OBJECTIVETo evaluate efficacy and safety of LixiLan (iGlarLixi), a novel titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide (Lixi), compared with both components, iGlar and Lixi, given separately in type 2 diabetes inadequately controlled on metformin with or without a second oral glucose-lowering drug. RESEARCH DESIGN AND METHODSAfter a 4-week run-in to optimize metformin and stop other oral antidiabetic drugs, participants (N = 1,170, mean diabetes duration ∼8.8 years, BMI ∼31.7 kg/m 2 ) were randomly assigned to open-label once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum insulin dose of 60 units/day, or to once-daily Lixi (20 mg/day) while continuing with metformin. The primary outcome was HbA 1c change at 30 weeks. RESULTSGreater reductions in HbA 1c from baseline (8.1% [65 mmol/mol]) were achieved with iGlarLixi compared with iGlar and Lixi (21.6%, 21.3%, 20.9%, respectively), reaching mean final HbA 1c levels of 6.5% (48 mmol/mol) for iGlarLixi versus 6.8% (51 mmol/mol) and 7.3% (56 mmol/mol) for iGlar and Lixi, respectively (both P < 0.0001). More subjects reached target HbA 1c <7% with iGlarLixi (74%) versus iGlar (59%) or Lixi (33%) (P < 0.0001 for all). Mean body weight decreased with iGlarLixi (20.3 kg) and Lixi (22.3 kg) and increased with iGlar (+1.1 kg, difference 1.4 kg, P < 0.0001). Documented symptomatic hypoglycemia (£70 mg/dL) was similar with iGlarLixi and iGlar (1.4 and 1.2 events/patient-year) and lower with Lixi (0.3 events/ patient-year). iGlarLixi improved postprandial glycemic control versus iGlar and demonstrated considerably fewer nausea (9.6%) and vomiting (3.2%) events than Lixi (24% and 6.4%, respectively). CONCLUSIONSiGlarLixi complemented iGlar and Lixi effects to achieve meaningful HbA 1c reductions, close to near normoglycemia without increases in either hypoglycemia or weight, compared with iGlar, and had low gastrointestinal adverse effects compared with Lixi.

AimsTo compare the efficacy and safety of insulin glargine 300 U/ml (Gla‐300) with glargine 100 U/ml (Gla‐100) in Japanese people with type 2 diabetes using basal insulin plus oral antihyperglycaemic drug(s) [OAD(s)].MethodsThe EDITION JP 2 study (NCT01689142) was a 6‐month, multicentre, open‐label, phase III study. Participants (n = 241, male 61%, mean diabetes duration 14 years, mean weight 67 kg, mean body mass index 25 kg/m2, mean glycated haemoglobin (HbA1c) 8.02 %, mean basal insulin dose 0.24 U/kg/day) were randomized to Gla‐300 or Gla‐100, while continuing OAD(s). Basal insulin was titrated to target fasting self‐monitored plasma glucose 4.4−5.6 mmol/l. The primary efficacy endpoint was HbA1c change over 6 months. Safety endpoints included hypoglycaemia and weight change.ResultsGla‐300 was non‐inferior to Gla‐100 for HbA1c reduction [least squares (LS) mean difference 0.10 (95% confidence interval [CI] −0.08, 0.27) %]. The mean HbA1c at month 6 was 7.56 and 7.52 % with Gla‐300 and Gla‐100, respectively. Nocturnal confirmed (≤3.9 mmol/l) or severe hypoglycaemia risk was 38% lower with Gla‐300 versus Gla‐100 [relative risk 0.62 (95% CI 0.44, 0.88)]; annualized rates were 55% lower at night [rate ratio 0.45 (95% CI 0.21, 0.96)] and 36% lower at any time [24 h; rate ratio 0.64 (95% CI 0.43, 0.96)]. Severe hypoglycaemia was infrequent. A significant between‐treatment difference in weight change favoured Gla‐300 [LS mean difference −1.0 (95% CI −1.5, −0.5) kg; p = 0.0003]. Adverse event rates were comparable between groups.ConclusionsJapanese people with type 2 diabetes using basal insulin plus OAD(s) experienced less hypoglycaemia with Gla‐300 than with Gla‐100, while glycaemic control did not differ.

AimTo compare efficacy and safety of new insulin glargine 300 U/ml (Gla‐300) with that of insulin glargine 100 U/ml (Gla‐100) in Japanese adults with type 1 diabetes.MethodsThe EDITION JP 1 study (NCT01689129) was a 6‐month, multicentre, open‐label, phase III study. Participants (n = 243) were randomized to Gla‐300 or Gla‐100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self‐monitored plasma glucose target of 4.4–7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight.ResultsGla‐300 was non‐inferior to Gla‐100 for the primary endpoint of HbA1c change over the 6‐month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) −0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla‐300 than with Gla‐100 at night [rate ratio 0.66 (95 % CI 0.48–0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65–0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla‐300 0.35 U/kg/day, Gla‐100 0.29 U/kg/day). A between‐treatment difference in body weight change over 6 months favouring Gla‐300 was observed [LS mean difference −0.6 kg (95 % CI −1.1 to −0.0); p = 0.035]. Adverse event rates were comparable between the groups.ConclusionsIn Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla‐300 than with Gla‐100, particularly during the night, while glycaemic control did not differ.

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Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. Conclusions GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. Trial registration ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014

ObjectivesWaterpipe smoking is highly prevalent among university students, and has been increasing in popularity despite mounting evidence showing it is harmful to health. The aim of this study was to measure preferences for waterpipe smoking and determine which product characteristics are most important to smokers.SettingA large university in the Southeastern USA.ParticipantsAdult waterpipe smokers attending the university (N=367).DesignParticipants completed an Internet-based discrete choice experiment to reveal their preferences for, and trade-offs between, the attributes of hypothetical waterpipe smoking sessions. Participants were presented with waterpipe lounge menus, each with three fruit-flavoured options and one tobacco flavoured option, in addition to an opt out option. Nicotine content and price were provided for each choice. Participants were randomised to either receive menus with a text-only health-warning message or no message.Outcome measuresMultinomial and nested logit models were used to estimate the impact on consumer choice of attributes and between-subject assignment of health warnings respectively.ResultsOn average, participants preferred fruit-flavoured varieties to tobacco flavour. They were averse to options labelled with higher nicotine content. Females and non-smokers of cigarettes were more likely than their counterparts to prefer flavoured and nicotine-free varieties. Participants exposed to a health warning were more likely to opt out.ConclusionsFruit-flavoured tobacco and lower nicotine content labels, two strategies widely used by the industry, increase the demand for waterpipe smoking among young adults. Waterpipe-specific regulation should limit the availability of flavoured waterpipe tobacco and require accurate labelling of constituents. Waterpipe-specific tobacco control regulation, along with research to inform policy, is required to curb this emerging public health threat.

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