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Aim To compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy. Method A cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120–365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations. Results A total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were −35% (IQR=−73% to 5%) and −31% (IQR=−72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99–1.47, P =0.063). Conclusion Our results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this.

SUMMARY Aim: To describe the drug management of T2DM patients in a real life cohort with suboptimal HbA1c after treatment with metformin monotherapy. Methods: we performed a retrospective cohort analysis of computerized medical records after measuring an HbA1c >7% for the first time following at least 90 days on metformin therapy. Results: Among 7705 eligible patients, 56% (n = 4336) changed treatment within 1-year, by increasing metformin dose (36%), adding drugs (60%), or switching to other medications (4%). Strongest predictors of change were higher HbA1c, younger age and higher socioeconomic status (SES). Conclusion: In this cohort, the extent of inertia appears to be smaller than that reported in previous studies. Nonetheless, disease management programs aimed at improving guideline adherence and reducing inertia are still warranted.

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.

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.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-β, proinsulin/insulin (P/I) ratio, and for monotherapy, 2 hour post-meal plasma glucose (PMG).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-β 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-β 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.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 β-cell function were observed over the course of treatment.

To compare the incidence of symptomatic hypoglycemia between sitagliptin and sulfonylurea in Muslim patients with type 2 diabetes who fasted during Ramadan.In a multicenter, pragmatic, randomized study, patients with type 2 diabetes were recruited from clinical centers in India (n = 765) and Malaysia (n = 105). Eligible patients (age ≥ 18 yrs) expressed their intention to daytime fast during Ramadan, were treated with a stable dose of sulfonylurea with or without metformin for ≥3 months prior to screening visit, and had an HbA(1c) ≤ 10%. Patients were randomized in a 1:1 ratio to either switch to sitagliptin 100 mg q.d. or remain on their pre-study sulfonylurea. Daily diary cards were completed to document information on hypoglycemic symptoms and complications. The primary endpoint was the overall incidence of symptomatic hypoglycemia during Ramadan.Of the 870 patients randomized, 848 (n = 421 for sitagliptin and 427 for sulfonylurea) returned ≥1 completed diary card and were included in the analysis. The proportion of patients who recorded ≥1 symptomatic hypoglycemic event during Ramadan was lower with sitagliptin (3.8%) compared to sulfonylurea (7.3%). The risk of symptomatic hypoglycemia was significantly lower with sitagliptin (risk ratio [95% CI] = 0.52 [0.29, 0.94]; p = 0.028). By country, the proportions of patients who recorded ≥1 symptomatic hypoglycemic event during Ramadan were 4.1% vs. 7.7% in India and 1.9% vs. 3.8% in Malaysia for sitagliptin and sulfonylurea, respectively. No patient discontinued treatment due to a hypoglycemic event. One patient on sitagliptin and seven on sulfonylurea had an event that required non-medical assistance. No events required medical assistance. Both treatments were generally well tolerated.Symptomatic hypoglycemic events did not require a confirmatory blood glucose measurement, which may have overestimated hypoglycemic events. Measures of glycemic control and body weight were not assessed.Switching antihyperglycemic treatment to sitagliptin from a sulfonylurea reduced the risk of symptomatic hypoglycemia by approximately 50% for Muslim patients with type 2 diabetes who fasted during Ramadan.Clinicaltrials.gov: NCT01340768.

Hypothyroidism suppresses muscle growth and alters myosin heavy chain (MHC) gene expression. To study the role of thyroid hormones in exercise-induced muscle growth and protein synthesis, we measured skeletal and cardiac muscle protein synthesis and MHC gene expression in hypothyroid rats allowed to exercise voluntarily. Female Sprague-Dawley rats (200-210 g) were separated into four groups for 28 days of treatment: control, hypothyroid (TX), hypothyroid plus running-wheel exercise (TX+Ex), and hypothyroid plus 25% overfed (TX+OF). Fractional protein synthesis rates (% incorporation/day) were measured using [3H]phenylalanine incorporation 10 min postinjection. The heart weight-to-body weight ratios of the TX and the TX+OF groups showed marked cardiac atrophy over the 28-day period (2.76 +/- 0.12 and 2.50 +/- 0.22 vs. 3.37 +/- 0.18 mg/g, respectively; P < 0.01). However, the TX+Ex group prevented heart, gastrocnemius, and soleus muscle atrophy over the same time period. Heart, gastrocnemius, and soleus muscles had markedly suppressed protein synthesis rates in the TX and TX+OF groups vs. the euthyroid controls (mean fall -72%; P < 0.01, analysis of variance). However, exercise increased protein synthesis rate by 50% (P < 0.05) compared with TX alone in all three muscle groups. Exercise did not modify hypothyroid-induced alterations of cardiac myosin isoform expression. Exercise-mediated effects on skeletal and cardiac muscle growth but not cardiac MHC gene expression appear to be independent of thyroid hormones.

To determine the incidence of hypoglycaemia during Ramadan in Muslim subjects with type 2 diabetes treated with a sulphonylurea.In an observational study, eligible subjects were Muslims with type 2 diabetes (age ≥18 years) who were treated with glimepiride, gliclazide, or glibenclamide with or without metformin and who expressed their intention to fast during Ramadan in 2009. Subjects were recruited by clinicians in India, Malaysia, Israel, the United Arab Emirates (UAE), and Saudi Arabia. Each day during Ramadan, patients completed diary cards, which collected information regarding hypoglycaemic symptoms and complications, time from last meal and from last medication, self-monitored blood glucose measurements, and need for assistance. The overall incidence of symptomatic hypoglycaemia recorded during Ramadan was the primary endpoint of interest.Of the enrolled subjects (N = 1397), 1378 returned their diary cards at study end and were included in the analysis. Overall, 89% of subjects who expressed their intention to fast prior to Ramadan reported that they observed the fast during Ramadan. A total of 271 subjects (19.7%) experienced one or more symptomatic hypoglycaemic events during Ramadan, with incidences of 25.6%, 16.8%, and 14.0% observed in subjects treated with glibenclamide, glimepiride, and gliclazide, respectively. By country, the highest incidence of hypoglycaemia was reported by subjects from Israel (40%) followed by those from Malaysia (24%), the UAE (18%), India (13%), and Saudi Arabia (10%). The overall incidence of severe hypoglycaemic events (i.e., events requiring medical or non-medical assistance) was 6.7%, with the highest incidence occurring in the glibenclamide group.This was an observational study and as such subjects were not randomised to treatments. While baseline measures appeared comparable, it is possible that differences in measured and unmeasured patient characteristics (e.g., measures of glycaemic control) could partially explain these results. Lastly, no inferential testing was performed on the comparisons between sulphonylurea types and/or countries.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.

Calorie restriction reduces thyroxine (T4) and 3,5,3'-triiodothyronine (T3) production, but the effects of exercise-induced weight loss on thyroid hormone metabolism in rodents are unclear. We studied the effects of chronic exercise on T4 and T3 metabolism comparing exercising (exercise) rats pair fed to sedentary (control) rodents and to weight-matched underfed sedentary animals (underfed; caloric intake 75% of ad libitum-fed controls). The exercise group utilized voluntary running wheels (28 days), and thyroid hormone metabolism was assessed using a three-compartment kinetics model. The exercise and underfed groups were equivalent in weight, but protein mass was greater in the exercise vs. underfed groups (30.4 +/- 0.5 vs. 27.9 +/- 0.5 g; P less than 0.05). During exercise, the T4 plasma clearance rate (PCR) was decreased (-39.2%; P less than 0.01) and the T4 concentration in serum was increased (48.6%; P less than 0.01), resulting in an unchanged T4 plasma appearance rate (PAR) vs. the control group. The decrease in T4 PCR in the exercise group was associated with a lower transport rate of T4 out of the slow pool (P less than 0.01). In the underfed group there was a reduction in both T4 serum concentration and PAR (-36%; P less than 0.01) compared with the control group, which was associated with a decrease in the volume of distribution (-25%; P less than 0.01). T3 PAR decreased 38.7% (P less than 0.01) during underfeeding but only 16.9% (P = not significant) during exercise vs. the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging in both man and rodent is associated with increases in body weight and body fat. In young adult rats, mixed calorie overfeeding increases triiodothyronine production and decreases weight gain efficiency compared with chow diets. This study was undertaken to determine whether 4- and 14-month-old adult rats have similar responses in thyroxine (T4) and triiodothyronine (T3) metabolism during mixed calorie overfeeding. Four- and 14-month-old male Sprague-Dawley rats were each separated into two groups (n = 14): control (CHOW) versus chow + mixed calorie (CAFE) overfeeding for 28 days. The 4-month-old CAFE-fed rats ingested 662 +/- 54 extra kcal over 28 days and gained 147 +/- 7 vs 113 +/- 5 g (P less than 0.01) for their age-matched CHOW group. The 14-month-old CAFE group ingested 309 +/- 45 extra kcal and gained 58 +/- 6 g weight vs -12 +/- 5 g for their age-matched CHOW group (P less than 0.01). Serum T4 concentrations were unchanged during overfeeding or aging. The serum T3 concentration was increased 24% in the 4-month-old CAFE group compared with the age-matched CHOW group (P less than 0.05), but there was no difference in the serum T3 concentration between the 14-month-old CAFE and CHOW groups. The metabolic clearance and production rates of T3 and T4 were decreased in the 14-month-old vs 4-month-old groups (P less than 0.01). The T3 metabolic clearance rate was increased in the CAFE versus CHOW group in the 4-month-old groups (137.3 +/- 11.2 vs 103.0 +/- 10.1 ml/kg/hr, P less than 0.01) but unchanged in the 14-month-old CAFE and CHOW groups (47.6 +/- 6.6 vs 53.4 +/- 5.3 ml/kg/hr, not significant). Liver type I iodothyronine 5'-deiodinase activity increased during overfeeding in the young (63.6%, P less than 0.02) but not in the older rat group. T4 and T3 production rates were decreased in the older rats and did not increase during overfeeding as observed in the young adult rat.

Long-term aerobic exercise and energy intake regulate body composition in a complex manner. To study the combined effects of exercise and energy restriction on muscle mass, we measured skeletal and cardiac muscle protein synthesis after 28 days of two levels of energy restriction with or without daily running-wheel exercise in female rats. Protein synthesis was measured as 3H-Phe incorporation 10 minutes' postbolus of a flooding pulse injection. The two exercise plus energy-restriction groups had greater skeletal muscle and cardiac muscle mass compared with their food-matched groups. Cardiac, gastrocnemius, and soleus muscle protein synthetic rates were proportional to their muscle masses. Exercise-induced energy deficits preserved cardiac and soleus mass to a greater extent than gastrocnemius mass, whereas the effects of energy restriction were similar in all three muscles. These findings suggest that energy intake and exercise have independent effects on the regulation of muscle mass and protein synthesis.

Overfeeding increases the thermogenic response of norepinephrine (NE) in normal but not in certain genetically obese rodents. It has been suggested that human obesity may be associated with a similar thermogenic defect. To determine whether there are differences in the thermogenic sensitivity to NE in human obesity, energy expenditure in response to graded infusions of NE (0.05, 0.10, 0.15, 0.20 micrograms/min/kg fat-free mass) was measured in six lean and six obese subjects (9.5 +/- 1.8 v 36.3 +/- 3.8% body fat P less than 0.005). Resting metabolic rate (RMR), thermogenic response to NE, and thermogenic response to exercise were measured during weight maintenance and during the third week of feeding 1000 extra Kcal/d in the lean and obese subjects. These components of energy expenditure were also measured in the obese subjects during the third week of a 589 Kcal/d diet. Resting metabolic rate increased during overfeeding in lean (6.6%, P less than 0.05) but not in the obese subjects (2.7%, P = NS) and fell during underfeeding in the obese (-9.1%, P less than 0.02). There was a logarithmic increment above baseline in VO2 v plasma NE concentration during the NE infusions (r = 0.75, P less than 0.005) in lean subjects which was unaltered by overfeeding. The obese exhibited equivalent VO2 responses to NE to that measured in the lean. Supine plasma NE concentrations were lower but metabolic clearance rates (MCR) of NE were similar in the obese compared to lean subjects during both weight maintenance and overfeeding. Overfeeding minimally increased plasma concentration but not MCR of NE in both groups. The thermogenic response to exercise was similar in the lean and obese subjects and was unaltered by overfeeding or underfeeding. The increments in plasma glycerol and free fatty acid in response to the NE infusions were proportional to the total fat mass of each individual and were greater in the obese subjects. Overfeeding partially suppressed the lipolytic response to NE in both groups and underfeeding increased the lipolytic response in the obese. There are no differences in thermogenic responses to NE in human obesity to account for excessive fat deposition. Overfeeding does not increase the thermogenetic responses to NE in humans as has been reported in small mammals.

Negative caloric balance reduces triiodothyronine (T3) production in both humans and rodents. The effects of chronic voluntary exercise and various levels of caloric intake and balance on T3 metabolism were studied in adult male C57/BL6 mice to determine if exercise had any direct effects on T3 production in vivo and in vitro. Chronic voluntary exercise was induced by the addition of running wheels to cages for 28 days. Ad libitum-fed exercising mice ingested 20% greater calories (P less than 0.02), maintained body weight, and increased T3 production (53.1 +/- 5.3 vs. 42.3 +/- 3.4 ng.h-1.100 mg body wt-1; P less than 0.01). Exercising animals pair fed to sedentary ad libitum-fed controls decreased their body mass to an equivalent degree as underfed sedentary animals (caloric intake 75% of ad libitum-fed controls) but had increased T3 clearance compared with weight-matched underfed sedentary control (P less than 0.05). Animals that were underfed and exercised decreased their body weight to a greater extent (P less than 0.01) compared with the sedentary underfed group, but T3 production rates were equal. Activity of liver 5'-deiodinase activity was decreased almost 50% (P less than 0.01) during both exercise plus pair feeding and exercise plus caloric restriction but decreased only 28% during caloric restriction alone (P less than 0.01). T3 metabolic clearance and production rates in vivo were correlated to caloric intake (r = 0.73, P less than 0.01), but an interaction between exercise and caloric balance was observed. Chronic voluntary exercise modulates T3 metabolism via several mechanisms. Exercise has an apparent stimulatory effect independent of caloric intake, but also there are regulatory effects dependent on the absolute level of caloric intake and relative caloric balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Controversy exists as to the validity and reliability of hood and mask systems in measuring indirect calorimetry. The purpose of this study was to evaluate the accuracy and reproducibility of repeat measurements of resting energy expenditure (REE) in volunteers. Paired REE measurements were performed in 23 subjects after an overnight fast using hood and mask systems. Lean body mass was calculated from four skinfold measurements and body weight determinations. Data were normalized to body weight and lean body mass and were calculated as percent predicted REE in paired tests taken within 5 minutes on the same subject. No significant difference in mean REE was noted between hood and mask systems. Linear regression analysis showed a strong positive correlation (r = 0.91, p less than 0.001) between hood and mask measurements of REE.

To assess whether thermogenesis or sympathetic nervous system (SNS) function might differ between lean and obese human subjects, studies of thermic and sympathetic responses to standard stimuli were undertaken in Pima Indians, an ethnic group with a high prevalence of obesity. Plasma levels of norepinephrine (NE) and energy expenditure at rest and in response to feeding, exercise, and graded infusions of NE were compared in five lean and five obese Indians during a period of weight maintenance (WM), after 3 weeks of overfeeding (OF) and, in the obese, also after 6 weeks of underfeeding (UF). Basal energy expenditure, when adjusted for fat free mass, was equivalent during WM and increased 3% with OF (P less than 0.01) in both groups. Thermic responses to exercise or a test meal did not differ in lean and obese and did not change with OF, while thermic responses to NE infusion fell during OF to a greater degree in obese than lean (P less than 0.05). A similar pattern (decreased effect in obese with OF) was also noted in the glycemic response to infused NE (P less than 0.05). Although not quantitatively different in lean and obese, the plasma NE concentration appeared to vary more in response to feeding or dietary alteration in the obese than lean, a finding that may reflect lower plasma clearance of NE in the obese. These studies, therefore, raise the possibility that overfeeding in obese Pima Indians may limit the contribution of sympathetically mediated thermogenesis to energy expenditure, though the implications of this for body weight regulation are speculative.