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Clinical study summaries created by Merck & Co., Inc.
Please consult the full publications for further information.

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

Raz I, Chen Y, Wu M, et al; for Sitagliptin Study 053 Group
Current Medical Research and Opinion. 24(2):537–550, February 2008.

Summary of clinical study created by Merck & Co., Inc. Please consult the full publication for further information.

A multinational, randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of adding sitagliptin to ongoing metformin therapy in patients with type 2 diabetes mellitus. After ≥6 weeks of stable metformin therapy (≥1500 mg/day, maximum 2550 mg/day), 190 patients (88 male, 102 female; age 29-77 years) were randomized to receive sitagliptin 100 mg/day (n=96) or placebo (n=94) in addition to metformin for 30 weeks. The primary endpoint was change in HbA_1c from baseline after 18 weeks (mean HbA_1c at baseline was 9.2%).  Secondary endpoints included change in fasting plasma glucose (FPG) and 2-hr postprandial glucose (PPG) after 18 weeks and change in HbA_1c after 30 weeks. A total of 159 patients completed the study. The proportion of patients who discontinued were similar in the 2 treatment groups.

At weeks 18 and 30, sitagliptin significantly reduced HbA_1c by 1% (placebo-adjusted; P<0.001). Treatment effects were consistent across subgroups defined by age, baseline body mass index, sex, race, duration of disease, HOMA-ß, HOMA-IR, prior therapy, and proinsulin/insulin ratio. Sitagliptin also significantly increased the probability of achieving an HbA_1c <7.0% at weeks 18 and 30 compared with placebo. Sitagliptin also significantly reduced FPG at weeks 18 and 30 and significantly reduced 2-hr PPG, HOMA-ß, and fasting proinsulin/insulin ratio at week 18. HOMA-IR did not change significantly.  Patients in the sitagliptin group had a significantly lower rate of needing rescue therapy compared with placebo (6 vs 23 patients).

The addition of sitagliptin was generally well tolerated. The 2 groups were similar in incidence of clinical adverse events and incidence of drug-related adverse events. No serious adverse events or discontinuations due to adverse events were reported in the sitagliptin group. The 2 groups were similar in incidence of hypoglycemia and GI adverse events (abdominal pain, diarrhea, nausea, vomiting). The number of patients with at least 1 adverse event was higher in the sitagliptin group than in the placebo group (15.6% vs 4.3%). There was no discernible pattern of particular adverse events with a higher rate except for decreased hemoglobin, which occurred in 4 patients in the sitagliptin group and none in the placebo group. Three of these 4 patients had illnesses that predisposed them to blood loss. Two patients in the sitagliptin group were discontinued due to a slight increase in serum creatinine and an increase in ALT >3 times the ULN. Neither of these discontinuations was considered drug-related.

The authors conclude that adding sitagliptin to ongoing metformin treatment in patients with type 2 diabetes resulted in significant and sustained improvements in HbA_1c, FPG and 2-hr PPG and in markers of beta-cell function. The addition of sitagliptin was well tolerated, with low incidence of hypoglycemia and no worsening of GI adverse events. This study was supported by Merck. Eight of the nine authors are Merck employees.

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

Nauck MA, Meininger G, Sheng D, et al; for Sitagliptin Study 024 Group
Diabetes Obes Metab. 9(2):194–205, Mar 2007.

Summary of clinical study created by Merck & Co., Inc. Please consult the full publication for further information.

A randomized, parallel-group study was conducted to compare sitagliptin and glipizide with respect to glycemic efficacy and safety in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Patients who were already receiving metformin ≥1500 mg/day and had a glycosylated hemoglobin level between 6.5 and 10% entered a 2-week, single-blind placebo run-in period. Afterwards, 1172 patients (age 18-78 years) were randomized to sitagliptin 100 mg/day (n=588) or glipizide 5 mg/day (n=584; uptitrated to a maximum of 20 mg/day) for 52 weeks. The primary endpoint was change from baseline in glycosylated hemoglobin at week 52 in the per-protocol analysis (n=382 for sitagliptin and n=411 for glipizide). The mean dose of glipizide was 10.3 mg/day in the per-protocol population. Approximately 58% of patients reached a dose of at least 10 mg/day, but because of down-titration for recurrent hypoglycemia, 10% of patients were not taking glipizide at the end of the study. For that reason, the mean duration of drug exposure was 297.1 days in the sitagliptin group and 287.5 days in the glipizide group.

The mean per-protocol change in glycosylated hemoglobin from baseline to week 52 was -0.67% in both groups from a mean baseline HbA_1c of 7.5%. The percentage of patients with a glycosylated hemoglobin level <7% at week 52 was 63% in the sitagliptin group and 59% in the glipizide group. The percentage of patients with a glycosylated hemoglobin level <6.5% at week 52 was 29% in both groups. The maximal effect on fasting plasma glucose occurred at week 24 in both groups, followed by a rise in fasting plasma glucose through week 52. The sitagliptin group had a decrease in fasting proinsulin and the proinsulin/insulin ratio at week 52; however, the glipizide group had an increase in these 2 endpoints at week 52. There was a small decrease in HOMA-IR. The sitagliptin group had a significant increase in HDL compared to the glipizide group.

The proportion of patients experiencing a drug-related adverse event was higher in the glipizide group than in the sitagliptin group (30.3% vs. 14.5%). There were 2 serious adverse events in the glipizide group and none in the sitagliptin group. There were 2 deaths in the glipizide group and 1 in the sitagliptin group; none was considered related to study drug. The incidence of overall GI events and of abdominal pain, diarrhea, nausea, and vomiting was similar in the 2 groups. The incidences of the following events were slightly higher in the sitagliptin group than in the glipizide group: fatigue, dizziness, nasopharyngitis, sinusitis, urinary tract infection, osteoarthritis, and pain in the extremity. There were 657 episodes of hypoglycemia in 187 patients (32%) in the glipizide group, compared to 50 episodes in 29 patients (4.9%) in the sitagliptin group. Seven patients in the glipizide group had an episode of hypoglycemia that required medical assistance, compared to only 1 patient in the sitagliptin group. Body weight significantly decreased with sitagliptin (-1.5 kg), but significantly increased with glipizide (+1.1 kg). The sitagliptin group had slight mean decreases in ALT and AST.

The authors conclude that although both agents led to similar decreases in glycosylated hemoglobin, sitagliptin had a lower risk of hypoglycemia than did glipizide and led to weight loss compared to weight gain compared to glipizide. 31 refs. Ed. note: All but one of the authors are Merck employees. This study was supported by Merck.

Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.

Aschner P, Kipnes MS, Lunceford JK, et al; for Sitagliptin Study 021 Group
Diabetes Care. 29(12):2632–2637, Dec 2006.

Summary of clinical study created by Merck & Co., Inc. Please consult the full publication for further information.

The sitagliptin study 021 was a randomized, double-blind, placebo-controlled study performed to compare the effects of sitagliptin 100 mg once daily (n=238; 136 M, 102 F, mean age 53.4 years) or 200 mg once daily (n=250; 117 M, 133 F, mean age 54.9 years) with those of placebo (n=253; 130 M, 123 F, mean age 54.3 years) for 24 weeks in 741 patients with type 2 diabetes. The average baseline level of glycosylated hemoglobin among participating patients was 8.0% (range 6.3%-10.9%); the average baseline level of fasting plasma glucose was 9.6 mmol/L. A total of 639 patients completed the study. More patients in the placebo group required rescue therapy with metformin (no dosage details; 20.6%) than did patients in the sitagliptin 100 mg (8.8%) and 200 mg groups (4.8%; P<0.001 for sitagliptin vs. placebo). The time to rescue therapy was shorter in the placebo group than in the sitagliptin groups.

After 24 weeks of therapy, least-squares mean changes in glycosylated hemoglobin levels were greater in the sitagliptin 100 mg (-0.61%) and 200 mg groups (-0.76%) than in the placebo group (+0.18%; P<0.001). A total of 41% of patients in the sitagliptin 100 mg group, 45% of patients in the sitagliptin 200 mg group, and 17% of patients in the placebo group achieved a glycosylated hemoglobin level of <7%. There was a significant interaction between baseline glycosylated hemoglobin levels and treatment effects (P<0.001) that was consistent with a greater effect of treatment in patients with higher baseline HbA_1c levels.

After 24 weeks of therapy, least-squares mean changes in fasting plasma glucose levels were greater in the sitagliptin 100 mg (-0.7 mmol/L) and 200 mg groups (-0.9 mmol/L) than in the placebo group (+0.3 mmol/L; P<0.001). Sitagliptin (both dosages) was also associated with improvements in the proinsulin/insulin ratio and homeostasis model assessments of beta-cell function compared with placebo. After 24 weeks of therapy, least-squares mean changes in 2-hr postprandial glucose levels were greater in the sitagliptin 100 mg (-2.7 mmol/L) and 200 mg groups (-3.1 mmol/L) than in the placebo group (-0.1 mmol/L; P<0.001). Furthermore, least-squares mean reductions in glucose total AUC were greater in the sitagliptin groups than in the placebo group (P<0.001) and improvements in insulin total AUC, C-peptide total AUC, and the ratio of insulin AUC/glucose AUC were greater in the sitagliptin groups than in the placebo group (all P<0.05).

There were no significant differences between the sitagliptin groups and the placebo group with regard to the overall incidence of adverse events and drug-related adverse events. Three patients experienced serious drug-related adverse events: cholecystitis (n=1 in the placebo group), over-dose of sitagliptin (2 100-mg tablets) resulting in mild diarrhea (n=1 in the sitagliptin 100-mg group), and mild nonalcoholic steatohepatitis (n=1 in the sitagliptin 100-mg group); all 3 patients discontinued the study. Two other patients also discontinued the study because of tachypnea (n=1 in the placebo group) and depression (n=1 in the sitagliptin 100-mg group). Hypoglycemia occurred in 3 patients (1.3%) in the sitagliptin 100-mg group, 2 patients (0.8%) in the sitagliptin 200-mg group, and 2 patients (0.8%) in the placebo group (NS among groups). Other clinical adverse events reported in all groups included constipation, fatigue, influenza, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infections, cough, urinary tract infections, viral infections, hyperglycemia, arthralgia, back pain, myalgia, neck pain, dizziness, headache, and hypertension. Laboratory adverse events reported in all groups included increased levels of creatine kinase and microalbuminuria. Patients in the sitagliptin groups experienced no significant changes in body weight over the course of the study relative to baseline.

The authors conclude that sitagliptin improves glycemic control and beta-cell function in patients with type 2 diabetes. 25 refs. Ed note: This study was sponsored by Merck; 4 of the authors are Merck employees.

Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea.

Mohan V, Yang W, Son H, et al; for Sitagliptin Study 040 Group
Diabetes Res Clin Pract. 2009;83:106–116.

Summary of clinical study created by Merck & Co., Inc. Please consult the full publication for further information.

The efficacy and safety of sitagliptin 100 mg once daily as monotherapy were evaluated in a  randomized, double-blind, placebo-controlled study in 530 Chinese, Indian, and Korean patients with type 2 diabetes inadequately controlled by diet and exercise. After a diet and exercise run-in period of 3-6 weeks, followed by a single-blind placebo run-in period of 2 weeks, patients with HbA_1c ≥7.5% and ≤11.0% and fasting plasma glucose (FPG) ≥7.2 mmol/L and ≤15.6 mmol/L were assigned in a 2:1 ratio to receive sitagliptin (n=352; 152 F, mean age 50.9 years, age range 25-75 years) or placebo (n=178; 72 F, mean age 50.9 years, age range 30-74 years) in tablet form for 18 weeks. The randomized cohort consisted of 245 patients from China, 190 from India, and 95 from Korea. The mean duration of type 2 diabetes at screening was 2 years, and 36% of the patients had not been treated previously with an antihyperglycemic agent. A total of 508 patients (96% of those randomized) were included in the full-analysis-set (FAS) analysis of HbA_1c at 18 weeks, the primary endpoint; 439 patients (83% of those randomized) completed the 18-week study. The proportions of patients discontinuing before study completion were 13% and 25% in the sitagliptin and placebo groups, respectively; the difference was primarily due to higher rates of discontinuation in the placebo group due to FPG values that exceeded prespecified criteria and withdrawal of patient consent.

Analysis showed that, compared with placebo, sitagliptin reduced HbA_1c from a mean of 8.7% at baseline to 8.0% after 18 weeks (-1.0% least-squares [LS]-mean between-group difference overall; P<0.001), with LS-mean reductions in HbA_1c with sitagliptin of -1.4% in India, -1.4% in Korea, and -0.7% in China. For the cohort of patients with baseline HbA_1c ≥10% (n=72), the effect of sitagliptin compared with placebo on HbA_1c was -1.4%, compared with -1.0% for the overall cohort with baseline HbA_1c of 8.7%. The proportion of patients achieving the glycemic goal of HbA_1c <7.0% was significantly (P<0.001) greater with sitagliptin than with placebo; overall, in the cohort of patients with mean baseline HbA_1c of 8.7%, 70/339 patients in the sitagliptin group (20.6% of the FAS population) and 9/169 patients in the placebo group (5.3%) met the goal of HbA_1c <7.0% at 18 weeks. The odds ratio for likelihood of achieving this goal with sitagliptin compared with placebo was 6.6 (95% confidence interval, 3.0 to 14.6). Sitagliptin resulted in a significant (P<0.001) reduction from baseline in FPG at 18 weeks, compared with placebo. The FPG-lowering effect seemed to be nearly complete by 6 weeks and remained stable thereafter. Significant and clinically meaningful reductions in FPG were observed in each of the 3 nationality-defined subpopulations. Sitagliptin resulted in a significant (P<0.001) reduction from baseline in 2-hr postprandial plasma glucose (PPG) at 18 weeks, compared with placebo, with significant and clinically meaningful reductions in 2-hr PPG observed in each of the 3 nationality-defined subpopulations. Several indices of fasting glucoregulation were improved significantly by sitagliptin at 18 weeks (HOMA-IR [P=0.015 for between-group difference] and QUICKI [P=0.005]). Some indices of postprandial b-cell function were also significantly improved by sitagliptin (insulinogenic index and disposition index [both P<0.001]). One patient died during the study: a 58-yr-old hypertensive man in the sitagliptin group with a history of cardiac ischemia who died on study day 20 due to myocardial infarction. This event was considered by the investigator to be unrelated to the study medication.

The incidence of clinical adverse events in the sitagliptin and placebo groups, respectively, was 23.3% and 15.2%; the incidence of drug-related clinical adverse events was 2.8% and 1.7%, respectively, and the incidence of serious drug-related clinical adverse events was 0.3% and 0.6%. Eighteen patients (5.1%) in the sitagliptin group experienced a GI adverse event, including constipation or toothache in 3 patients each; enteritis, epigastric discomfort, gastritis, or periodontitis in 2 patients each; and gingival pain or stomach discomfort in 1 patient each. There were no reports of hypoglycemia. Laboratory adverse events were reported in 6.5% and 7.0% of patients in the sitagliptin and placebo groups, respectively. None were considered serious, and few were considered to be drug-related by the investigators (2.6% and 1.8%, respectively). One patient in each group discontinued treatment because of a laboratory adverse event of increased fasting blood glucose; both events were considered unrelated to the study medication. A small increase from baseline in body weight was observed in the sitagliptin group at 18 weeks; the mean increase was 0.6 +/- 0.1 kg in the sitagliptin group, compared with 0.0 +/- 0.2 kg in the placebo group.

In conclusion, treatment with sitagliptin 100 mg once daily as monotherapy improved fasting and postprandial glycemic control and measures of insulin secretion over 18 weeks in type 2 diabetic patients from China, India, and Korea. Sitagliptin was generally well tolerated, with a low incidence of GI adverse events and no reported hypoglycemic events. 42 refs. Ed. Note: This study was sponsored by Merck & Co., Inc., 6 of the co-authors are current or former Merck employees. This study has ClinicalTrials.gov number NCT00289848.