Combination Of Sitagliptin Research Articles

Assessment of AACE/ACE Recommendations for Initial Dual Antihyperglycemic Therapy Using the Fixed-Dose Combination of Sitagliptin and Metformin Versus Metformin

The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) diabetes algorithm recommends a stratified approach to initial therapy to achieve a glycated hemoglobin (HbA1c) goal of ≤6.5% in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control. Data from a double-blind study in drug-naïve T2DM patients comparing initial monotherapy with metformin (MET) with initial dual therapy with a fixed-dose combination of sitagliptin and MET (SITA/MET FDC) was used to determine AACE/ACE HbA1c goal attainment in these treatment groups. A total of 1,250 patients (mean baseline HbA1c = 9.9%) were randomized 1:1 to SITA/MET FDC 50/500 mg twice daily (b.i.d.) or MET 500 mg b.i.d. for 18 weeks. SITA/MET FDC and MET were uptitrated over 4 weeks to 50/1,000 mg b.i.d. and 1,000 mg b.i.d., respectively. At week 18, a higher percentage of patients receiving SITA/MET FDC had HbA1c levels ≤6.5% and <7% than those receiving MET alone within each of the 3 AACE/ACE HbA1c categories (6.5-7.5%, >7.5-9.0%, and >9.0%). Of patients with a baseline HbA1c >7.5-9.0% who initiated SITA/MET FDC, 48.6% achieved an HbA1c ≤6.5% at week 18 compared with 23.1% of patients who initiated MET monotherapy (P<.001). In patients with a baseline HbA1c >9.0%, 24.0% on SITA/MET FDC achieved an HbA1c ≤6.5% compared with 12.8% on MET alone (P<.001). In T2DM patients with a baseline HbA1c >7.5-9.0%, substantially more achieved the HbA1c goal of ≤6.5% with initial dual therapy (SITA/MET FDC) than with initial monotherapy (MET), which is in agreement with the AACE/ACE diabetes algorithm.

Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone—a factorial study

To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses. Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.

Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function

The effects of sitagliptin and pioglitazone, alone and in combination, on α- and β-cell function were assessed in patients with type 2 diabetes. Following a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4 mmol/l were randomized (1 :1 :1 : 1) to sitagliptin, pioglitazone, sitagliptin + pioglitazone or placebo. At baseline and after 12 weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. After 12 weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with sitagliptin + pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with sitagliptin versus all other treatments and increased with sitagliptin + pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with sitagliptin versus placebo and decreased with sitagliptin + pioglitazone versus pioglitazone or placebo. Φ(s), a measure of dynamic β-cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with sitagliptin + pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and sitagliptin + pioglitazone versus placebo. The disposition index, a measure of the relationship between β-cell function and insulin sensitivity, improved with all active treatments versus placebo. Sitagliptin and pioglitazone enhanced β-cell function (increasing postmeal Φ(s)), and sitagliptin improved α-cell function (decreasing postmeal glucagon) after 12 weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone.

Bone loss in the oestrogen‐depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione

Antihyperglycaemic therapy on bone was evaluated in the ovariectomized (OVX), non-diabetic adult rat. Animals were treated daily for 12 weeks with various doses of sitagliptin, pioglitazone, rosiglitazone, combinations of sitagliptin with pioglitazone or vehicle alone. Sitagliptin target engagement was confirmed by assessing inhibition of plasma dipeptidyl peptidase-4 (DPP-4) and oral glucose tolerance. Parameters related to bone health were evaluated in femur and vertebrae by dual-energy X-ray absorptiometry and histomorphometry. Bone mineral density (BMD) generally did not differ significantly between OVX-sitagliptin-treated animals and OVX-vehicle controls. In lumbar vertebrae, however, there was significantly less BMD loss with increasing sitagliptin dose. Thiazolidinedione (TZD) treatment generally resulted in lower BMD; OVX-TZD-treated (but not OVX-sitagliptin-treated) animals also had lessened cortical thickness in central femur and profoundly greater bone marrow adiposity in lumbar vertebrae. These findings support prior findings with TZDs and suggest a neutral or beneficial impact of DPP-4 inhibition on bone health.

Dipeptidyl peptidase IV inhibitory properties of a whey protein hydrolysate: Influence of fractionation, stability to simulated gastrointestinal digestion and food–drug interaction

The in vitro dipeptidyl peptidase IV (DPP-IV) inhibitory activity of a whey protein hydrolysate (WPH) generated with a food-grade pancreatic enzyme preparation was studied. The 50% inhibitory concentration (IC50) value in the presence of WPH was 1.34 ± 0.11 mg mL−1. Ultrafiltration (UF) fractionation of WPH allowed enrichment in DPP-IV inhibitory peptides. The permeates generated by UF through 5 and 2 kDa membranes along with the hydrophilic fraction isolated by solid-phase extraction were significantly more potent DPP-IV inhibitors than WPH. Simulated gastrointestinal digestion of WPH resulted in an increased DPP-IV inhibitory potency (IC50 value of 1.02 ± 0.05 mg mL−1). Competitive inhibition of DPP-IV was observed with WPH and all its fractions, indicating a direct interaction of the bioactive peptides therein with the active site of DPP-IV. Combinations of sitagliptin, a conventional drug-inhibitor of DPP-IV, and whey-derived peptides resulted in an additive effect on DPP-IV inhibition.

Effects of LX4211, a Dual SGLT1/SGLT2 Inhibitor, Plus Sitagliptin on Postprandial Active GLP-1 and Glycemic Control in Type 2 Diabetes

BackgroundCombination therapy is required to provide adequate glycemic control in many patients with type 2 diabetes mellitus (T2DM). Because sodium-dependent glucose transporter (SGLT)-1 inhibition results in an increased release of glucagon-like peptide (GLP)-1, and because dipeptidyl peptidase (DPP)-4 inhibitors prevent its inactivation, the 2 mechanisms together provide an intriguing potential combination therapy. ObjectivesThis combination was explored in preclinical models and then tested in patients with T2DM to compare the effects of single-dose LX4211 400 mg and sitagliptin 100 mg, administered as monotherapy or in combination, on GLP-1, peptide tyrosine tyrosine (PYY), gastric inhibitory peptide (GIP), glucose, and insulin. MethodsPreclinical: Obese male C57BL6J mice were assigned to 1 of 4 treatment groups: LX4211 60 mg/kg, sitagliptin 30 mg/kg, LX4211 + sitagliptin, or inactive vehicle. Clinical: This 3-treatment, 3-crossover, randomized, open-label study was conducted at a single center. Patients on metformin monotherapy were washed out from metformin and were randomly assigned to receive sequences of single-dose LX4211, sitagliptin, or the combination. In both studies, blood was collected for the analysis of pharmacodynamic variables (GLP-1, PYY, GIP, glucose, and insulin). In the clinical study, urine was collected to assess urinary glucose excretion. ResultsPreclinical: 120 mice were treated and assessed (5/time point/treatment group). With repeat daily dosing, the combination was associated with apparently synergistic increases in active GLP-1 relative to monotherapy with either agent; this finding was supported by findings from an additional 14-day repeated-dose experiment. Clinical: 18 patients were enrolled and treated (mean age, 49 years; 56% male; 89% white). The LX4211 + sitagliptin combination was associated with significantly increased active GLP-1, total GLP-1, and total PYY; with a significant reduction in total GIP; and with a significantly improved blood glucose level, with less insulin, compared with sitagliptin monotherapy. LX4211 was associated with a significant increase in total GLP-1 and PYY and a reduced total GIP, likely due to a reduction in SGLT1-mediated intestinal glucose absorption, whereas sitagliptin was associated with suppression of all 3 peptides relative to baseline. All treatments were well tolerated, with no evidence of diarrhea with LX4211 treatment. ConclusionsThe findings from the preclinical studies suggest that the LX4211 + sitagliptin combination produced synergistic increases in active GLP-1 after a meal challenge containing glucose. These initial clinical results also suggest that a LX4211 + DPP-4 inhibitor combination may provide an option in patients with T2DM. The potential long-term clinical benefits of such combination treatment need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01441232.

Stimulating β-Cell Regeneration by Combining a GPR119 Agonist with a DPP-IV Inhibitor

BackgroundActivating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.Materials & MethodsDiabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.ResultsNormoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.ConclusionOur results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.

Effect of Sitagliptin in Combination with Glimepiride on Glycemic Control and Islet Cell Diameter/Proliferation in A Model of Type 2 Diabetic Rats

The aim of the present study was to investigate the effect of monotherapy with sitagliptin, or its combination with glimepiride in glycemic control, islet cell diameter and its proliferation in type 2 diabetic rats. Rats were fed with a high fat diet followed by injection with a low dose of streptozotocin to induce type 2 diabetes. Then, rats were switched to normal diet and for other 28 days. Monotherapy with sitagliptin did not affect the body weight, while its combination with glimepiride did not induce a significant change. The combination increased the % change in body weight compared to sitagliptin alone. All the treatment regiment enhanced glucose clearance as indicated by a reduction in the area under the curve. Pancreatic immunohistochemistry and morphometric analysis were performed to measure the diameter of islet cells, insulin-positive area and the number of Ki-67 positive nuclei. In sitagliptin group, diameter of large-sized islets was 2-fold greater than those observed in diabetic group. The monotherapy with glimepiride did not change the islet-cell diameter. Further, the combination group showed better glycemic control and greater cell proliferation compared to monotherapies. Consequently, we conclude that the combination therapy of sitagliptin/glimepiride has synergistic effect.

Management of dyslipidemia and hyperglycemia with a fixed-dose combination of sitagliptin and simvastatin.

The risk of death due to heart disease and stroke is up to four times higher in individuals with diabetes compared to individuals without diabetes. Most guidelines that address treatment of dyslipidemia in patients with diabetes consider diabetes a cardiovascular disease (CVD) “risk equivalent” and recommend intensive treatment of dyslipidemia for the purpose of CVD prevention. Statins (3-hydroxy 3-methylglutaryl coenzyme A reductase [HMG-CoA reductase] inhibitors) are first-line agents in achieving lipid goals as an adjunct to diet and exercise and should be used in most patients. In addition to lipid management and blood pressure control, glycemic control is a basic component in the management of diabetes. Glycemic control is achieved by combining diabetes self-management education, diet and exercise, and, where required, antihyperglycemic agents (OHAs). Persistence and adherence to therapy are critical in achieving recommended treatment goals. However, overall compliance with concomitantly prescribed OHAs and statins is low in patients with type 2 diabetes. Fixed-dose combination (FDC) therapies have been shown to improve adherence by reducing pill burden, the complexity of treatment regimen, and, potentially, cost. Based on the available evidence regarding the pharmacokinetics and the efficacy and safety profiles of each component drug, the sitagliptin/simvastatin FDC may provide a rational and well-tolerated approach to achieving better adherence to multiple-drug therapy and improved lipid lowering and glycemic control, with consequent reduction in cardiovascular risk, diabetic microvascular disease, and mortality in diabetic patients for whom treatment with both compounds is appropriate.

Hypoglycemia due to the Combination of Sitagliptin and a SU Drug, and Changes in the Daily Dose of the SU Drug Based on the New Safety Measures

Hypoglycemia due to the Combination of Sitagliptin and a SU Drug, and Changes in the Daily Dose of the SU Drug Based on the New Safety Measures

Effects of a combination of sitagliptin plus metformin vs metformin monotherapy on glycemic control, β-cell function and insulin resistance in type 2 diabetic patients

AimsTo evaluate the impact on glycemic control, insulin resistance, and insulin secretion of sitagliptin+metformin compared to metformin in type 2 diabetic patients. MethodsPatients were instructed to take metformin for 8±2 months, then they were randomly assigned to sitaglipin 100mg or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, adiponectin (ADN), and high sensitivity-C reactive protein (Hs-CRP). Before, and after 12 months since the addition of sitagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. ResultsBoth treatments similarly decreased body weight, and BMI; on the other hand, they both improved glycemic control, glucagon and HOMA-IR, but sitagliptin+metformin were more effective in reducing these parameters. Sitagliptin+metformin, but not placebo+metformin, decreased FPPr, FPPR/FPI ratio, and increased C-peptide values, even if no differences between the groups were recorded. Sitaglitin+metformin gave also a greater increase of HOMA-β, M value, C-peptide response to arginine and disposition index compared to placebo+metformin group. ConclusionsOther than improving glycemic control, sitagliptin+metformin also improved β-cell function better than metformin alone.

Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes

Introduction: Patients with type 2 diabetes (T2DM) are exposed to a high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing CVD events in T2DM patients. Dipeptidylpeptidase-4 inhibitors (gliptins), which are increasingly used to target hyperglycemia, also offer promising preliminary results regarding a possible reduction in CVD events. As most patients with T2DM may be treated with both a statin and a gliptin, dual pharmacological therapy, possibly as a fixed-dose combination (FDC), deserves further consideration.Areas covered: The reader is provided with an update of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin and sitagliptin. The article provides an analysis of the potential PK/PD interactions between the two compounds and puts into perspective the potential cardiovascular protection that such a dual therapy may offer in patients with T2DM.Expert opinion: Atorvastatin and sitagliptin are not prone to PK drug–drug interactions. Their coadministration, either separately or in an FDC, improves both blood glucose levels and cholesterol concentrations, without clinically relevant adverse events. The atorvastatin plus sitagliptin combination may be used to reduce LDL cholesterol and hyperglycemia in patients with T2DM, with the aim to improve CVD prognosis and adherence to therapy.

Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54‐week study

To assess the 54-week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazone was increased from 30 to 45 mg/day, in drug-naÏve patients with type 2 diabetes mellitus and inadequate glycaemic control [haemoglobin A1c (HbA1c) 8-12%]. Following a 24-week, randomized, double-blind, parallel-group study (Sitagliptin Protocol 064, Clinicaltrials.gov: NCT00397631; Yoon KH, Shockey GR, Teng R et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycaemic control and measures of beta-cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154-164) in which patients were treated with the combination of sitagliptin 100 mg/day and pioglitazone 30 mg/day or monotherapy with pioglitazone 30 mg/day, patients entered a 30-week extension study. In the extension study, the pioglitazone dose was increased from 30 to 45 mg/day in both groups. Depending upon treatment allocation, patients took one tablet of sitagliptin 100 mg or matching placebo daily. Pioglitazone was administered in an open-label fashion as a single 45-mg tablet taken once daily. Patients not meeting specific glycaemic goals in the extension study were rescued with metformin therapy. Efficacy and safety results for the extension study excluded data after initiation of rescue therapy. Of the 520 patients initially randomized, 446 completed the base study and, of these, 317 entered the extension. In this extension study cohort, the mean reductions from baseline in HbA1c and fasting plasma glucose (FPG) at the end of the base study (week 24) were -2.5% and -62.1 mg/dl with the combination of sitagliptin 100 mg and pioglitazone 30 mg versus -1.9% and -48.7 mg/dl with pioglitazone monotherapy. At the end of the extension study (week 54), the mean reduction in haemoglobin A1c (HbA1c) was -2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg versus -1.9% with pioglitazone monotherapy [between-group difference (95% CI) = -0.5% (-0.8, -0.3)] and the mean reduction in FPG was -61.3 mg/dl versus -52.8 mg/dl, respectively [between-group difference (95% CI) = -8.5 mg/dl (-16.3, -0.7)]. Safety and tolerability of initial treatment with the combination of sitagliptin and pioglitazone and pioglitazone monotherapy were similar. As expected, increases in body weight from baseline were observed in both treatment groups at week 54: 4.8 and 4.1 kg in the combination and monotherapy groups, respectively [between-group difference (95% CI) = 0.7 kg (-0.7, 2.1)]. In this study, initial combination therapy with sitagliptin 100 mg and pioglitazone 30 mg increased to 45 mg after 24 weeks led to a substantial and durable incremental improvement in glycaemic control compared with initial treatment with pioglitazone monotherapy during a 54-week treatment period. Both initial combination therapy with sitagliptin and pioglitazone and pioglitazone monotherapy were generally well tolerated (Clinicaltrials.gov: NCT01028391).

Initial therapy with the fixed‐dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes

To evaluate the efficacy and safety of initial therapy with a fixed-dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug-naÏve patients with type 2 diabetes. After a 2-week single-blind placebo run-in period, patients with type 2 diabetes, HbA1c of 7.5-12% and not on antihyperglycaemic agent therapy were randomized in a double-blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up-titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were -1.9 and -1.4% for sitagliptin/metformin and pioglitazone, respectively (between-group difference = -0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [-56.0 mg/dl (-3.11 mmol/l) vs. -44.0 mg/dl (-2.45 mmol/l), p < 0.001] and in 2-h post-meal glucose [-102.2 mg/dl (-5.68 mmol/l) vs. -82.0 mg/dl (-4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [-40.5 mg/dl (-2.25 mmol/l) vs. -13.0 mg/dl (-0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β-cell function (HOMA-β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA-IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (-1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between-group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between-group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.

Effect of initial combination therapy with sitagliptin and metformin on β‐cell function in patients with type 2 diabetes

To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β-cell function in patients with type 2 diabetes. The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI. At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β-cell function relative to their respective monotherapy groups. After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β-cell function were found with treatments for up to 2 years.

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes

The efficacy and safety of sitagliptin (SITA) monotherapy and SITA/metformin (MET) vs. pioglitazone (PIO) were assessed in patients with type 2 diabetes and moderate-to-severe hyperglycaemia (A1C = 7.5-12.0%). In an initial 12-week phase (Phase A), 492 patients were randomised 1 : 1 in a double-blind fashion to SITA (100 mg qd) or PIO (15 mg qd, up-titrated to 30 mg after 6 weeks). In Phase B (28 additional weeks), the SITA group was switched to SITA/MET (up-titrated to 50/1000 mg bid over 4 weeks) and the PIO group was up-titrated to 45 mg qd At the end of Phase A, mean changes from baseline were -1.0% and -0.9% for A1C; -26.6 mg/dl and -28.0 mg/dl for fasting plasma glucose; and -52.8 mg/dl and -50.1 mg/dl for 2-h post-meal glucose for SITA and PIO, respectively. At the end of Phase B, improvements in glycaemic parameters were greater with SITA/MET vs. PIO: -1.7% vs. -1.4% for A1C (p = 0.002); -45.8 mg/dl vs. -37.6 mg/dl for fasting plasma glucose (p = 0.03); -90.3 mg/dl vs. -69.1 mg/dl for 2-h postmeal glucose (p = 0.001); and 55.0% vs. 40.5% for patients with A1C < 7% (p = 0.004). A numerically higher incidence of gastrointestinal adverse events and a significantly lower incidence of oedema were observed with SITA/MET vs. PIO. The incidence of hypoglycaemia was similarly low in both groups. Body weight decreased with SITA/MET and increased with PIO (-1.1 kg vs. 3.4 kg; p < 0.001). Improvements in glycaemic control were greater with SITA/MET vs. PIO, with weight loss vs. weight gain. Both treatments were generally well tolerated.

Sitagliptin and metformin combination therapy for the treatment of Type 2 diabetes

Insulin secretion and insulin sensitivity are impaired in Type 2 diabetes. Metformin improves insulin sensitivity by inhibiting hepatic glucose release. It is the preferred drug for first-line treatment in Type 2 diabetes. Sitagliptin, the first marketed dipeptidyl peptidase-IV inhibitor, improves insulin and glucagon secretions of the pancreatic β- and α-cells, respectively, in a strictly glucose-dependent manner by raising endogenous active glucagon-like peptide-1 concentrations. The combination of metformin and sitagliptin thus offers a beneficial and complementary addition of important drug actions on insulin resistance and insulin secretion. Metformin and sitagliptin are also available as a fixed-dose combination. This article reviews the published clinical studies on both substances and their combination, and evaluates the potential benefit of the metformin plus sitagliptin combination.

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus

This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed-dose combination of sitagliptin and metformin versus metformin monotherapy in drug-naive patients with type 2 diabetes. This double-blind study (18-week Phase A and 26-week Phase B) randomized 1250 drug-naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. At week 18, mean change from baseline HbA1c was -2.4% for sitagliptin/metformin FDC and -1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (-3.8 mmol/l) versus metformin monotherapy (-3.0 mmol/l; p < 0.001). Homeostasis model assessment of β-cell function (HOMA-β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.

257 Acute Interstitial Nephritis Associated with Sitagliptin Use

ACUTE INTERSTITIAL NEPHRITIS ASSOCIATED WITH SITAGLIPTIN USE Mohammad Quasem, Yan Liu. United Health Services Hospitals, Binghamton, New York, USA. Sitagliptin is an oral hypoglycemic agent classified under Dipeptidyl 4 (DPP-4) inhibitor. It is used for treatment of type 2 diabetes. Apart from hypoglycemia, common adverse effects are mainly nasopharyngitis (5%) and gastrointestinal (2-4%). No report of acute interstitial nephritis (AIN) from Sitagliptin has, so far, been reported although a case of rhabdomyolysis and acute renal failure (ARF) from combination of Sitagliptin and Simvastatin was reported about two years ago (Diabet Med: 2008). We present a patient who developed ARF after starting Sitagliptin. She developed an erythematous rash day after Sitagliptin was started which rapidly spread all over her body. At the same time, her renal function also got worse with serum creatinine as high as 4.2 after six days (baseline serum creatinine 1.5-1.7) with peripheral blood leukocytosis and eosinophilia. Sitagliptin was discontinued and patient was put on steroid. Renal function gradually returned to baseline. Drugs are the most common cause of AIN. Although kidney biopsy was not done, the clinical scenario, the time course of drug exposure and improvement of renal function on withdrawal (plus steroid) suggested Sitagliptin was the cause. With the widespread use of Sitagliptin, increased awareness for AIN is needed.

Efficacy and safety of insulin detemir once daily in combination with sitagliptin and metformin: the TRANSITION randomized controlled trial

The aim of this trial was to evaluate the efficacy and safety of the combination of once-daily insulin detemir (IDet) and sitagliptin (SITA) versus SITA ± sulphonylurea (SU), both in combination with metformin (MET) in insulin-naive subjects. In a 26-week, open-label, randomized, parallel-group study in type 2 diabetes, insulin-naive subjects concomitantly treated with MET ± second oral antidiabetic drug (OAD) were randomized 1 : 1 to IDet + SITA + MET or SITA + MET ± SU. All continued with MET treatment, and those treated with SU continued if randomized to SITA + MET ± SU. Efficacy endpoints included glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), 9-point self-measured plasma glucose (SMPG), weight, body mass index (BMI). Safety endpoints included adverse events (AEs) and hypoglycaemia. Significantly higher reductions in HbA1c, FPG and SMPG were achieved with IDet + SITA + MET compared with SITA + MET ± SU. Estimated HbA1c decreased by 1.44% in the IDet + SITA + MET group versus 0.89% in SITA + MET ± SU, p < 0.001. FPG decreased by 3.7 mmol/l (66.3 mg/dl) versus 1.2 mmol/l (22.2 mg/dl), p < 0.001, respectively. Small decreases in weight and BMI were observed in both arms, with no significant differences. AEs were mild or moderate and were more common in the SITA + MET ± SU arm than in the IDet + SITA + MET arm. There was no major hypoglycaemia. Observed rates of hypoglycaemia were very low (1.3/1.7 episodes/patient year) in both arms. The subgroup treated with MET and SUs prior to the trial achieved similar results. The combination of once-daily IDet with SITA showed a clinically and significantly better improvement in glycaemic control than SITA in combination with or without SUs. Both regimens were associated with a low rate of hypoglycaemia and slight weight reduction.