A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: In patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. CLINICAL TRIAL NUMBER: EudraCT: 2020-005136-30; NCT: 04944992. IMPACT AND IMPLICATIONS: 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.

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

CONTEXT: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. OBJECTIVE: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. METHODS: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 µg if weight ≤ 60 kg, or 150 µg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. RESULTS: After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. CONCLUSION: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

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).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

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).

Factors associated with clinical inertia in type 2 diabetes mellitus patients treated with metformin monotherapy.

Aims: To assess demographic and clinical characteristics associated with clinical inertia in a real-world cohort of type 2 diabetes mellitus patients not at hemoglobin A1c goal (<7%) on metformin monotherapy.Methods: Adult (≥18 years) type 2 diabetes mellitus patients who received care at Massachusetts General Hospital/Brigham and Women's Hospital and received a new metformin prescription between 1992 and 2010 were included in the analysis. Clinical inertia was defined as two consecutive hemoglobin A1c measures ≥7% ≥3 months apart while remaining on metformin monotherapy (i.e. without add-on therapy). The association between clinical inertia and demographic and clinical characteristics was examined via logistic regression.Results: Of 2848 eligible patients, 43% did not achieve a hemoglobin A1c goal of <7% 3 months after metformin monotherapy initiation. A sub-group of 1533 patients was included in the clinical inertia analysis, of which 36% experienced clinical inertia. Asian race was associated with an increased likelihood of clinical inertia (OR = 2.43; 95% CI = 1.48-3.96), while congestive heart failure had a decreased likelihood (OR = 0.58; 95% CI = 0.32-0.98). Chronic kidney disease and cardiovascular/cerebrovascular disease had weaker associations but were directionally similar to congestive heart failure.Conclusions: Asian patients were at an increased risk of clinical inertia, whereas patients with comorbidities appeared to have their treatment more appropriately intensified. A better understanding of these factors may inform efforts to decrease the likelihood for clinical inertia.

Prevalence of type 1 and type 2 diabetes among US pediatric population in the MarketScan Multi-State Database, 2002 to 2016.

OBJECTIVES: To estimate the prevalence of type 1 (T1DM) and type 2 diabetes mellitus (T2DM) among U.S. Medicaid pediatric population aged <18 years 2002 to 2016 by age, sex, and race/ethnicity. METHODS: Participants aged <18 years old from 2002 to 2016 were identified from the MarketScan Multi-State Medicaid Database. Diabetes was defined as having (a) ≥1 claims for an outpatient or inpatient diabetes diagnosis and ≥2 prescriptions for any anti-diabetes medications or (b) records of ≥2 claims for an outpatient or inpatient diabetes diagnosis that were at least 30 days apart. Annual prevalence of diabetes and 95% confidence intervals (CIs) were calculated. Age-, sex-, and race-stratified prevalence were also assessed. RESULTS: The annual prevalence of T1DM increased from 1.29 to 2.34/1000 pediatric persons from 2002 to 2016. The prevalence of T2DM rose from 0.70 in 2002 to 2.76/1000 in 2011, but then dropped to 2.12/1000 pediatric persons in 2016 in the Medicaid population. Prevalence of both T1DM and T2DM increased with age. While the prevalence of T1DM was similar in both sexes, and was most prevalent in Whites, prevalence of T2DM was higher in girls and was most prevalent in Blacks. CONCLUSIONS: While the annual prevalence of T1DM in pediatric persons enrolled in Medicaid increased continuously from 2002 to 2016, the annual prevalence of T2DM increased from 2002 to 2011, with a subsequent decrease in 2016, possibly because of the increase of relatively healthier participants with the expanded eligibility through the ACA between 2011 and 2016.

Efficacy and safety of sitagliptin added to treatment of patients with type 2 diabetes inadequately controlled with premixed insulin.

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.

Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study.

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.

Changes in diabetes medication regimens and glycemic control in adolescents and young adults with youth-onset type 2 diabetes: The SEARCH for diabetes in youth study.

OBJECTIVE: The aim of this study was to describe recent medication patterns and changes in medication patterns and glycemic control in adolescents and young adults with incident type 2 diabetes (T2D). METHODS: Using data from the SEARCH for Diabetes in Youth Study, we conducted a cross-sectional analysis of treatments for adolescents and young adults with incident T2D in 2 periods (2002-2005 vs 2008/2012), and a longitudinal analysis of medications and glycemic control for a subset with baseline and follow-up visits. Comparisons were performed using χ2 , Fisher's exact, or ANOVA. RESULTS: Of 646 individuals in the cross-sectional analysis, a majority in each period received metformin (64.9% vs 70.4%) and/or insulin (38.1% vs 38.4%), while fewer used sulfonylureas (5.6% vs 3.6%) with non-significant changes over time. There was a significant reduction in thiazolidinedione use (5.0% vs 2.0%, P < .05). In the longitudinal analysis, 322 participants were followed for 7 years, on average. Baseline metformin users had a lower A1C (6.4% [46.7 mmol/mol]) compared to insulin (8.4% [68.2 mmol/mol], P < .001) or insulin plus any oral diabetes medication (ODM) users (7.7% [60.4 mmol/mol], P < .001). Among baseline metformin users (n = 138), 29.7% reported metformin at follow-up, with the remainder adding (19.6%) or switching to insulin (8.0%), ODM (15.9%), or lifestyle only (26.8%). Of those receiving insulin (±ODM) (n = 129), 76% reported insulin use at follow-up. Overall, 35% were at A1C goal (<7.0%, 53 mmol/mol) at follow-up. CONCLUSIONS: Youth-onset T2D is still largely being treated with metformin and/or insulin. The majority treated were not at American Diabetes Association (ADA)-recommended goal 7 years after diagnosis.

Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes.

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of ß-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.

Hypoglycemia in type 2 diabetes: understanding patients' and physicians' knowledge and experience.

PURPOSE: The aim of the current study is to assess the patient and physician experience and knowledge of hypoglycemia in the management of type 2 diabetes (T2DM). METHODS: T2DM patients (N = 1002) completed questionnaires on hypoglycemia experience, familiarity, and fear. Their responses were compared across various antihyperglycemic treatment regimens; specifically, (1) insulin only or insulin combined with sulfonylurea [SU] and/or metformin, (2) SU only with/without metformin, and (3) neither insulin nor SU. Physicians (N = 1003) completed questionnaires on hypoglycemia knowledge and decision-making, and their responses were compared by specialty [75% primary care providers (PCPs) and 25% endocrinologists]. RESULTS: T2DM patients treated with, (1) insulin only, or (2) insulin plus SU or metformin, reported the most experience and familiarity with-but also fear of-hypoglycemic events. Insulin-treated patients (insulin alone or insulin plus SU/metformin) also reported experiencing more hypoglycemia (all p-values <0.012). For physicians, endocrinology specialty was significantly associated with higher hypoglycemia knowledge scores (all p-values <.001). Irrespective of specialty, physician hypoglycemia knowledge, in turn, was associated with correct treatment decision-making (all p-values <0.001). CONCLUSIONS: Insulin-based antihyperglycemic regimens were associated with high prevalence, severity, familiarity, and fear of hypoglycemia. An effective strategy to mitigate the burden of hypoglycemia may be to optimize pharmacological therapy to prevent these events. Since physician hypoglycemia knowledge was highly correlated to correct therapeutic decision-making, continued physician education regarding this acute complication of diabetes treatment should be prioritized for those managing patients with T2DM.

Insulin secretory effect of sitagliptin: assessment with a hyperglycemic clamp combined with a meal challenge.

Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively ( P < 0.001 for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1. Robust reproducibility of the sitagliptin-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins.

A randomized, double-blind trial evaluating the efficacy and safety of monotherapy with the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in people with type 2 diabetes.

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.

A randomized clinical trial evaluating the efficacy and safety of the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy.

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.

Direct medical costs of severe hypoglycaemic events in patients with type 2 diabetes in England: A retrospective database study.

AIMS: Hypoglycaemia in patients with diabetes can be induced by insulins and sulfonylureas. We assessed the real-world impact of specific monotherapy and combination regimens on hypoglycaemic events requiring hospitalisation and related secondary costs to the English healthcare system. METHODS: This retrospective observational study used the Clinical Practice Research Datalink with linked hospital admission data during 2008-2012. Patients with type 2 diabetes mellitus (T2DM) using antihyperglycaemic agents (AHAs) were assigned to mutually exclusive subgroups (insulin- and non-insulin-containing regimens; treatment groups of interest; age group) based on treatment at index date (date of first AHA prescription). Outcomes were number and cost of hospital admissions with hypoglycaemic event-related diagnosis codes. RESULTS: We identified 110 206 patients with T2DM (mean age 64.9 years, time since diagnosis 5.4 years, HbA1c at index 7.4%), with 439 hypoglycaemic events requiring inpatient hospitalisation (mean length of stay 6.3 days, mean cost/stay £1351). Event rates and cost of stay were highest in patients treated with sulfonylurea- or insulin-based regimens. Event rates, duration and cost of stay were higher in older patients. CONCLUSION: Rates of severe hypoglycaemic events varied substantially between T2DM regimens. In this study of patients treated in clinical practice in England, sulfonylurea- and insulin-based regimens were associated with the highest event rates and costs associated with hospitalisation for severe hypoglycaemic events; hospitalisation for severe hypoglycaemic events was not observed with dipeptidyl peptidase-4 inhibitor monotherapy or with metformin.

An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism.

BACKGROUND: Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. METHODS: This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 µg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 106/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). RESULTS: Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 106/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. CONCLUSIONS: Corifollitropin alfa 150 µg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01709331 .

Sitagliptin added to stable insulin therapy with or without metformin in Chinese patients with type 2 diabetes.

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.

Randomized trial assessing the safety and efficacy of sitagliptin in Chinese patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea alone or combined with metformin.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant burden in China, where approximately 114 million patients have been diagnosed with diabetes. Chinese patients present with prominent ß-cell failure, with resulting deficiency in insulin secretion, particularly early phase insulin secretion leading to postprandial hyperglycemia. Sitagliptin, a selective once-daily oral dipeptidyl peptidase-4 inhibitor, has been shown to improve glycemic control as monotherapy and in combination with other antihyperglycemic agents, including sulfonylureas and metformin. METHODS: This was a multicenter randomized double-blind placebo-controlled study conducted in China. The study assessed the safety and efficacy of the addition of sitagliptin 100 mg once daily versus placebo on changes from baseline at Week 24 in HbA1c, fasting plasma glucose (FPG) and 2-h post-meal glucose (PMG). Patients were aged 18-79 years, had T2DM with inadequate glycemic control, and were taking a sulfonylurea, with or without metformin. RESULTS: After 24 weeks, sitagliptin reduced HbA1c, FPG, and 2-h PMG significantly more than placebo (between-treatment differences: -0.61 %, -16.8 mg/dL, and -32.9 mg/dL, respectively; P < 0.001 for all). The addition of sitagliptin was generally well tolerated, with a comparable incidence of adverse events and drug-related adverse events in both treatment groups. The sitagliptin group had a higher incidence of symptomatic hypoglycemia than the placebo group (25/248 [10.1 %] vs 13/249 [5.2 %], respectively; P = 0.042). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycemic control in Chinese patients with T2DM who had inadequate glycemic control with sulfonylurea, with or without metformin therapy. The addition of sitagliptin was generally well tolerated. (clinicaltrials.gov: NCT01590771).

A randomized clinical trial of the safety and efficacy of sitagliptin in patients with type 2 diabetes mellitus inadequately controlled by acarbose alone.

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.

The Effects of a Sitagliptin Formulary Restriction Program on Diabetes Medication Use.

BACKGROUND: Health plans have responded to the many treatment options for type 2 diabetes mellitus by implementing formulary restriction policies, including step therapy, to control costs. Little is known about the impact of step therapy programs on antidiabetes medication use. OBJECTIVE: To assess the impact of a sitagliptin step therapy program on antidiabetes medication use among sitagliptin users. METHODS: Using pharmacy claims from the Symphony Health Solutions' Integrated Dataverse, we compared the use of sitagliptin and other antidiabetes medications by patients enrolled in a health plan (Plan A) that implemented a sitagliptin step therapy program on July 1, 2013, with the use by patients who were contemporaneously enrolled in 2 comparison plans-Plans B and C-without step therapy programs. Sitagliptin-a dipeptidyl peptidase (DPP)-4 inhibitor-was in tier 3 in Plans A and B and in tier 2 in Plan C during the study period. We assessed the use of antidiabetes medications during the pre-step therapy period (January-June 2013) and the post-step therapy period (October 2013-March 2014). RESULTS: We identified 2995 patients enrolled in Plan A, 751 enrolled in Plan B, and 394 enrolled in Plan C who received sitagliptin during the pre-step therapy period. Patient characteristics and pre-step therapy sitagliptin use were similar across plans. During the post-step therapy period, more patients in Plan A (approximately 70%) discontinued sitagliptin than patients in Plan B (approximately 51%) and Plan C (approximately 25%). Approximately 30% of patients in Plan A switched to another DPP-4 inhibitor compared with approximately 15% and 2% of patients in Plans B and C, respectively. Seventeen percent of patients in Plan A discontinued sitagliptin without replacement but continued using other antidiabetes medications compared with approximately 13% and 8% of patients in Plans B and C, respectively. In all, 17% of patients in Plans A and B and 11% of patients in Plan C discontinued using all antidiabetes medications. CONCLUSION: The step therapy program changed patients' use of sitagliptin, which was the target of the step therapy program, as well as of other antidiabetes medications. Most patients stopped sitagliptin treatment after the step therapy program started. Some patients discontinued sitagliptin treatment without replacement, but others discontinued using all antidiabetes medications.