pfizer Inc.Trial Registration: Clinicaltrials.gov identifier NCT01986855. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride. Methods: Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%. Results: From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was -0.67% in the omarigliptin group and -0.06% in the placebo group, with a between-group difference (95% CI) of -0.61% (-0.85, -0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [-1.4, -0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of -0.1 kg and -0.9 kg, respectively. Conclusion: In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated. Trial registration: ClinicalTrials.gov: NCT01704261, EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012. [ABSTRACT FROM AUTHOR]

Aims To assess the safety and efficacy of omarigliptin in Japanese patients with type 2 diabetes ( T2D). Methods In a 24-week double-blind trial, 414 patients with T2D were randomized to omarigliptin 25 mg once weekly, sitagliptin 50 mg once daily or placebo. The double-blind period was followed by a 28-week open-label extension during which all patients received omarigliptin 25 mg once weekly. Efficacy endpoints were glycated haemoglobin ( HbA1c), 2-hour postprandial glucose ( PPG) and fasting plasma glucose ( FPG) levels. Results After 24 weeks, the least squares ( LS) mean change from baseline in HbA1c was −0.66% for omarigliptin, −0.65% for sitagliptin and 0.13% for placebo. The difference in LS mean for omarigliptin vs placebo was −0.80% ( P < .001). The difference in LS mean for omarigliptin vs sitagliptin was −0.02% (95% confidence interval −0.15, 0.12), which met the criterion for non-inferiority to sitagliptin. Both active treatments provided significant reductions in FPG and 2-hour PPG compared with placebo ( P < .001). Over the 24-week double-blind period, there were no clinically meaningful differences in the incidence rates of adverse events among the treatment groups. There was 1 episode of symptomatic hypoglycaemia in the sitagliptin group and none in the omarigliptin or placebo groups. In the 28-week open-label period, omarigliptin provided persistent improvements in glycaemic control without notable change in safety profile compared with the double-blind period. Omarigliptin had no meaningful effect on body weight. Conclusions In Japanese patients with T2D, omarigliptin 25 mg once weekly provided significant glucose-lowering compared with placebo and was non-inferior to sitagliptin 50 mg once daily. Omarigliptin was generally well tolerated for up to 52 weeks. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to evaluate diabetes-related healthcare resource use and associated costs in patients with type 2 diabetes (T2DM) treated with a sulfonylurea (SU), with and without hypoglycemia.Methods: In this retrospective cohort study, patients 18years or older receiving SU monotherapy or as add-on to metformin were identified from a US healthcare claims database (MarketScan®). Of 113,743 patients (56.8% male, average age 62.6years), 61.6% were on SU/metformin dual therapy and 38.4% were on SU monotherapy, and 5% had one or more episodes of hypoglycemia during the 12-month follow-up period.Results: Adjusted for baseline characteristics, patients with hypoglycemia were three times more likely than those without to use emergency room services (OR 3.04, 95% CI: 2.82, 3.25), almost four times more likely to have inpatient admissions (OR 3.84, 95% CI: 3.58, 4.12), and had more frequent physician office visits (4.3 vs 3.0 visits, p<0.01) in the 12-month follow-up period. The adjusted annual diabetes-related medical expenditure was three times higher in patients with hypoglycemia compared with those without ($6884 vs $2392, p<0.001).Conclusions: This study demonstrated the higher healthcare utilization and costs associated with hypoglycemia in patients with T2DM treated with an SU. [ABSTRACT FROM AUTHOR]

Aims Certain treatments for type 2 diabetes mellitus cause hypoglycaemia and weight gain, and thus might counteract the benefits of intensive glucose control. We quantify the association of cardiovascular disease ( CVD) outcomes with hypoglycaemia and weight gain among patients with type 2 diabetes treated with sulfonylureas. Materials and Methods This cohort study included patients from January 2009 through December 2014 who were selected from within a deidentified nationwide electronic health records repository, including multiple provider networks and electronic medical records systems. Hypoglycaemia measures from structured data fields and free text clinical notes were categorized as serious or non-serious. Covariate adjusted Poisson regression analysis was used to assess the association between frequency of hypoglycaemia (by severity), or magnitude of weight change, and incidence of acute myocardial infarction ( AMI), congestive heart failure ( CHF) and stroke. Results Among 143 635 eligible patients, we observed 5669 cases of AMI, 14 109 incident cases of CHF and 7017 cases of stroke. Overall incidence rates were 1.53, 4.26 and 1.92 per 100 person-years for AMI, CHF and stroke, respectively. The associations between overall hypoglycaemia and each of the CVD outcomes were positive, with stronger associations observed for serious hypoglycaemia and attenuated or null associations observed for non-serious hypoglycaemia. Weight change exhibited a U-shaped association with increased risks associated with both weight loss and weight gain relative to stable weight. Conclusions This study provides evidence of increased CVD risk associated with hypoglycaemia, especially with serious hypoglycaemia events. While associations were attenuated with non-serious hypoglycaemia, the results were suggestive of a potential increased risk. [ABSTRACT FROM AUTHOR]

Purpose The objective of this clinical trial was to assess the efficacy and safety of omarigliptin monotherapy in young adult patients with type 2 diabetes mellitus (T2DM). Unexpected efficacy results in this trial led to a series of investigations that identified the use of prohibited medication by a substantial number of trial patients. Methods Patients with T2DM who were ≥18 to <45 years of age and either drug-naive or not on an antihyperglycemic agent for ≥12 weeks with inadequate glycemic control were randomized in a double-blind manner to receive omarigliptin 25 mg once weekly (n = 102) or placebo once weekly (n = 101) for 24 weeks. The objectives of the trial were to assess the effect of treatment with omarigliptin on glycemic parameters, including levels of glycosylated hemoglobin (HbA 1c ), 2-hour postmeal glucose, and fasting plasma glucose, and to assess the safety and tolerability of omarigliptin. Additional investigations into trial conduct included the measurement of drug levels for omarigliptin and metformin in blood samples collected for future biomedical research, available for approximately one half of the patients. Findings The mean age of trial participants was 39.2 years, approximately 60% were male, mean body mass index was 32.5 kg/m2, and mean duration of diabetes was 3.1 years. The mean baseline HbA 1c value was 7.9% in the omarigliptin group and 8.1% in the placebo group. After 24 weeks, the least squares mean change (95% CI) in HbA 1c value from baseline was –0.33% (–0.60 to –0.06) in the omarigliptin group and –0.45% (–0.72 to –0.18) in the placebo group, with a between-group difference of 0.12% (–0.26 to 0.49; P = 0.535). Similarly, no between-group difference was observed for the other glycemic parameters (2-hour postmeal glucose and fasting plasma glucose levels). No issues were identified in drug allocation, dispensing or supply, patient compliance with trial medication, sample handling or analysis, or site trial conduct that explained the observed results. Measurement of drug levels from future biomedical research samples uncovered the use, with no investigator knowledge, of an antihyperglycemic agent that was prohibited by the protocol (ie, metformin) by 42.4% (39 of 92) of patients. Metformin was used by more patients in the placebo group (57% [25 of 44]) than in the omarigliptin group (29% [14 of 48]). Implications The use of prohibited metformin in a trial of a dipeptidyl peptidase– 4 inhibitor, omarigliptin, introduced a confounding factor that invalidated the results of the trial. This behavior may have been encouraged in the trial by protocol-specified self-monitoring of blood glucose levels. Use of prohibited medication may be an underappreciated confounder in clinical trial research. Trial registrations: MK-3102-028 (US); ClinicalTrials.gov identifier, NCT01814748; EudraCT number, 2012-004303-12 (EU). [ABSTRACT FROM AUTHOR]

Objective:To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy. Methods:In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500 mg/day) with glycated hemoglobin (HbA1c) of 7.0–10.5% were randomized to omarigliptin 25 mg q.w. or matching placebo (n = 201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period. Results:At week 24, from a mean baseline HbA1c of 8.0–8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was –0.54% (–0.69%, –0.40%) in the omarigliptin group and 0.00% (–0.14%, 0.15%) in the placebo group, for a between-group difference of –0.55% (–0.75%, –0.34%);p < .001. Between-group differences (LS mean 95% CI) for the secondary end-points of 2-h post-meal glucose and fasting plasma glucose (omarigliptin vs placebo) were –0.8 mmol/L (–1.4, –0.2) (p = .011) and –0.5 mmol/L (–0.9, –0.1) (p = .010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c. Conclusions:In patients with T2DM, adding omarigliptin 25 mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate the efficacy and safety of adding the once-weekly DPP-4 inhibitor omarigliptin or the sulfonylurea glimepiride to the treatment regimen of patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.Methods: Patients with T2DM and HbA1c ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500 mg/day) were randomized to omarigliptin 25 mg once-weekly (n = 376) or glimepiride up to 6 mg once daily (n = 375) for 54 weeks. The primary hypothesis was that omarigliptin is non-inferior to glimepiride in reducing HbA1c at week 54.Results: The mean baseline HbA1c was 7.5% in the omarigliptin group and 7.4% in the glimepiride group. After 54 weeks, the least squares (LS) mean change from baseline in HbA1c was -0.30% in the omarigliptin group and -0.48% in the glimepiride group, with a between-group difference (95% CI) of 0.18% (0.06, 0.30), which met the pre-specified criterion for declaring non-inferiority. The incidence of symptomatic hypoglycemia was 5.3% in the omarigliptin group and 26.7% in the glimepiride group. With the exception of hypoglycemia, the incidences of adverse events and discontinuations were similar between treatment groups. Relative to baseline, omarigliptin was associated with a mean weight loss (-0.4 kg) and glimepiride a mean weight gain (+1.5 kg).Conclusions: After 54 weeks, as add-on therapy to metformin, once-weekly omarigliptin was generally well tolerated and non-inferior to glimepiride in improving glycemic control, with a lower incidence of hypoglycemia and with weight loss vs weight gain. [ABSTRACT FROM AUTHOR]

Background: Omarigliptin is a once-weekly (q.w.) oral DPP-4 inhibitor that is approved for the treatment of patients with type 2 diabetes mellitus (T2DM) in Japan. To support approval of omarigliptin in the United States, the clinical development program included a cardiovascular (CV) safety study. Subsequently, a business decision was made not to submit a marketing application for omarigliptin in the United States, and the CV safety study was terminated. Herein we report an analysis of data from that early-terminated study. Methods: In this randomized, double-blind study, 4202 patients with T2DM and established CV disease were assigned to either omarigliptin 25 mg q.w. or matching placebo in addition to their existing diabetes therapy. A Cox proportional hazards model was used to summarize the primary endpoint of time to first major adverse CV event (MACE, the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) and the analysis of first event of hospitalization for heart failure (hHF). Results: The median follow-up was approximately 96 weeks (range 1.1-178.6 weeks). The primary MACE outcome occurred in 114/2092 patients in the omarigliptin group (5.45%; 2.96/100 patient-years) and 114/2100 patients in the placebo group (5.43%; 2.97/100 patient-years), with a hazard ratio (HR) of 1.00 (95% confidence interval [CI] 0.77, 1.29). The hHF outcome occurred in 20/2092 patients in the omarigliptin group (0.96%; 0.51/100 patient-years) and 33/2100 patients in the placebo group (1.57%; 0.85/100 patient-years), with an HR of 0.60 (95% CI 0.35, 1.05). After 142 weeks, the least-squares mean difference (omarigliptin vs. placebo) in glycated hemoglobin levels was -0.3% (95% CI -0.46, -0.14). The numbers of patients with adverse events, serious adverse events or discontinued from study medication due to adverse events were similar in the omarigliptin and placebo groups. Conclusions: In this CV safety study of patients with T2DM and established CV disease, omarigliptin did not increase the risk of MACE or hHF and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Objective: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used for the management of type 2 diabetes (T2D) for over a decade; however, there is a limited understanding of the evolution of their use in the real-world setting over this time period. This study evaluated the demographics and clinical characteristics of patients initiating sitagliptin over a 10 year period in the United States.Research Design and Methods: Quintiles electronic medical records database was used to identify adults with a new prescription of sitagliptin over two 5 year time periods: 2006-2010 (n = 57,604), and 2011-2015 (n = 147,326). In addition, we also evaluated how the most recent (year 2015) profile of sitagliptin initiators (n = 29,295) compares to the treated T2D patients (N = 474,877) in 2015.Main Outcome Measures: No outcomes were assessed. Descriptive statistics were used to summarize baseline patient characteristics.Results: The overall demographics and clinical characteristics of patients initiating sitagliptin were generally similar over the two time periods; however, baseline HbA1c (median) was higher in the later time period: 7.6% vs. 7.9% respectively. Sitagliptin was initiated in patients across a broad range of age (18-79) years, body mass index (BMI) (10-70) kg/m2 and HbA1c (3-20) %. The most prevalent comorbidities observed in these patients were hypertension (93%), hyperlipidemia (81%), obesity (55%), chronic kidney disease (22%) and cardiovascular disease (21%). Additionally, when we assessed the treated T2D patients and patients initiating sitagliptin in 2015, several characteristics were comparable such as age (median) (64 vs. 63) years and BMI (33 vs. 33) kg/m2, and the most prevalent comorbidities were hypertension (97 vs. 95) %, and hyperlipidemia (86 vs. 81) % respectively.Conclusion: The overall demographic and comorbidity profile of patients initiating sitagliptin did not substantially change over the last decade and is similar to the treated T2D population. [ABSTRACT FROM AUTHOR]

Introduction We evaluated the tolerability and efficacy of the addition of sitagliptin in Chinese patients with type 2 diabetes mellitus receiving stable insulin therapy alone or in combination with metformin. Materials and Methods A total of 467 patients with inadequate glycemic control on insulin (glycated hemoglobin [HbA1c] ≥7.5% and ≤11%) were randomized 1:1 to receive sitagliptin 100 mg once daily or a matching placebo for 24 weeks. Randomization was stratified based on metformin use (on or not on metformin) and type of insulin (pre-mixed vs intermediate-/long-acting) at screening. The primary end-point was the change from baseline at week 24 in HbA1c. Results The addition of sitagliptin led to a significantly ( P < 0.001) greater week 24 HbA1c reduction (0.7%) compared with the reduction (0.3%) with placebo. A significantly ( P = 0.013) greater proportion of patients taking sitagliptin (16%) had an HbA1c of <7.0% at week 24 compared with placebo (8%). The addition of sitagliptin significantly ( P < 0.001) reduced 2-h post-meal glucose by 26.5 mg/ dL (1.5 mmol/L) relative to placebo. Reductions from baseline in fasting plasma glucose were observed in both the sitagliptin (14.4 mg/ dL reduction) and placebo (10.7 mg/ dL reduction) groups; the between-group difference was not significant. A total of 64 (27.4%) patients taking sitagliptin and 51 (21.9%) taking placebo experienced adverse events of hypoglycemia (symptomatic or asymptomatic). Neither group had a significant change from baseline in bodyweight. Conclusions After 24 weeks, sitagliptin added to stable insulin therapy (±metformin) was generally well tolerated and improved glycemic control in Chinese patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]