BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity.This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS:Patients with obesity (BMI, 35-50 kg/m 2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 − 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE 24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY 3-36 , and GIP), insulin and glucagon.RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC 0-4h ) and suppressed insulin by 90% (P < 0.01; incremental AUC 0-4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE 24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY 3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes. K E Y W O R D S clinical trial, continuous glucose monitoring (CGM), incretins, obesity therapy, phase I-II study, weight control

Aim: To test the hypothesis that an improving body composition in insulin-resistant individuals could enhance insulin sensitivity.Methods: A total of 16 people with a mean body mass index of 29.3 kg/m 2 and insulin resistance, received a single dose of bimagrumab or placebo and were assessed at week 10 for insulin sensitivity, using a hyperinsulinaemic-euglycaemic clamp and an intravenous glucose tolerance test (IVGTT), and for body composition using dual energy X-ray absorptiometry and positron-emission tomography.Results: Bimagrumab increased lean mass by 2.7% (P < .05) and reduced fat mass by 7.9% (P = .011) at week 10 compared with placebo, and had a neutral effect on body weight. Bimagrumab reduced glycated haemoglobin by 0.21% at week 18 (P < .001) and improved insulin sensitivity by~20% (according to the clamp) to~40% (according to the IVGTT). Conclusion:Taking the observed changes together, and given that these occurred without accompanying dietary intervention and without any prescribed regular physical exercise, bimagrumab may offer a novel approach for the treatment of the metabolic complications of obesity.

BackgroundFamilial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS.MethodsSix FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored.ResultsFollowing once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events.ConclusionThe novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease.Trial registrationClinicalTrials.gov identifier NCT01146522.

No abstract

New data indicate that niacin alters lipoprotein metabolism in novel ways, and mediates other beneficial nonlipid changes that may be atheroprotective. This information forms the rationale for the use of niacin in combination with agents possessing complementary mechanisms of action (e.g. statins) for cardiovascular risk reduction beyond that observed with monotherapy. Further research into the specific mechanisms of niacin may identify additional targets for future drug development.

No abstract

No abstract

Pradigastat is a potent and selective inhibitor of diacylglycerol acyltransferase 1, an enzyme highly expressed in the small intestine that plays a key role in postprandial triglyceride synthesis. This first-in-human study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat administered at single and multiple doses in overweight or obese healthy subjects. In single-dose cohorts (n = 72), subjects were randomized sequentially to receive single doses of pradigastat (1, 3, 10, 30, 100, or 300 mg) or placebo under fasted condition and prior to breakfast. In multiple-dose cohorts (n = 106), subjects were randomized to receive pradigastat (1, 5, 10, or 25 mg) or placebo prior to breakfast for 14 days. Following a single oral dosing, pradigastat was absorbed slowly, with a median tmax of ∼10 hours and eliminated slowly with a long half-life. With multiple oral doses, a 10- to 17-fold higher systemic exposure was observed. Pradigastat treatment (single and multiple doses) led to dose-dependent suppression of postprandial triglyceride excursions over 9 hours following a high-fat meal test. In addition, pradigastat suppressed postprandial glucose and insulin and increased plasma glucagon-like peptide-1 levels. Overall, pradigastat was safe and tolerated at single and multiple doses in healthy subjects.