Peter P. Stein

Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: A randomized, double-blind, non-inferiority trial

Aim:  To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A1c (HbA1c) ≥ 6.5 and ≤10%] on metformin monotherapy.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin

Aim:  To assess the efficacy and safety of a 24‐week treatment with sitagliptin, a highly selective once‐daily oral dipeptidyl peptidase‐4 (DPP‐4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA1c) ≥7.5% and ≤10.5%] while on glimepiride alone or in combination with metformin.

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A1c ≥ 8.0% and ≤ 11.0%) type 2 diabetes mellitus (T2DM). Research design and methods: This was a multinational, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥ 6 weeks of stable metformin monotherapy (≥ 1500 mg/day), patients were randomized to either the addition of sitagliptin 100 mg once daily or placebo to ongoing metformin for 30 weeks. Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A1c (HbA1c) measured after 18 weeks of sitagliptin treatment. Key secondary endpoints included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA1c at 30 weeks. The proportion of patients meeting the goal of HbA1c < 7.0% was also analyzed. Results: Sitagliptin significantly reduced HbA1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA1c < 7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not significantly increase the risk of hypoglycemia or gastrointestinal adverse events. Conclusions: Addition of sitagliptin 100 mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks. Trial registration: ClinicalTrials.gov identifier: NCT00337610.

Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes

The aim of this study was to assess the efficacy and tolerability of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, in patients with type 2 diabetes who have inadequate glycaemic control on diet and exercise. In a randomised, double‐blind, placebo‐ and active‐controlled study, 743 patients with type 2 diabetes and a mean baseline HbA1c of 7.9% were randomised to receive one of six treatments for 12 weeks: placebo, sitagliptin 5, 12.5, 25 or 50 mg b.i.d., or glipizide 5 mg/day (electively titrated up to 20 mg/day). At week 12, treatment with sitagliptin at all doses tested led to a significant (p < 0.001) reduction in HbA1c relative to placebo, with the largest reductions occurring in the 50‐mg b.i.d. group. The placebo‐subtracted differences in HbA1c for the sitagliptin dose groups ranged from −0.38% to −0.77% in a dose‐dependent manner, and −1.00% in the glipizide group. Sitagliptin also produced significant reductions in fasting plasma glucose and mean daily glucose across the dose range studied. Sitagliptin treatment was well tolerated and resulted in no significant weight change relative to placebo. There was a modest weight gain observed with glipizide treatment relative to placebo. Hypoglycaemia adverse experiences were reported with the highest incidence in the glipizide group (17%) compared with the placebo (2%) or sitagliptin groups (0–4%, not dose‐dependent). In summary, in this study sitagliptin improved glycaemic control, with 50 mg b.i.d. being the most effective dose, and was generally well‐tolerated in patients with type 2 diabetes.

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Objective:  To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end‐stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed.

Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2‐year study

Objectives:  To evaluate the 2‐year safety and efficacy of adding sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes.

A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience.

Pheochromocytoma is an unusual but potentially devastating tumor. Although a high index of suspicion is necessary, the likelihood of a pheochromocytoma is lower in the absence of the typical symptoms and findings. Nonetheless, screening must be broadened to include patients with a lower risk of the disease, such as those with resistant or labile hypertension who are minimally symptomatic. Extensive diagnostic evaluations should be reserved for those whose clinical or laboratory findings are more suggestive. Symptoms in a group of patients in whom a pheochromocytoma was seriously considered but excluded overlap symptoms in patients with a pheochromocytoma. Certain symptoms are useful: flushing to suggest a non-pheochromocytoma illness; visual symptoms, flank pain, and pallor to suggest that a pheochromocytoma is more likely. Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients. The presence of the entire triad is more specific, but less sensitive. New hypertension, or hypertension associated with unexplained orthostatic hypotension, are suggestive of an underlying pheochromocytoma. Twenty-four-hour urine studies are consistently abnormal in patients with a pheochromocytoma, but are also elevated in a significant proportion of non-pheochromocytoma patients. Values greater then 1.5-2-fold above the upper limit of normal are very suggestive that a pheochromocytoma is present, and warrant a more intensive subsequent evaluation. Imaging studies are reliable in the diagnosis of pheochromocytoma, and can help to confirm or exclude the disease. Patients with a higher clinical likelihood and any elevated urinary testing, or with a lower clinical likelihood and persistently and/or significantly elevated urinary testing, should have imaging studies performed. This combination of clinical screening, 24-hour urinary testing, and imaging studies is a useful and reliable approach to patients suspected of harboring a pheochromocytoma.

Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes*

ABSTRACT Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP‑4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100 mg daily was evaluated as a once-daily (100 mg once-daily) or twice-daily (50 mg twice-daily) dosing regimen. Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100 mg once-daily, or sitagliptin 50 mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model. Results: Mean baseline HbA1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤ 7%. After 12 weeks, treatment with all doses of sitagliptin significantly ( p < 0.05) reduced HbA1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2 mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly ( p < 0.05) reduced by –14.0 to –22.6 mg/dL with all doses of sitagliptin relative to placebo. HOMA‑β was significantly ( p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA‑IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100 mg once-daily and 50 mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100 mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study. Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100 mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.

Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and β-cell function in patients with type 2 diabetes

Aim:  The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on 24‐h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy.