Progression to insulin therapy among patients with type 2 diabetes treated with sitagliptin or sulphonylurea plus metformin dual therapy.

AIM: To assess time to insulin initiation among patients with type 2 diabetes mellitus (T2DM) treated with sitagliptin versus sulphonylurea as add-on to metformin. METHODS: This retrospective cohort study used GE Centricity electronic medical records and included patients aged ≥18 years with continuous medical records and an initial prescription of sitagliptin or sulphonylurea (index date) with metformin for ≥90 days during 2006-2013. Sitagliptin and sulphonylurea users were matched 1 : 1 using propensity score matching, and differences in insulin initiation were assessed using Kaplan-Meier curves and Cox regression. We used conditional logistic regression to examine the likelihood of insulin use 1-6 years after the index date for each year. RESULTS: Propensity score matching produced 3864 matched pairs. Kaplan-Meier analysis showed that sitagliptin users had a lower risk of insulin initiation compared with sulphonylurea users (p = 0.003), with 26.6% of sitagliptin users initiating insulin versus 34.1% of sulphonylurea users over 6 years. This finding remained significant after adjusting for baseline characteristics (hazard ratio 0.76, 95% confidence interval 0.65-0.90). Conditional logistic regression analyses confirmed that sitagliptin users were less likely to initiate insulin compared with sulphonylurea users [odds ratios for years 1-6: 0.77, 0.79, 0.81, 0.57, 0.29 and 0.75, respectively (p < 0.05 for years 4 and 5)]. CONCLUSIONS: In this real-world matched cohort study, patients with T2DM treated with sitagliptin had a significantly lower risk of insulin initiation compared with patients treated with sulphonylurea, both as add-on to metformin.

Long-term efficacy of sitagliptin as either monotherapy or add-on therapy to metformin: improvement in glycemic control over 2 years in patients with type 2 diabetes.

OBJECTIVE: To evaluate the efficacy of once daily sitagliptin 100 mg as monotherapy or as add-on to metformin in patients with type 2 diabetes mellitus (T2DM) over 2 years of treatment. RESEARCH DESIGN AND METHODS: The monotherapy analysis used pooled 104 week data from 64 patients in two randomized, double-blind trials evaluating the safety and efficacy of sitagliptin monotherapy. Data used were from patients who were randomized to sitagliptin 100 mg/day, were not on an antihyperglycemic agent at the screening visit, had baseline A1C of 7.0%-10.0%, and had Week 104 A1C measurements. The add-on to metformin analysis used pooled data from 347 patients in two randomized double-blind trials evaluating the safety and efficacy of sitagliptin + metformin combination therapy. Data used were from patients who were randomized to sitagliptin 100 mg/day + metformin ≥1500 mg/day, had baseline A1C of 7%-10%, and had Week 104 A1C measurements. Excluded from either analysis were patients who discontinued prior to 2 years (e.g., due to lack of efficacy, a need for rescue medications, or adverse experiences). Analysis endpoints were A1C, fasting plasma glucose (FPG), HOMA-ß, proinsulin/insulin (P/I) ratio, and for monotherapy, 2 hour post-meal plasma glucose (PMG). RESULTS: For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2 hour PMG decreased from baseline values of 7.9%, 156 mg/dL, and 223 mg/dL to 6.9%, 143 mg/dL, and 191 mg/dL, respectively, while HOMA-ß increased from 67% to 85% and P/I ratio improved from 0.57 to 0.28. For the pooled add-on to metformin cohort, after 2 years of treatment, mean A1C and FPG decreased from baseline values of 7.7% and 160 mg/dL to 6.9% and 140 mg/dL, respectively, while HOMA-ß increased from 50% to 62% and P/I ratio improved from 0.33 to 0.28. These analyses are limited in that only patients who were able to complete 104 weeks of study were included. CONCLUSION: In the subset of patients with T2DM who maintained and completed treatment for 2 years with sitagliptin as monotherapy or as add-on to metformin, improvements in glycemic control and measures of ß-cell function were observed over the course of treatment.

A comparison of glycaemic effects of sitagliptin and sulfonylureas in elderly patients with type 2 diabetes mellitus.

INTRODUCTION: In the USA, 45% of patients with type 2 diabetes mellitus (T2DM) are elderly (≥ 65 years old). In general, use of sulfonylurea increases with patient age as does the associated risk for hypoglycaemia, and the consequences of hypoglycaemia can be more pronounced in elderly patients. Sitagliptin, a DPP-4 inhibitor, improves glycaemic control in adult patients of all ages with T2DM, with a low risk of hypoglycaemia when used alone or in combination with other antidiabetic agents that are not generally associated with hypoglycaemia when used independently. METHODS: In a post hoc analysis, pooled data from elderly patients who participated in one of three double-blind studies comparing the effects of therapy with sitagliptin (100 mg/day) vs. sulfonylurea (in titrated doses) were analysed for changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight and for the incidence of reported symptomatic hypoglycaemia. In these studies, patients on diet alone or metformin were randomised to sitagliptin or glipizide for 104 weeks (studies 1 and 2) or glimepiride for 30 weeks (study 3). The analysis included 372 elderly patients who completed a trial through 25 or 30 weeks. RESULTS: Both HbA1c and FPG decreased from baseline with each treatment, with no statistically significant differences between treatments. A significantly lower incidence of reported hypoglycaemia was observed with sitagliptin compared with sulfonylurea (6.2% vs. 27.8%; p < 0.001). Body weight decreased significantly with sitagliptin but not with sulfonylurea. Significantly more patients on sitagliptin than on sulfonylureas achieved a composite end-point of >0.5% HbA1c reduction with no reported hypoglycaemia or increase in body weight (44.1% vs. 16.0%; p < 0.001). CONCLUSION: In this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.

Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis.

AIMS: Guidelines for type 2 diabetes recommend add-on agents when metformin alone fails to provide adequate glycaemic control. However, early combination therapy may benefit health outcomes. We conducted a systematic review and meta-analysis to investigate this question. METHODS: We searched MEDLINE and Cochrane CENTRAL (up to July 2012) without language restrictions. We sought randomized controlled trials (RCTs) evaluating initial combination therapy with metformin versus metformin monotherapy in patients with untreated type 2 diabetes. Weighted mean differences (WMDs) for changes from baseline and relative risks (RRs) [with 95% confidence intervals (CIs)] were calculated using random-effects model. RESULTS: In 15 RCTs (N = 6693), the mean age range was 48.4-62.7 years; mean baseline glycosylated haemoglobin (A1c) was 7.2-9.9% and mean diabetes duration was 1.6-4.1 years, with median follow-up of 6 months and with 13 comparisons for A1c change, 14 comparisons for A1c goal attainment of <7% and 13 comparisons for change in fasting plasma glucose (FPG). Drugs combined with metformin included thiazolidinediones (TZDs), insulin secretagogues, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium glucose transporterase (SGLT-2) inhibitors. Compared to metformin alone, combination therapy with metformin provided statistically significant reductions in A1c (WMD -0.43%, 95% CI -0.56, -0.30), increases in attainment of A1c goal of less than 7% (RR 1.40, 95% CI 1.33-1.48) and reductions in FPG (WMD -14.30 mg/dl, 95% CI -16.09, -12.51). CONCLUSIONS: These results suggest a potential benefit of initial combination therapy on glycaemic outcomes in diabetes compared to metformin monotherapy across a wide range of baseline A1c levels. Further research should explore if early combination treatment may also affect longer term health outcomes in diabetes.

Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis.

AIMS: Sulphonylurea use has been linked with increased cardiovascular disease risk; however, previous studies have been inconsistent. Type 2 diabetes independently increases risk for cardiovascular disease, so understanding the link between longer-term use of anti-diabetic medications and cardiovascular disease has important clinical implications. METHODS: Literature search in MEDLINE and CENTRAL was conducted throughout December 2011 for clinical and observational studies that reported the association between sulphonylurea and cardiovascular disease events. Ratios (relative risk, odds ratios or hazard ratios) adjusted for potential confounders (concomitant medications, baseline cardiovascular risk, diabetes severity) were pooled using a random-effects model to yield relative risks and associated 95% confidence intervals. RESULTS: This meta-analysis included 33 studies (n = 1,325,446 patients), followed for a range of 0.46-10.4 years. In all studies, compared with other oral diabetes drugs, sulphonylurea use was associated with a significantly increased risk of cardiovascular death (relative risk 1.27, 95% confidence interval 1.18-1.34, n = 27 comparisons) and composite cardiovascular event (including myocardial infarction, stroke, cardiovascular-related hospitalization or cardiovascular death) (relative risk 1.10, 95% confidence interval 1.04-1.16, n = 43 comparisons). In studies comparing sulphonylurea vs. metformin, these relative risks were 1.26 (95% confidence interval 1.17-1.35, n = 17 comparisons) and 1.18 (95%confidence interval 1.13-1.24, n = 16 comparisons), respectively. CONCLUSIONS: Results suggest that sulphonylurea use may elevate the risk of cardiovascular disease among patients with diabetes. This meta-analysis expands the pool of studies evaluating cardiovascular mortality compared with prior observations while using adjusted estimates, and assessing an additional outcome of a composite cardiovascular event. This finding warrants consideration in clinical practice when other treatment options may be available.

Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial.

AIMS/HYPOTHESIS: The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy. METHODS: In a 26 week, open-label study, 653 patients (baseline HbA1c = 8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18-79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA1c ≥ 7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA1c ≥ 7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA1c change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%. RESULTS: In the PP population (522 patients included: oral strategy, n = 269; injectable strategy, n = 253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA1c decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA1c at week 26 was -1.3% (95% CI -1.4, -1.2) in the oral strategy group and -1.4% (95% CI -1.5, -1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy. CONCLUSIONS/INTERPRETATION: An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA1c and had good overall tolerability. Trial registration ClinicalTrials.gov NCT01296412 Funding The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.

Recent trends in the characteristics of patients prescribed sitagliptin and other oral antihyperglycaemic agents in a large U.S. claims database.

AIM: This study was designed to determine if differences in baseline characteristics of patients with type 2 diabetes mellitus (T2DM) being treated with sitagliptin vs. other oral antihyperglycaemic agents (OAHA) during the initial 2 years following sitagliptin's introduction in the U.S. continued during the second 2 years of sitagliptin availability. METHODS: Patients with T2DM and at least one new prescription for sitagliptin or another OAHA from Oct 2006 to April 2010 were identified in an insurance claims database. Multivariate logistic regression adjusting for age, gender, treatment type (monotherapy, dual or triple therapy), new or existing T2DM diagnosis, and comorbidities and diabetes complications in the prior 12 months was used to estimate odds ratios for sitagliptin vs. other OAHAs. RESULTS: During 2006-2007 or 2008-2010, new sitagliptin users were older and more likely to be male, have prior diagnosis of T2DM, or initiating combination therapy compared with new users of other OAHAs. Prevalence of comorbidities and complications was consistently higher for new sitagliptin users across most of the conditions assessed during both time periods. CONCLUSIONS: New sitagliptin users consistently tended to be older and have greater comorbidity/complication burden compared with new users of other OAHAs. These differences in baseline characteristics persisted up to 4 years postapproval. This observation has significant implications for observational studies using electronic medical record or insurance claims databases. Appropriate adjustment is needed to try to control for potential confounding and channelling bias resulting from this non-random prescribing pattern, and the limitations of such analyses acknowledged.

Impact of diabetes duration and chronic pancreatitis on the association between type 2 diabetes and pancreatic cancer risk.

AIM: To examine the impact of diabetes duration, chronic pancreatitis and other factors on pancreatic cancer risk. METHODS: This retrospective cohort study using the UK General Practice Research Database compared pancreatic cancer incidence and risk in patients with type 2 diabetes mellitus (T2DM) versus patients without diabetes. Multivariate Cox regression adjusting for age, sex, history of chronic pancreatitis, gallbladder disease, obesity, smoking and alcohol use and Charlson comorbidity index was used to estimate hazard ratio (HR) [95% confidence interval, CI]. Analyses were repeated using various time windows for diabetes duration. RESULTS: A total of 1903 incident pancreatic cancers were identified, 436 in patients with T2DM (78.76 per 100 000 person-years [95% CI: 71.54, 86.51]) and 1467 in patients without diabetes (11.46 per 100 000 person-years [10.88, 12.06]). Pancreatic cancer risk was significant for T2DM (adjusted HR 1.80 [1.52, 2.14]), increasing age, history of chronic pancreatitis and tobacco use. For patients with chronic pancreatitis and T2DM, the adjusted HR was 12.12 [6.02, 24.40]. Incidence was highest in patients with ≥5 year duration of T2DM. In patient populations with duration of T2DM ranging from ≥1 to ≥5 years, adjusted HRs remained significant but point estimates attenuated slightly with longer duration of T2DM. CONCLUSIONS: Patients with T2DM had an 80% increased risk of pancreatic cancer versus patients without diabetes. Patients with T2DM and chronic pancreatitis were 12 times more likely to develop pancreatic cancer.

Time to treatment initiation with oral antihyperglycaemic therapy in US patients with newly diagnosed type 2 diabetes.

AIM: To compare the time from initial diagnosis to initiation with oral antihyperglycaemic treatment in younger versus older patients with type 2 diabetes, and to evaluate factors associated with initiating treatment. METHODS: This was a retrospective US cohort study with a 2-year follow-up period after diagnosis of type 2 diabetes. Using the General Electric Healthcare's Clinical Data Services electronic medical record database, eligible patients included those aged ≥30 years at initial diagnosis of type 2 diabetes between January 2003 and December 2005. In the 2-year period following diagnosis, the time to the first prescription of an oral antihyperglycaemic agent was compared between younger (30-64 years) and older (≥65 years) patients. Factors associated with time to treatment with an oral antihyperglycaemic agent were examined using Cox proportional hazards regression. RESULTS: Of the 10 743 patients with newly diagnosed type 2 diabetes, 43% were ≥65 years old. The mean age at diagnosis was 73 years for older patients and 52 years for younger patients. Compared to younger patients, a greater proportion of older patients had a baseline haemoglobin A1c (HbA1c) value <7% (38 vs. 32%; p < 0.001). In the 2-year follow-up period, a significantly greater proportion of younger patients (59%) received oral antihyperglycaemic treatment compared to older patients (44%; p < 0.001). The median time between diagnosis and initiating treatment with an oral antihyperglycaemic agent was 350 days for younger patients and >2 years for older patients. After adjusting for covariates, older patients had a greater risk of not receiving treatment with oral antihyperglycaemic therapy than younger patients [adjusted hazard ratio = 0.82 (95% confidence interval: 0.75, 0.90)]. CONCLUSIONS: In patients with newly diagnosed type 2 diabetes, the time to initiation of oral antihyperglycaemic therapy was significantly longer in older patients (≥65 years old) than younger patients (<65 years).

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.

AIMS: 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. METHODS: 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. RESULTS: 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 ß-cell function (HOMA-ß) 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). CONCLUSION: 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.

The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial.

AIMS: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. METHODS: Patients with type 2 diabetes (age ≥ 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA(1c) < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. RESULTS: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel-Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. CONCLUSIONS: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin.

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

AIM: 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%). METHODS: 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 RESULTS: 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). CONCLUSION: Improvements in glycaemic control were greater with SITA/MET vs. PIO, with weight loss vs. weight gain. Both treatments were generally well tolerated.

Treatment intensification in patients with type 2 diabetes who failed metformin monotherapy.

AIM: To evaluate the time to and factors associated with treatment intensification in patients with type 2 diabetes who failed metformin monotherapy. METHODS: In a retrospective analysis using a large US electronic medical record database, eligible patients included those with type 2 diabetes and an HbA(1c) of ≥7.0% or at least two fasting blood glucose levels of ≥126 mg/dl while on metformin monotherapy for at least 6 months within the period of 1 January 1997 to 31 December 2008. Time to treatment intensification was calculated as the time between index date (date on which HbA(1c) ≥ 7% after metformin monotherapy for at least 6 months) and first prescription for additional antihyperglycaemic agent during follow-up period. All patients were required to have data for at least 12 months prior to and following the index date. A Cox proportional hazards model was employed to determine patient baseline characteristics associated with time to treatment intensification. RESULTS: Of the 12 566 patients identified, mean age at index date was 63 years and 51% were female. Mean index HbA(1c) was 8.0% overall, with 66, 19 and 15% of patients having an index HbA(1c) of 7 to <8%, 8 to <9% and ≥9%, respectively. Median time to treatment intensification was 14.0 months overall and 19.0, 8.7 and 4.5 months for patients with index HbA(1c) of 7 to <8%, 8 to <9% and ≥9%, respectively. Factors associated with treatment intensification included higher index HbA(1c) , younger age, higher Charlson co-morbidity index, metformin daily dose ≥ 1500 mg and later index date (all p < 0.05). CONCLUSIONS: In US clinical practice, median time to receive additional antihyperglycaemic medication is more than 1 year for patients with type 2 diabetes who failed metformin monotherapy.

Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis.

Recent case reports of acute pancreatitis in patients with type 2 diabetes (T2DM) treated with incretin-based therapies have triggered interest regarding the possibility of a mechanism-based association between pancreatitis and glucagon-like peptide-1 mimetics or dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review was to describe the controlled preclinical and clinical trial data regarding the incidence of pancreatitis with sitagliptin, the first DPP-4 inhibitor approved for use in patients with T2DM. Tissue samples from multiple animal species treated with sitagliptin for up to 2 years at plasma exposures substantially in excess of human exposure were evaluated to determine whether any potential gross or histomorphological changes suggestive of pancreatitis occurred. Sections were prepared by routine methods, stained with haematoxylin and eosin and examined microscopically. A pooled analysis of 19 controlled clinical trials, comprising 10,246 patients with T2DM treated for up to 2 years, was performed using patient-level data from each study for the evaluation of clinical and laboratory adverse events. Adverse events were encoded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 system. Incidences of adverse events were adjusted for patient exposure. Tissue samples from preclinical studies in multiple animal species did not reveal any evidence of treatment-related pancreatitis. The pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patient-years vs. 0.10 events per 100 patient-years, respectively). Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin.

Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes.

OBJECTIVE: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. METHODS: After a 2 week placebo run-in period, eligible patients inadequately controlled on long-acting, intermediate-acting or premixed insulin (HbA1c > or = 7.5% and < or = 11%), were randomised 1:1 to the addition of once-daily sitagliptin 100 mg or matching placebo over a 24-week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. RESULTS: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m(2)), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long-acting and intermediate-acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2-h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol-specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. CONCLUSION: In this 24-week study, the addition of sitagliptin to ongoing, stable-dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.

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

AIM: To assess the addition of sitagliptin to ongoing metformin therapy in patients with type 2 diabetes who were inadequately controlled [haemoglobin A(1c) (HbA(1c)) 7-11%] on metformin monotherapy. METHODS: Patients (n = 273) on metformin (>/=1500 mg/day) were randomized to receive the addition of once-daily placebo, sitagliptin 100 mg or rosiglitazone 8 mg in a 1 : 1 : 1 ratio for 18 weeks. The efficacy analysis was based on the all-patients-treated population using an analysis of co-variance with change in HbA(1c) from baseline as the primary endpoint. RESULTS: The mean baseline HbA(1c) was 7.7% for the entire cohort. After 18 weeks, both active add-on therapies led to greater improvements in HbA(1c) from baseline: -0.73% for sitagliptin (p < 0.001 vs. placebo) and -0.79% for rosiglitazone compared with -0.22% for placebo. No difference was observed between the sitagliptin and rosiglitazone treatments (0.06% [95% confidence interval (CI): -0.14 to 0.25]). The proportion of patients achieving an HbA(1c) < 7% was greater with sitagliptin (55%) and rosiglitazone (63%) compared with placebo (38%). Body weight increased from baseline with rosiglitazone (1.5 kg) compared with body weight reduction with sitagliptin (-0.4 kg) and placebo (-0.8 kg). The difference in body weight between the sitagliptin and rosiglitazone groups was 1.9 kg (95% CI: 1.3-2.5). In a prespecified analysis, the proportion of patients experiencing a greater than 3-kg increase in body weight was 21% in the rosiglitazone group compared with 2% in both the sitagliptin and placebo groups. Both active treatments were generally well tolerated, with no increased risk of hypoglycaemia or gastrointestinal adverse events compared with placebo. CONCLUSIONS: In this 18-week study, the addition of sitagliptin was effective and well tolerated in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Treatment with sitagliptin produced similar reductions in HbA(1c) compared with the addition of rosiglitazone.

Dissemination of diabetes care guidelines: lessons learned from community health centers.

PURPOSE: This study was conducted to evaluate the impact of a provider problem-based learning (PBL) intervention on screening for complications of diabetes in community health centers. METHODS: A successive sampling design was used to compare selected standards of diabetes care delivered preintervention with the care delivered postintervention at 2 community health centers and 1 comparison centers. Two randomly assigned intervention sites received a PBL intervention focused on care guidelines for prevention of diabetes complications, with telephone follow-up over 12 months. Effects of the intervention were determined from an audit of 200 charts from each site. RESULTS: The odds of having a glycosylated hemoglobin test more than doubled from preintervention to postintervention, and the odds of having a foot examination more than tripled across centers. Measurement of creatinine and glycosylated hemoglobin were associated; the odds of having one test tripled when the other had been measured. Rates for documentation of patient education were significantly lower at the intervention site where free patient education booklets were distributed. CONCLUSIONS: Improvements in diabetes care were not consistent among community health centers. Interventions involving system and policy changes may be more effective in implementing and sustaining improvements than just provider education.

Computer-assisted diabetes nutrition education increases knowledge and self-efficacy of medical students.

Medical students and physicians need to improve their understanding of the role of nutrition and the multidisciplinary team in diabetes care. To assist in this learning, an interactive computer program was developed that focused on prescribing diets for patients with diabetes. Parallel 10-item knowledge tests and an 8-item self-efficacy scale were used to evaluate the efficacy of the computer program among 41 third-year medical students. Mean knowledge scores increased significantly after using the computer program. Posttest knowledge scores for the medical students approached the level achieved by general practice dietitians with no diabetes specialty training. Mean self-efficacy scores increased significantly. The mean time spent on the educational component of the program was under 30 minutes. Computer-assisted diabetes nutrition education proved to be an efficient and effective method for teaching basic nutrition competencies to medical students. This program is available on the World Wide Web (http:/(/)medicine.aecom.yu.edu/diabetes/DEC.htm ) and may be a useful means for providing basic diabetes nutrition education to primary healthcare providers from a variety of disciplines as well as for medical students.

The scope of practice of diabetes educators in a metropolitan area.

A survey of 108 members of a local metropolitan AADE chapter was conducted to assess (1) current roles and responsibilities of diabetes educators with respect to medical management and patient education, and (2) the use of behavioral strategy techniques among diabetes educators. Nurses and dietitians specializing in diabetes care performed a range of responsibilities. Approximately 75% of the nurses performed standard patient education roles and 20% performed the majority of roles traditionally considered to be in the medical domain, including insulin adjustment. More than half of the respondents had not received formal training in the use of behavioral strategies. Formal training was positively associated with greater use of behavioral techniques. Training for diabetes educators should include behavioral intervention strategies. Nurses specializing in diabetes care may also need training regarding physical assessment for chronic complications, and knowledge regarding adjustment of insulin and oral hypoglycemic medications.