Safety and efficacy of linagliptin as add‐on therapy to metformin in patients with type 2 diabetes: a randomized,double‐blind,placebo‐controlled study

Aim: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin administered as add‐on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control. Methods: This 24‐week, randomized, placebo‐controlled, double‐blind, parallel‐group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0–10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run‐in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add‐on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). Results: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (?0.49 vs. 0.15%), FPG (?0.59 vs. 0.58 mmol/l) and 2hPPG (?2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (?0.5 kg placebo, ?0.4 kg linagliptin). Conclusions: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.     

A phase II,randomized, double‐blind,placebo‐controlled,dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

Objective

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods

Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52‐week study. Coprimary end points were the percent change in the SELENA–SLEDAI score at week 24 and the time to first SLE flare.

Results

Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA–SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer ≥1:80 and/or anti–double‐stranded DNA [anti‐dsDNA] ≥30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA–SLEDAI score (?28.8% versus ?14.2%; P = 0.0435), physician's global assessment (?32.7% versus ?10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63–71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti‐dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion

Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

     

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight,liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial

We compared the effects of weight loss induced by the glucagon‐like peptide 1‐agonist liraglutide with a structured lifestyle intervention in obese adults with non‐alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m², mean weight 96.0 ± 16.3 kg) non‐diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate‐intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (?3.5 ± 3.3 vs ?3.5 ± 2.1 kg, respectively, P = .72), LFF (?8.9 ± 13.4 vs ?7.2% ± 7.1%, P = .70), serum alanine aminotransferase (?42 ± 46 vs ?34 ± 27 U/L, P = .52) and aspartate aminotransferase (?23 ± 24 vs ?18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight‐loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.     

Long‐term effect of exercise on improving fatty liver and cardiovascular risk factors in obese adults: A 1‐year follow‐up study

Exercise training can reduce hepatic fat accumulation and cardiovascular risk among patients with non‐alcoholic fatty liver disease (NAFLD), but how long these benefits extend beyond the period of active intervention is unclear. Intrahepatic triglyceride (IHTG) content, measured by proton magnetic resonance spectroscopy, and metabolic risk factors among 220 obese people with NAFLD, who were randomly assigned to vigorous/moderate exercise, moderate exercise or no exercise (control), were assessed at 1 year after the 12‐month exercise intervention. IHTG content was significantly reduced in the 2 exercise groups compared with the control group over the 12‐month active intervention. It was significantly lower (by ?2.39%) in the vigorous/moderate exercise group compared with the control group at the 1‐year follow‐up (95% confidence interval ?4.72 to ?0.05%; P = .045). Waist circumference and blood pressure remained significantly lower in the vigorous/moderate exercise group and the moderate exercise group compared with the control group at the 1‐year follow‐up. Visceral adipose fat remained significantly reduced, but with no differences among 3 groups. These findings suggest 12‐month exercise intervention induced reductions in hepatic fat accumulation, abdominal obesity and blood pressure for up to 1 year after the active intervention, with some attenuation of the benefits.     

Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: A forty‐eight–week,multicenter, randomized,double‐blind,placebo‐controlled study

Objective

To study the effect of folates on discontinuation of methotrexate (MTX) as single‐drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48‐week, randomized, double‐blind, placebo‐controlled trial.

Methods

Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX.

Results

Toxicity‐related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between‐group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between‐group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively).

Conclusion

Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

     

The effects of catechin rich teas and caffeine on energy expenditure and fat oxidation: a meta‐analysis

Different outcomes of the effect of catechin‐caffeine mixtures and caffeine‐only supplementation on energy expenditure and fat oxidation have been reported in short‐term studies. Therefore, a meta‐analysis was conducted to elucidate whether catechin‐caffeine mixtures and caffeine‐only supplementation indeed increase thermogenesis and fat oxidation. First, English‐language studies measuring daily energy expenditure and fat oxidation by means of respiration chambers after catechin‐caffeine mixtures and caffeine‐only supplementation were identified through PubMed. Six articles encompassing a total of 18 different conditions fitted the inclusion criteria. Second, results were aggregated using random/mixed‐effects models and expressed in terms of the mean difference in 24 h energy expenditure and fat oxidation between the treatment and placebo conditions. Finally, the influence of moderators such as BMI and dosage on the results was examined as well. The catechin‐caffeine mixtures and caffeine‐only supplementation increased energy expenditure significantly over 24 h (428.0 kJ (4.7%); P < 0.001 and 429.1 kJ (4.8%); P < 0.001, respectively). However, 24 h fat oxidation was only increased by catechin‐caffeine mixtures (12.2 g (16.0%); P < 0.02 and 9.5 g (12.4%); P = 0.11, respectively). A dose‐response effect on 24 h energy expenditure and fat oxidation occurred with a mean increase of 0.53 kJ mg^?1 (P < 0.01) and 0.02 g mg^?1 (P < 0.05) for catechin‐caffeine mixtures and 0.44 kJ mg^?1 (P < 0.001) and 0.01 g mg^?1 (P < 0.05) for caffeine‐only. In conclusion, catechin‐caffeine mixtures or a caffeine‐only supplementation stimulates daily energy expenditure dose‐dependently by 0.4–0.5 kJ mg^?1 administered. Compared with placebo, daily fat‐oxidation was only significantly increased after catechin‐caffeine mixtures ingestion.     

Timing of protein ingestion relative to resistance exercise training does not influence body composition, energy expenditure, glycaemic control or cardiometabolic risk factors in a hypocaloric, high protein diet in patients with type 2 diabetes

Aim: To investigate timing of protein ingestion relative to resistance exercise training (RT) on body composition, cardiometabolic risk factors, glycaemic control and resting energy expenditure (REE) during weight loss on a high‐protein (HP) diet in overweight and obese patients with type 2 diabetes (T2DM). Methods: Thirty‐four men/women with T2DM (age 57 ± 7 years and body mass index 34.9 ± 4.2 kg m^?2) were randomly assigned to the ingestion of a HP meal (860 kJ, 21 g protein, 0.7 g fat, 29.6 g carbohydrate) either immediately prior to RT or at least 2 h following RT. All participants followed a 16‐week, energy‐restricted (6–7 MJ day^?1), HP diet (carbohydrate : protein : fat 43 : 33 : 22) and participated in supervised RT (3 day week^?1). Outcomes were assessed pre‐ and postintervention at 16 weeks. Results: There was an overall reduction in bodyweight (?11.9 ± 6.1 kg), fat mass (?10.0 ± 4.4 kg), fat‐free mass (?1.9 ± 3.1 kg), waist circumference (?12.1 ± 5.3 cm), REE (?742 ± 624 kJ day^?1), glucose (?1.9 ± 1.7 mmol l^?1), insulin (?6.1 ± 6.7 mU l^?1) and glycosylated haemoglobin (?1.1 ± 0.1%), p ≤ 0.01 time for all variables, with no difference between groups (p ≥ 0.41 group effect). Strength improved and cardiometabolic risk factors were reduced similarly in both groups; single repetition maximum chest press 11.0 ± 8.7 kg, single repetition maximum lat pull down 9.9 ± 6.0 kg, total cholesterol ?0.6 ± 0.5 mmol l^?1, high‐density lipoprotein cholesterol ?0.1 ± 0.2 mmol l^?1, low‐density lipoprotein cholesterol ?0.3 ± 0.5 mmol l^?1, triglycerides ?0.6 ± 0.7 mmol l^?1, blood pressure (systolic/diastolic) ?13 ± 10/?7 ± 7 mmHg (p ≤ 0.04 time effect, p ≥ 0.24 group effect). Conclusion: A HP, energy‐restricted diet with RT was effective in improving glycaemic control, body composition, strength and cardiometabolic risk factors in overweight/obese patients with T2DM irrespective of altering the timing of protein ingestion relative to RT.     

Metformin extended‐release versus immediate‐release: An international,randomized, double‐blind,head‐to‐head trial in pharmacotherapy‐naïve patients with type 2 diabetes

This international, randomized, double‐blind trial (NCT01864174) compared the efficacy and safety of metformin extended‐release (XR) and immediate‐release (IR) in patients with type 2 diabetes. After a 4‐week placebo lead‐in, pharmacotherapy‐naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once‐daily metformin XR 2000 mg or twice‐daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: ?0.93% vs ?0.96%; ?21.1 vs ?20.6 mg/dL (?1.2 vs ?1.1 mmol/L); ?24.7 vs ?27.1 mg/dL (?1.4 vs ?1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once‐daily dosing.     

Saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin with or without metformin: Results from the SUPER study,a randomized,double‐blind,placebo‐controlled trial

This prospective, multicentre, phase III study (NCT02104804) evaluated the efficacy and safety of saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin ± metformin. Patients with glycated haemoglobin (HbA1c) 7.5% to 10.5% and fasting plasma glucose (FPG) <15 mmol/L (270 mg/dL) on stable insulin therapy (20‐150 U/d) were randomized (1:1) to saxagliptin 5 mg once daily (N = 232) or placebo (N = 230) for 24 weeks, stratified by metformin use. The primary efficacy measure was change in HbA1c. Saxagliptin treatment resulted in a greater adjusted mean change in HbA1c from baseline to week 24 than placebo (?0.58%; P < .001), irrespective of metformin use, and a greater mean change in FPG (0.9 mmol/L [?15.9 mg/dL]; P < .001). More patients achieved HbA1c <7% with saxagliptin (11.4%) than with placebo (3.5%, P = .002). Adverse events and incidence of hypoglycaemia were similar in both groups. Overall, add‐on saxagliptin 5 mg once daily significantly improved glycaemic control without increasing hypoglycaemia risk and was well tolerated in Chinese patients with type 2 diabetes inadequately controlled by insulin (± metformin).     

Fenofibrate concomitantly decreases serum proprotein convertase subtilisin/kexin type 9 and very‐low‐density lipoprotein particle concentrations in statin‐treated type 2 diabetic patients

Aim: Diabetic dyslipidaemia, characterized by hypertriglyceridaemia as a result of elevated serum very‐low‐density lipoprotein (VLDL) concentrations, contributes to the increased risk of cardiovascular disease (CVD) in type 2 diabetes (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) may play a role in regulating VLDL metabolism. We investigated the effect of fenofibrate on serum PCSK9 and VLDL particle concentrations in T2DM patients already receiving statin therapy. Methods: In a double‐blind randomized crossover study, 15 statin‐treated T2DM patients (63 ± 8 years, body mass index (BMI) 29 ± 3 kg/m²) were treated with fenofibrate (145 mg/day) or matching placebo for 12 weeks. Serum PCSK9 concentrations were measured by immunoassay. VLDL particle concentration and size were determined by nuclear magnetic resonance spectroscopy. Results: Fenofibrate decreased serum triglycerides (?23%), VLDL‐triglycerides (?51%), total cholesterol (?11%), LDL‐cholesterol (?16%), apolipoprotein B‐100 (?16%), apolipoprotein C‐III (?20%) and PCSK9 (?13%) concentrations compared with placebo (p < 0.05). Fenofibrate also decreased serum concentrations of large (?45%), medium (?66%) and small VLDL (?67%) particles (p < 0.05), without altering VLDL particle size. Serum PCSK9 reduction correlated with decreases in total (r = 0.526, p = 0.044) and small (r = 0.629, p = 0.021) VLDL particle concentrations. Conclusions: Fenofibrate concomitantly decreased serum PCSK9 and VLDL particle concentrations in statin‐treated T2DM patients. These findings support a mechanistic link between PCSK9 and VLDL metabolism, possibly through an effect of PSK9 on VLDL receptor degradation.     

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Objective: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end‐stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed. Methods: In a 54‐week, randomized, double‐blind, parallel‐group study, patients with baseline glycosylated haemoglobin A_1c (HbA_1c) values of 6.5–10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. Results: Patients (N = 91) with a mean baseline HbA_1c value of 7.7% (range: 6.2–10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA_1c was ?0.6% (?0.8, ?0.4) in the sitagliptin group compared with ?0.2% (?0.4, 0.1) in the placebo group [between‐group difference (95% CI) = ?0.4% (?0.7, ?0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA_1c of ?0.7% (?0.9, ?0.4). The overall incidence of adverse experiences was generally similar between groups. Between‐group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54‐week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug‐related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. Conclusions: In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.     

Effects of lorcaserin on fat and lean mass loss in obese and overweight patients without and with type 2 diabetes mellitus: the BLOSSOM and BLOOM‐DM studies

Body composition was determined using dual‐energy X‐ray absorptiometry (DXA) in a subset of patients without (BLOSSOM) and with (BLOOM‐DM) type 2 diabetes who received diet and exercise counselling along with either lorcaserin 10 mg twice daily or placebo. DXA scans were performed on study day 1 (baseline), week 24 and week 52. Baseline demographics of the subpopulations (without diabetes, n = 189; with diabetes, n = 63) were similar between studies and representative of their study populations. At week 52, patients without diabetes on lorcaserin lost significantly more fat mass relative to those on placebo (?12.06% vs ?5.93%; p = 0.008). In patients with diabetes, fat mass was also decreased with lorcaserin relative to placebo (?9.87% vs ?1.65%; p < 0.05). More fat mass was lost in the trunk region with lorcaserin compared with placebo (without diabetes: ?3.31% vs ?2.05%; with diabetes: ?3.65% vs ?0.36%). Weight loss with lorcaserin was associated with a greater degree of fat mass loss than lean mass loss, and most of the fat mass lost for patients without and with diabetes was from the central region of the body.     

Dapagliflozin for prednisone‐induced hyperglycaemia in acute exacerbation of chronic obstructive pulmonary disease

The aim of the present study was to compare the effectiveness and safety of add‐on treatment with dapagliflozin to placebo in patients with prednisone‐induced hyperglycaemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicentre double‐blind randomized controlled study in which add‐on treatment with dapagliflozin 10 mg was compared with placebo. Glycaemic control and incidence of hypoglycaemia were measured through a blinded subcutaneous continuous glucose monitoring device. Participants in the dapagliflozin group spent 54 ± 27.7% of the time in target range (3.9–10 mmol/L) and participants in the placebo group spent 53.6 ± 23.4% of the time in target range (P = .96). The mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (P = .66). One participant using dapagliflozin and 2 participants using placebo experienced symptomatic hypoglycaemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycaemia compared with placebo. Dapagliflozin did not result in better glycaemic control compared with placebo in participants with prednisone‐induced hyperglycaemia during AECOPD.     

High versus low dosing of oral colchicine for early acute gout flare: Twenty‐four–hour outcome of the first multicenter,randomized, double‐blind,placebo‐controlled,parallel‐group,dose‐comparison colchicine study

Objective

Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low‐dose colchicine (abbreviated at 1 hour) and high‐dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers.

Methods

This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study compared self‐administered low‐dose colchicine (1.8 mg total over 1 hour) and high‐dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was ≥50% pain reduction at 24 hours without rescue medication.

Results

There were 184 patients in the intent‐to‐treat analysis. Responders included 28 of 74 patients (37.8%) in the low‐dose group, 17 of 52 patients (32.7%) in the high‐dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low‐dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high‐dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low‐dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7–3.2). High‐dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low‐dose colchicine or placebo. With high‐dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9–56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low‐dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8–4.8]), none had severe diarrhea, and none had vomiting.

Conclusion

Low‐dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high‐dose colchicine, with a safety profile indistinguishable from that of placebo.

     

Tadalafil for the Treatment of Lower Urinary Tract Symptoms in Japanese Men with Benign Prostatic Hyperplasia: Results from a 12‐week Placebo‐controlled Dose‐finding Study with a 42‐week Open‐label Extension

Objectives: To examine the efficacy, safety, and dose response of tadalafil once daily in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH‐LUTS). Methods: Men ≥45 years with moderate‐to‐severe BPH‐LUTS were randomized to once‐daily placebo (N = 140), tadalafil 2.5 mg (N = 142), or tadalafil 5.0 mg (N = 140), in a 12‐week double‐blind phase, followed by a 42‐week, tadalafil 5.0 mg open‐label extension (OLE) phase (N = 394). The primary outcome was total International Prostate Symptom Score (IPSS) change from baseline to last available observation in the double‐blind phase. Results: The least squares (LS) mean difference between placebo and tadalafil in total IPSS change from baseline was ?0.7 (P = 0.201) and ?1.1 (P = 0.062) for tadalafil 2.5 and 5 mg, respectively (ANCOVA; a dose‐dependent improvement in placebo‐adjusted total IPSS for tadalafil 5 mg versus 2.5 mg of 57%). Repeated‐measures analyses identified a significant total IPSS change for tadalafil 5 mg (LS mean difference between placebo and tadalafil 5 mg: ?1.2; P = 0.035), but not tadalafil 2.5 mg, at week 12. Significant improvements for tadalafil 5 mg were demonstrated (ANCOVA) for IPSS obstructive subscore (P = 0.033) and IPSS quality of life index (P = 0.022). Numerical improvements in IPSS scores were maintained over the OLE phase. Tadalafil was well tolerated with no unexpected adverse events. Conclusion: Tadalafil (5.0 mg) had a favorable benefit‐to‐risk profile, supporting further investigation of tadalafil (5.0 mg) in Japanese men with BPH‐LUTS.     

Comparison of efficacy of low‐carbohydrate and low‐fat diet education programs in non‐alcoholic fatty liver disease: A randomized controlled study

Aim

Composition of macronutrients is important in non‐alcoholic fatty liver disease (NAFLD). Diet education programs that mainly emphasize reducing fat consumption have been used for NAFLD patients. We compared the efficacy of conventional low‐fat diet education with low‐carbohydrate diet education in Korean NAFLD patients.

Methods

One hundred and six NAFLD patients were randomly allocated to low‐fat diet education or low‐carbohydrate education groups for 8 weeks. Liver chemistry, liver / spleen ratio, and visceral fat using abdominal tomography were measured.

Results

Intrahepatic fat accumulation decreased significantly in the low‐carbohydrate group compared to low‐fat group (liver/spleen 0.85 vs. 0.92, P < 0.05). Normalization of ALT activity at week 8 was 38.5% for the low‐carbohydrate and 16.7% for the low‐fat group (P = 0.016). Not only liver enzyme, but also low density lipoprotein cholesterol and blood pressure levels significantly decreased in the low‐carbohydrate group. Total energy intake was also further decreased in the low‐carbohydrate group compared to the low‐fat group. Although body weight changes were not different between the two groups, the carbohydrate group had a lower total abdominal fat amount.

Conclusions

A low‐carbohydrate diet program is more realistic and effective in reducing total energy intake and hepatic fat content in Korean NAFLD patients. This trial is registered with the National Research Institute of Health: KCT0000970 ( https://cris.nih.go.kr/cris/index.jsp ).     

Effects of probiotics on body weight,body mass index,fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta‐analysis of randomized controlled trials

A systematic review and meta‐analysis of randomized controlled trials was conducted to examine the effects of probiotic supplementation on body weight, body mass index (BMI), fat mass and fat percentage in subjects with overweight (BMI 25–29.9 kg m^?2) or obesity (BMI ≥30 kg m^?2). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for studies published between 1946 and September 2016. A meta‐analysis, using a random effects model, was performed to calculate the weighted mean difference between the intervention and control groups. Of 800 studies identified through the literature search, 15 were finally included. The studies comprised a total of 957 subjects (63% women), with the mean BMI being 27.6 kg m^?2 and the duration of the interventions ranging from 3 to 12 weeks. Administration of probiotics resulted in a significantly larger reduction in body weight (weighted mean difference [95% confidence interval]; ?0.60 [?1.19, ?0.01] kg, I ² = 49%), BMI (?0.27 [?0.45, ?0.08] kg m^?2, I ² = 57%) and fat percentage (?0.60 [?1.20, ?0.01] %, I ² = 19%), compared with placebo; however, the effect sizes were small. The effect of probiotics on fat mass was non‐significant (?0.42 [?1.08, 0.23] kg, I ² = 84%).     

Evaluation of body fat composition after linagliptin treatment in a rat model of diet‐induced obesity: a magnetic resonance spectroscopy study in comparison with sibutramine

The effects of linagliptin on fat content in diet‐induced obese rats were compared with those of the appetite suppressant sibutramine. Female Wistar rats fed a high‐fat diet (HFD) for 3 months received vehicle, linagliptin (10 mg/kg) or sibutramine (5 mg/kg) treatment orally, once daily for 6 additional weeks, while continuing the HFD. Magnetic resonance spectroscopy analysis of fat content was performed at baseline and at the end of the 6‐week treatment period. Linagliptin treatment profoundly reduced hepatic fat compared with vehicle, with an effect comparable to that of sibutramine. The vehicle‐corrected mean change (95% CI) from baseline in hepatic fat and intramyocellular lipid was ?59.0% (?104.3%, ?13.6%; p = 0.015) and ?62.1% (?131.6%, 7.4%; p = 0.073), respectively, for linagliptin compared with ?54.3% (?101.5%, ?7.1%; p = 0.027) and ?72.4% (?142.4%, ?2.4%; p = 0.044), respectively, for sibutramine.     

Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis—a pilot randomized controlled trial

Pseudomonas aeruginosa forms biofilms in the cystic fibrosis lung. Quorum sensing (QS) controls biofilm maturation, immune evasion, antibiotic tolerance and virulence factor production. Garlic shows QS inhibitory activity in vitro and in animal models. We report the first clinical trial in man of a QS inhibitor. We randomized 34 patients to garlic or olive oil capsules (both 656 mg daily). Clinical outcomes and safety bloods were measured at baseline and after 8 weeks treatment. In this exploratory study, analysis was per protocol. Eight patients withdrew, leaving 26 for analysis (13 garlic). With placebo, there was a greater decline in mean (SD) percentage change from baseline FEV₁ [?3.6% (11.3)] than with garlic [?2.0% (12.3)]. This was not significant (mean difference = 1.6, 95% CI ?12.7 to 15.9, P = 0.8). The mean (SD) increase in weight was greater with garlic [1.0% (2.0)] than with placebo [0.6% (2.0)]—non‐significant (mean difference = 0.4%, 95% CI ?1.3 to 2.0, P = 0.6). The median (range) change in clinical score with garlic was ?1 (?3 to 5) and 1 (?1 to 4) with placebo (negative score means improvement). This was non‐significant [median difference = ?1 (?3 to 0), P = 0.16]. In the garlic group, seven patients had IV antibiotics versus five placebo. There was a highly significant correlation between plasma and sputum measurements of the QS molecule 3‐oxo‐C12‐HSL (Pearson correlation coefficient = 0.914, P = 0.004). At the end of treatment five patients in each group had abnormal liver function or triglycerides and five garlic patients (one placebo) reported minor adverse effects. Garlic capsules were well tolerated. Although there was no significant effect of garlic compared to placebo in this pilot study, there was a suggestion of improvement with garlic which should be investigated in a larger trial. Pediatr Pulmonol. 2010; 45:356–362. © 2010 Wiley‐Liss, Inc.     

Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial

Women with polycystic ovary syndrome (PCOS) were treated with the GLP‐1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT) and the prevalence of nonalcoholic fatty liver disease (NAFLD). In a double‐blind, placebo‐controlled, randomized clinical trial 72 women with PCOS, with a BMI > 25 kg/m² and/or insulin resistance, were treated with liraglutide or received placebo 1.8 mg/d (2:1) for 26 weeks. Liver fat content was assessed by ¹ HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test. Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD by two‐thirds (all P < .01). Sex‐hormone‐binding‐globulin (SHBG) levels increased by 19% (P = .03), and free testosterone decreased by 19% (P = .054). HbA1c, fasting glucose and leptin were reduced (all: P < .05), whereas measures of insulin resistance, adiponectin and glucagon did not change. In conclusion, 26 weeks of liraglutide treatment in PCOS resulted in significant reductions in liver fat content, VAT and the prevalence of NAFLD.