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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]

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]

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: 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]

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 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 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 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: 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]

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]

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: 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]

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: To evaluate the safety and efficacy of sitagliptin when added to the treatment of patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on acarbose monotherapy.Research Design and Methods: This was a multicenter, randomized, placebo-controlled, double-blind clinical trial. Patients (N = 381) with T2DM and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥ 7.0% and ≤10.0%) on acarbose monotherapy (at least 50 mg three times daily) were randomized in a 1:1 ratio to receive the addition of sitagliptin 100 mg or matching placebo once daily for 24 weeks.Main Outcome Measures: Changes from baseline in HbA1c and fasting plasma glucose (FPG) at Week 24.Results: The mean baseline HbA1c in randomized patients was 8.1%. At Week 24, the placebo-controlled, least squares mean changes from baseline (95% confidence interval) in HbA1c and FPG in the sitagliptin group were -0.62% and -0.8 mmol/L (p < .001), respectively. At Week 24, 37.8% of patients in the sitagliptin group were at HbA1c goal of <7% compared with 17.2% in the placebo group (p < .001). Sitagliptin was generally well tolerated, and there were no significant between-group differences in prespecified safety parameters (symptomatic hypoglycemia, diarrhea, abdominal pain, nausea, vomiting). A higher incidence of serious adverse events was observed in the sitagliptin group (5.2%) relative to placebo (0.5%); all but one, in the sitagliptin group, were not considered related to drug.Conclusions: Sitagliptin was generally well tolerated and provided statistically superior and clinically meaningful improvements in glycemic control after 24 weeks of treatment compared to placebo when added to treatment of patients with inadequate glycemic control on acarbose monotherapy. Clinicaltrials.gov: NCT01177384. [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 evaluate chronic kidney disease (CKD) and cardiovascular outcomes in TECOS (Clinical trial reg. no. NCT00790205, clinicaltrials.gov) participants with type 2 diabetes and cardiovascular disease treated with sitagliptin, a dipeptidyl peptidase 4 inhibitor, according to baseline estimated glomerular filtration rate (eGFR).Research Design and Methods: We used data from 14,671 TECOS participants assigned in a double-blind design to receive sitagliptin or placebo added to existing therapy, while aiming for glycemic equipoise between groups. Cardiovascular and CKD outcomes were evaluated over a median period of 3 years, with participants categorized at baseline into eGFR stages 1, 2, 3a, and 3b (≥90, 60-89, 45-59, or 30-44 mL/min/1.73 m2, respectively).Results: Participants with eGFR stage 3b were older, were more often female, and had a longer duration of diabetes. Four-point major adverse cardiovascular event rates increased with lower baseline eGFR (3.52, 3.55, 5.74, and 7.34 events/100 patient-years for stages 1-3b, respectively). Corresponding adjusted hazard ratios for stages 2, 3a, and 3b versus stage 1 were 0.93 (95% CI 0.82-1.06), 1.28 (1.10-1.49), and 1.39 (1.13-1.72), respectively. Sitagliptin therapy was not associated with cardiovascular outcomes for any eGFR stage (interaction P values were all >0.44). Kidney function declined at the same rate in both treatment groups, with a marginally lower but constant eGFR difference (-1.3 mL/min/1.73 m2) in those participants who were assigned to sitagliptin. Treatment differences in these eGFR values remained after adjustment for region, baseline eGFR, baseline HbA1c, time of assessment, and within-study HbA1c levels.Conclusions: Impaired kidney function is associated with worse cardiovascular outcomes. Sitagliptin has no clinically significant impact on cardiovascular or CKD outcomes, irrespective of baseline eGFR. [ABSTRACT FROM AUTHOR]

Introduction The results of a clinical trial to evaluate the efficacy and safety of initial combination therapy with sitagliptin and metformin in Chinese patients with type 2 diabetes and inadequate glycemic control are reported here. Materials and Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel group, 24-week clinical trial carried out in China. Patients ( n = 744) with type 2 diabetes and inadequate glycemic control (glycated hemoglobin ≥7.5 and ≤11.0%) who were either drug-naïve or washed out of previous therapy were randomized in equal ratios to sitagliptin 100 mg once daily (q.d.; S100), metformin 500 mg twice daily (b.i.d.; M1000), metformin 850 mg b.i.d. (M1700), sitagliptin 50 mg b.i.d. plus metformin 500 mg b.i.d. (S100/M1000), sitagliptin 50 mg b.i.d. plus metformin 850 mg b.i.d. (S100/M1700), or placebo. Results The mean baseline glycated hemoglobin in randomized patients was 8.7%. Least squares mean changes from baseline in glycated hemoglobin were −0.59% (placebo), −0.99% (S100), −1.29% (M1000), −1.56% (M1700), −1.67% (S100/M1000) and −1.83% (S100/M1700) ( P < 0.05 for each active group vs placebo, for S100/M1700 and S100/M1000 vs S100, and for S100/M1000 vs M1000). All treatments were generally well-tolerated. The overall incidence of hypoglycemia (symptomatic or asymptomatic) was higher in the two co-administration groups (S100/M1700 and S100/M1000) compared with the placebo. The incidence of symptomatic hypoglycemia was low, and similar, across all treatment groups. The incidences of gastrointestinal adverse events were generally higher in high-dose metformin groups than in the placebo group. Conclusions In Chinese patients with type 2 diabetes, initial combination therapy with sitagliptin and metformin was generally well-tolerated, and provided improvement in glycemic control. [ABSTRACT FROM AUTHOR]

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]

Objective: Patients with type 2 diabetes (T2DM) often have multiple comorbidities which may impact the selection of antihyperglycemic therapies. The purpose of this study was to quantify the prevalence and co-prevalence of common comorbidities.Research Design and Methods: A retrospective study was conducted using the Quintiles Electronic Medical Record database. Adult patients with T2DM who had ≥1 encounter from July 2014 to June 2015 (index period) with ≥1 year medical history available were included. The index date was defined as the most recent encounter date during the 1 year index period.Main Outcome Measures: Comorbid conditions were assessed using all data available prior to and including the index date. Patient characteristics, laboratory measures, and comorbidities were summarized via descriptive analyses, overall and by subgroups of age (<65, 65-74, 75+ years) and gender.Results: Of the 1,389,016 eligible patients, 53% were female and the median age was 65 years. 97.5% of patients had at least one comorbid condition in addition to T2DM and 88.5% had at least two. The comorbidity burden tended to increase in older age groups and was higher in men than women. The most common conditions in patients with T2DM included hypertension (HTN) in 82.1%; overweight/obesity in 78.2%; hyperlipidemia in 77.2%; chronic kidney disease (CKD) in 24.1%; and cardiovascular disease (CVD) in 21.6%. The highest co-prevalence was demonstrated for the combination of HTN and hyperlipidemia (67.5%), followed by overweight/obesity and HTN (66.0%), overweight/obesity and hyperlipidemia (62.5%), HTN and CKD (22.4%), hyperlipidemia and CKD (21.1%), HTN and CVD (20.2%), hyperlipidemia and CVD (20.1%), overweight/obesity and CKD (19.1%) and overweight/obesity and CVD (17.0%).Limitations: Limitations include the potential for misclassification/underreporting due to the use of diagnostic codes, drug codes, or laboratory measures for identification of medical conditions.Conclusions: The vast majority of patients with T2DM have multiple comorbidities. To ensure a comprehensive approach to patient management, the presence of multimorbidity should be considered in the context of clinical decision making. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to determine the optimal dose of omarigliptin, a once-weekly (q.w.) dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of patients with type 2 diabetes and evaluate the long-term safety of that dose.Research Design and Methods: In a multicenter, double-blind, 12-week, dose-range finding study, 685 oral antihyperglycemic agent-naïve or washed-out subjects with type 2 diabetes were randomized to one of five once-weekly doses of omarigliptin (0.25 mg, 1 mg, 3 mg, 10 mg, or 25 mg) or placebo. The primary efficacy end point was change from baseline in HbA1c, and secondary end points were 2-h postmeal glucose (PMG) and fasting plasma glucose (FPG). Analysis included all patients who received at least one dose of the study medication. Subjects who completed the base study were eligible to enter a 66-week extension study.Results: Once-weekly treatment for 12 weeks with omarigliptin provided dose-related reductions in HbA1c, 2-h PMG, and FPG. At week 12, the omarigliptin 25-mg dose provided the greatest glycemic efficacy. The placebo-adjusted least-squares mean reductions from baseline in HbA1c, 2-h PMG, and FPG were -0.72% (-7.8 mmol/mol), -2.5, and -1.3 mmol/L, respectively (all P < 0.001). The incidence of adverse events was similar across dose groups, with a low incidence of symptomatic hypoglycemia and no effect on body weight. Omarigliptin was generally well-tolerated throughout the base and extension studies.Conclusions: Omarigliptin 25 mg q.w., compared with placebo, provided significant glucose lowering and was generally well tolerated for up to 78 weeks in patients with type 2 diabetes. [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: The present study was conducted to evaluate the efficacy, safety and tolerability of sitagliptin added to ongoing metformin therapy in Chinese patients with type 2 diabetes (T2DM) who failed to achieve adequate glycemic control with metformin monotherapy. Methods: After a metformin titration/stabilization period and a 2-week, single-blind, placebo run-in period, 395 Chinese patients with T2DM aged 25-77 years (baseline HbA1c 8.5%) were randomized (1:1) to double-blind placebo or sitagliptin 100 mg q.d. added to ongoing open-label metformin (1000 or 1700 mg/day) for 24 weeks. Results: Significant ( P < 0.001) changes from baseline in HbA1c (−0.9%), fasting plasma glucose (−1.2 mmol/L), and 2-h post-meal plasma glucose (−1.9 mmol/L) were seen with sitagliptin compared with placebo. There were no significant differences between sitagliptin and placebo in the incidence of hypoglycemia or gastrointestinal adverse events. A small decrease from baseline body weight was observed in the placebo group compared with no change in the sitagliptin group (between-group difference 0.5 kg; P = 0.018). Conclusions: The addition of sitagliptin 100 mg to ongoing metformin therapy significantly improved glycemic control and was generally well tolerated in Chinese patients with T2DM who had inadequate glycemic control on metformin alone. [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]

Summary: Aims: TECOS was a randomized, double‐blind, placebo‐controlled trial assessing the impact of sitagliptin vs. placebo on cardiovascular outcomes when added to usual care in patients with type 2 diabetes. We report the use of concomitant diabetes medications and the risk for progression to insulin during follow‐up. Materials and Methods: TECOS enrolled 14 671 participants with HbA1c 6.5%‐8.0% on monotherapy with metformin, pioglitazone, sulfonylurea (SU), or dual therapy with two oral agents or insulin with or without metformin. Subsequent diabetes management was by the participant's usual care physician. Time to initiation of insulin and risk of hypoglycaemia were estimated using Cox proportional hazards models. Results: The most common glucose‐lowering regimens at baseline were metformin monotherapy (30.2%), SU monotherapy (8.5%), metformin/SU therapy (35.1%), and insulin with or without metformin (13.9% and 8.6%, respectively). Over a median 3.0 years' follow‐up, diabetes therapy was intensified in 25.2% of participants (sitagliptin 22.0%, placebo 28.3%). Medications most commonly added were SU (8.3%) or insulin (8.8%). Insulin initiation in the usual care setting occurred at mean (standard deviation) HbA1c of 8.5 (1.5)%. Sitagliptin did not impact rates of severe hypoglycaemia, but delayed progression to insulin when added to metformin or metformin/SU regimens. Conclusion: Consistent with the trial's pragmatic design, TECOS participants underwent typical progression of diabetes medications. Sitagliptin was associated with lower HbA1c, without increased risk for severe hypoglycaemia and was associated with delayed progression to insulin when added to metformin with or without SU. The TECOS study assessed the impact of sitagliptin compared to placebo on cardiovascular outcomes in 14 671 participants with type 2 diabetes over a median duration of 3 years. During the study, diabetes therapy was intensified in 25.2% of participants, most commonly by the addition of a sulfonylurea or insulin. A delay in the progression to insulin was observed in sitagliptin‐treated participants who entered the study on metformin or metformin/sulfonylurea treatment [ABSTRACT FROM AUTHOR]

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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: Accurate measures of hypoglycemia within electronic health records (EHR) can facilitate clinical population management and research. We quantify the occurrence of serious and mild-to-moderate hypoglycemia in a large EHR database in the US, comparing estimates based only on structured data to those from structured data and natural language processing (NLP) of clinical notes.Methods: This cohort study included patients with type 2 diabetes identified from January 2009 through March 2014. We compared estimates of occurrence of hypoglycemia derived from diagnostic codes to those recorded within clinical notes and classified via NLP. Measures of hypoglycemia from only structured data (ICD-9 Algorithm), only note mentions (NLP Algorithm), and either structured data or notes (Combined Algorithm) were compared with estimates of the period prevalence, incidence rate, and event rate of hypoglycemia, overall and by seriousness.Results: Of the 844,683 eligible patients, 119,695 had at least one recorded hypoglycemic event identified with ICD-9 or NLP. The period prevalence of hypoglycemia was 12.4%, 25.1%, and 32.2% for the ICD-9 Algorithm, NLP Algorithm, and Combined Algorithm, respectively. There were 6128 apparent non-serious events utilizing the ICD-9 Algorithm, which increased to 152,987 non-serious events within the Combined Algorithm.Conclusions: Ascertainment of events from clinical notes more than doubled the completeness of hypoglycemia capture overall relative to measures from structured data, and increased capture of non-serious events more than 20-fold. The structured data and clinical notes are complementary within the EHR, and both need to be considered in order to fully assess the occurrence of hypoglycemia. [ABSTRACT FROM AUTHOR]

Aim: To compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy.Method: A cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120-365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations.Results: A total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were -35% (IQR=-73% to 5%) and -31% (IQR=-72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99-1.47, P=0.063).Conclusion: Our results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this. [ABSTRACT FROM AUTHOR]

Aims: Type 2 diabetes is a reported risk factor for more frequent and severe urinary tract infections (UTI). We sought to quantify the annual healthcare cost burden of UTI in type 2 diabetic patients. Methods: Adult patients diagnosed with type 2 diabetes were identified in MarketScan administrative claims data. UTI occurrence and costs were assessed during a 1-year period. We examined UTI-related visit and antibiotic costs among patients diagnosed with UTI, comparing those with versus without a history of UTI in the previous year (prevalent vs. incident UTI cases). We estimated the total incremental cost of UTI by comparing all-cause healthcare costs in patients with versus without UTI, using propensity score-matched samples. Results: Within the year, 8.2% (6,014/73,151) of subjects had ≥ 1 UTI, of whom 33.8% had a history of UTI. UTI-related costs among prevalent versus incident cases were, respectively, $603 versus $447 (p = 0.033) for outpatient services, $1,607 versus $1,819 (p = NS) for hospitalizations, and $61 versus $35 (p < 0.0001) for antibiotics. UTI was associated with a total all-cause incremental cost of $7,045 (95% CI: 4,130, 13,051) per patient with UTI per year. Conclusions: UTI is common and may impose a substantial direct medical cost burden among patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]