Background This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea.

Aim To compare the efficacy and safety of Gla‐300 versus Gla‐100 in insulin‐naïve people with type 2 diabetes in Asia Pacific. Materials and Methods In this open‐label, randomized, active‐controlled, 26‐week study, insulin‐naïve participants with type 2 diabetes inadequately controlled with non‐insulin antihyperglycaemic drugs were randomized (2:1) to Gla‐300 or Gla‐100. The initial daily dose of basal insulin was 0.2 U/kg and was adjusted at least weekly for 8–12 weeks to a target fasting self‐monitored plasma glucose (SMPG) of 4.4–5.6 mmol/L. Results Of the 604 participants randomized, 570 (Gla‐300, n = 375; Gla‐100, n = 195) completed the study. Non‐inferiority of Gla‐300 versus Gla‐100 in HbA1c reduction from baseline to week 26 was confirmed. In the Gla‐300 and Gla‐100 groups, 51.1% and 52.2% of participants achieved the HbA1c target of <7.0% (rate ratio [95% CI]: 0.98 [0.84 to 1.14]) and 19.1% and 21.9% achieved the target without hypoglycaemia during the last 12 weeks of treatment (rate ratio [95% CI]: 0.87 [0.63 to 1.20]). Changes in fasting plasma glucose and 24‐hour average eight‐point SMPG were comparable between groups. Incidence of hypoglycaemia at any time of day was similar between treatment groups at week 26, but incidence of any nocturnal hypoglycaemia was numerically lower with Gla‐300 than Gla‐100 over the initial 12‐week titration period and 26‐week on‐treatment period. Rates of adverse events were similar between groups and low for serious adverse events. Conclusions Glycaemic control of Gla‐300 is non‐inferior to Gla‐100 with a similar or lower incidence and proportion of hypoglycaemia in people with type 2 diabetes in Asia Pacific, reinforcing the results in the global EDITION programme.

Thiazide diuretics are specific inhibitors of the Na-Cl cotransporter in the distal convoluted tubule (DCT). In addition to producing diuresis and natriuresis, they have a hypocalciuric effect. Recently, two apical calcium channels have been identified, transient receptor potential vanilloid 5 (TRPV5) and TRPV6; both are expressed in the DCT. We studied the effects of thiazides on mouse renal calcium handling and renal gene expression of TRPV5 and TRPV6, as well as calbindin-D(28k) and calbindin-D(9k), both of which are calcium transport facilitators located in the DCT. Upregulation of renal TRPV5 was found 4 h after intraperitoneal injection of chlorothiazide (CTZ) at both 25 and 50 mg/kg, but not at 100 mg/kg. Chronic treatment with CTZ at 25 mg/kg twice daily for 3 days, with or without salt supplementation of 0.8% NaCl and 0.1% KCl in the drinking water, caused hypocalciuria, but the gene expression patterns were different. Without salt supplementation, mice developed volume contraction and there were no changes in gene expression. When volume contraction was prevented by salt supplementation, there was a significant increase in gene expression of TRPV5, calbindin-D(28k), and calbindin-D(9k). Salt supplementation alone also induced significant upregulation of TRPV5, TRPV6, and both calbindins. The upregulation of TRPV5 by CTZ and salt supplementation and salt alone was further confirmed with immunofluorescent staining studies. Our studies suggest that thiazides induce hypocalciuria through different mechanisms depending on volume status. With volume contraction, increased calcium reabsorption in the proximal tubule plays the major role. Without volume contraction, hypocalciuria is probably achieved through increased calcium reabsorption in the DCT by the activation of a transcellular calcium transport system and upregulation of apical calcium channel TRPV5, calbindin-D(28k), and calbindin-D(9k).

AimsTo assess the effects on glycaemic control of lixisenatide vs placebo as add‐on treatment to basal insulin (BI) ± metformin and effects on glycated haemoglobin (HbA1c) reduction in patients with insufficiently controlled type 2 diabetes (T2D).MethodsPatients (n = 448) with inadequately controlled T2D were randomized (1:1) to lixisenatide or placebo as add‐on to BI ± metformin for 24 weeks after an 8‐week run‐in phase, during which BI was titrated to a target self‐monitored plasma glucose (SMPG; 4.4‐5.6 mmol/L). The primary endpoint was absolute change in HbA1c from baseline to week 24. Secondary efficacy endpoints included: percentage of responders; changes in 2‐hour postprandial plasma glucose (PPG); 7‐point SMPG (daily average); body weight (BW); total daily BI dose; fasting plasma glucose; and safety assessments.ResultsBaseline demographics were similar in the two treatment groups. After insulin optimization during run‐in, lixisenatide was superior to placebo in mean change from baseline (7.9% [standard deviation {s.d.}, 0.66] and 7.9% [0.70], respectively) to week 24 in HbA1c (least squares mean [standard error {s.e.}] change −0.62% [0.09] vs −0.11% [0.09]; P < .0001, respectively) and higher proportions of patients achieved HbA1c targets. Two‐hour PPG, daily mean SMPG and mean BW were reduced further and daily BI dose was lower with lixisenatide than placebo (−1.12 kg vs 0.04 kg [P < .0001]; −3.0 U vs −1.9 U [P = .0033], respectively). Treatment‐emergent adverse events were greater with lixisenatide than placebo (63.8% vs 40.8%, respectively). The incidence of symptomatic hypoglycaemia was similar (lixisenatide 15.6% vs placebo 13.5%).ConclusionsIn Asian patients insufficiently controlled on BI ± metformin, lixisenatide was superior to placebo in glycaemic control, with a tolerability profile in line with other glucagon‐like peptide‐1 receptor agonists.Clinical trial numberNCT01632163 (clinicaltrials.gov).

Background. We investigated the association between blood pressure control and common cardiometabolic risk factors from a global and regional perspective. Methods. In the present analysis of a large cross-sectional i-SEARCH study, 17.092 outpatients receiving antihypertensive treatment were included in 26 countries. According to clinical guidelines for the management of arterial hypertension, patients were classified based on the level of seated systolic/diastolic blood pressure (SBP/DBP). Uncontrolled hypertension was defined as SBP/DBP ≥140/90 mmHg for non-diabetics, and ≥130/80 mmHg for diabetics. Results. Overall, mean age was 63.1 years, 52.8% were male, and mean BMI was 28.9 kg/m2. Mean SBP/DBP was 148.9/87.0 mmHg, and 76.3% of patients had uncontrolled hypertension. Diabetes was present in 29.1% with mean HbA1c of 6.8%. Mean LDL-cholesterol was 3.2 mmol/L, HDL-cholesterol 1.3 mmol/L, and triglycerides 1.8 mmol/L; 49.0% had hyperlipidemia. Patients with uncontrolled hypertension had a higher BMI (29.4 versus 28.6 kg/m2), LDL-cholesterol (3.4 versus 3.0 mmol/L), triglycerides (1.9 versus 1.7 mmol/L), and HbA1c (6.8 versus 6.7%) than those with controlled blood pressure (P < 0.0001 for all parameters). Conclusions. Among outpatients treated for arterial hypertension, three quarters had uncontrolled blood pressure. Elevated SBP/DBP and uncontrolled hypertension were associated with increasing BMI, LDL-cholesterol, triglycerides, and HbA1c, both globally and regionally.