Prevalence and pathophysiology of early dumping in patients after primary Roux-en-Y gastric bypass during a mixed-meal tolerance test

Background

Early dumping is a poorly defined and incompletely understood complication after Roux-en-Y gastric (RYGB).

Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects*

ABSTRACT

Background: Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simvastatin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. Therefore, this study was conducted to determine the potential for pharmacokinetic drug–drug interaction between vildagliptin and simvastatin at steady-state.

Methods: An open label, single center, multiple dose, three period, crossover study was conducted in 24?healthy subjects. All subjects received once daily doses of either vildagliptin 100?mg or simvastatin 80?mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin β-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively.

Results: The 90% confidence intervals of C_max and AUC_τ of vildagliptin, simvastatin, and simvastatin β-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were administered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study.

Conclusions: The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.     

Whey protein: The “whey” forward for treatment of type 2 diabetes?

A cost-effective nutritional approach to improve postprandial glycaemia is attractive considering the rising burden of diabetes throughout the world. Whey protein, a by-product of the cheese-making process, can be used to manipulate gut function in order to slow gastric emptying and stimulate incretin hormone secretion, thereby attenuating postprandial glycaemic excursions. The function of the gastrointestinal tract plays a pivotal role in glucose homeostasis, particularly during the postprandial period, and this review will discuss the mechanisms by which whey protein slows gastric emptying and stimulates release of gut peptides, including the incretins. Whey protein is also a rich source of amino acids, and these can directly stimulate beta cells to secrete insulin, which contributes to the reduction in postprandial glycaemia. Appetite is suppressed with consumption of whey, due to its effects on the gut-brain axis and the hypothalamus. These properties of whey protein suggest its potential in the management of type 2 diabetes. However, the optimal dose and timing of whey protein ingestion are yet to be defined, and studies are required to examine the long-term benefits of whey consumption for overall glycaemic control.     

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

Patients with type 2 diabetes mellitus are at risk for accelerated cognitive decline and dementia. Furthermore, their risk of stroke is increased and their outcome after stroke is worse than in those without diabetes. Incretin‐based therapies are a class of antidiabetic agents that are of interest in relation to these cerebral complications of diabetes. Two classes of incretin‐based therapies are currently available: the glucagon‐like‐peptide‐1 agonists and the dipeptidyl peptidase‐4 ‐inhibitors. Independent of their glucose‐lowering effects, incretin‐based therapies might also have direct or indirect beneficial effects on the brain. In the present review, we discuss the potential of incretin‐based therapies in relation to dementia, in particular Alzheimer's disease, and stroke in patients with type 2 diabetes. Experimental studies on Alzheimer's disease have found beneficial effects of incretin‐based therapies on cognition, synaptic plasticity and metabolism of amyloid‐β and microtubule‐associated protein tau. Preclinical studies on incretin‐based therapies in stroke have shown an improved functional outcome, a reduction of infarct volume as well as neuroprotective and neurotrophic properties. Both with regard to the treatment of Alzheimer's disease, and with regard to prevention and treatment of stroke, randomized controlled trials in patients with or without diabetes are underway. In conclusion, experimental studies show promising results of incretin‐based therapies at improving the outcome of Alzheimer's disease and stroke through glucose‐independent pleiotropic effects on the brain. If these findings would indeed be confirmed in large clinical randomized controlled trials, this would have substantial impact.     

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

ABSTRACT

Objective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA_1c 7.5–11%) on diet and exercise.

Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50?mg b.i.d.?+?metformin 1000?mg b.i.d. (S100?+?M2000), sitagliptin 50?mg b.i.d.?+?metformin 500?mg b.i.d. (S100?+?M1000), metformin 1000?mg b.i.d. (M2000), metformin 500?mg b.i.d. (M1000), and sitagliptin 100?mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.

Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100?+?M2000 n?=?161, S100+M1000 n?=?160, M2000 n?=?153, M1000 n?=?147, S100 n?=?141, PBO/M2000 n?=?123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32?kg/m², mean HbA_1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA_1c from baseline were ?1.8% (S100?+?M2000), ?1.4% (S100?+?M1000), ?1.3% (M2000), ?1.0% (M1000), and ?0.8% (S100). The proportions of continuing patients with an HbA_1c?<?7% at week 54 were 67% (S100?+?M2000), 48% (S100?+?M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA_1c from baseline were ?1.9% (S100?+?M2000), ?1.7% (S100?+?M1000), ?1.6% (M2000), ?1.2% (M1000), and ?1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.

Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA_1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA_1c?>?8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.

Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.     

Incretins: Clinical Physiology and Bariatric Surgery –Correlating the Entero-endocrine System and a Potentially Anti-dysmetabolic Procedure

The digestive tract is well known for its endocrine functions. Recently, many studies have been reinforcing its role as a therapeutic target for both diabetes and obesity. Losing weight is clinically very difficult for most obese patients and the reason for this could be the effect of the physiological adipostatic system that triggers central nervous stimuli to compensate for variations in food intake and in physical activity. Gut hormones seem to have a key role in this complex, regulating body weight and satiety and contributing to glucose homeostasis. The enteroinsular axis appears to be impaired in both obese and diabetic patients. Recent data on bariatric surgery shows its striking effects on glucose control soon after the procedure, before a significant weight loss is achieved. The procedure appears to work beyond anti-obesity having a key metabolic impact possibly sharing a common mechanism with the new class of agents to treat type 2 diabetes mellitus: the incretin mimetics. This symposium discussed new data on the upcoming perspectives on both the pharmacological and the surgical approach to diabetes and obesity.     

The Multiple Faces of Glucagon-Like Peptide-1—Obesity, Appetite, and Stress: What Is Next? A Review

By itself, glucagon-like peptide-1(GLP-1) appears to be an excellent drug for appetite control and the treatment of obesity. Unfortunately, few enzymes, such as IV dipeptidyl peptidase and renal excretin, degrade and render GLP-1 inactive within minutes. A receptor agonist, exendin-4, with a longer biological half-life than GLP-1, has been tried. Subcutaneous injection of exendin-4 or continuous IV injection of GLP-1 warrants further research and investigation.