Aim:To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment-naïve patients with type 2 diabetes. Methods: In a double-blind study, 1050 treatment-naïve patients (i.e. not taking an antihyperglycaemic agent for ≥16 weeks prior to study entry) with type 2 diabetes and an HbA 1c 6.5-9% were randomized (1:1) to treatment with once-daily sitagliptin 100 mg (N = 528) or twice-daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up-titrated from 500 to 2000 mg per day (or maximum tolerated daily dose ≥1000 mg) over a period of 5 weeks. The primary analysis used a per-protocol (PP) approach to assess whether sitagliptin was non-inferior to metformin based on HbA 1c change from baseline at week 24. Non-inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between-group difference in this endpoint was <0.40%. Results:From a mean baseline HbA 1c of 7.2% in the PP population, HbA 1c change from baseline was −0.43% with sitagliptin (n = 455) and −0.57% with metformin (n = 439). The between-group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non-inferiority. Baseline HbA 1c influenced treatment response, with larger reductions in HbA 1c observed in patients with baseline HbA 1c ≥8% in the sitagliptin (-1.13%; n = 74) and metformin (-1.24%; n = 73) groups. The proportions of patients at week 24 with HbA 1c values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were −11.5 mg/dL (-0.6 mmol/l) and −19.4 mg/dl (-1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg/dl [4.5, 11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment-β cell function (HOMA-β) and insulin resistance (HOMA-IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal-related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = −9.1% [−13.6, −4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = −0.6 kg [−0.9, −0.4]) and metformin (-1.9 kg [-2.2, −1.7]) (p < 0.001 for sitagliptin vs. metformin). Conclusions:In this 24-week monotherapy study, sitagliptin was non-inferior to metformin in improving HbA 1c in treatment-naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal-related adverse experiences was observed with sitagliptin.

Summary 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 HbA1c < 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.

This study examined the hypothesis that postischemic levels of oxidized and/or ubiquitinated proteins may be predictive of functional recovery as they may be indicative of activity of the 20S and/or 26S proteasomes, respectively. Subjecting isolated rat hearts to 15 min of ischemia had no effect on 20S- and 26S-proteasome activities; however, both were significantly (p < 0.05) decreased by 70% and 54%, respectively, following 30 min of ischemia and 60 min of reperfusion, changes associated with increased levels of protein carbonyls and ubiquitinated proteins. Preischemic treatment of hearts with the proteasome inhibitor, MG132, resulted in dose-dependent decreases (p < 0.05) in recovery of postischemic function [MG132 (microM), heart rate x pressure product: 0, 11,158 +/- 2,423; 6, 11,400 +/- 3,009; 12, 5,513 +/- 2,225; 25, 2,325 +/- 992] and increased accumulation of ubiquitinated proteins. Preconditioning with repetitive ischemia (IP) or preischemic treatment with nicorandil (Nic) resulted in a significant increase in postischemic 20S-proteasome activity after 60 min of reperfusion (control, 95 +/- 4; IP, 301 +/- 65; Nic, 242 +/- 61 fluorescence units). Only Nic had similar effects on 26S-proteasome activity. These results support the conclusion that a correlation exists between eventual recovery of postischemic function and levels of oxidized and/or ubiquitinated proteins, a phenomenon that may be dependent on activity of the 20S and 26S proteasomes.

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In this five-country observational study, nearly 20% of sulphonylurea-treated Muslim subjects with type 2 diabetes experienced symptomatic hypoglycaemia while fasting during Ramadan, with variations across sulphonylureas and countries.

Clinicaltrials.gov: NCT01340768.

Basal energy expenditure accounts for a large component of energy losses, and a clinical estimate of this form of thermogenesis is usually derived from a prediction equation. The most widely used prediction equation was developed in 1919 by Harris and Benedict. The energy requirements of healthy and diseased individuals are often estimated from application of this formula. Using a direct gradient-layer calorimeter and two different indirect calorimeters, our two centers found that the Harris-Benedict equation overestimated basal energy requirements by 10 to 15% (X +/- SD, 12.3 +/- 11%) in 201 studies of healthy men and women. These results raise questions regarding the accuracy of predicting an individual's energy requirements.

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