AimsInsulin glargine 300 U/mL (Gla‐300) offers a flatter pharmacodynamic profile than insulin glargine 100 U/mL (Gla‐100). We have compared these insulins over 1 year in people with type 1 diabetes (T1DM).Methods EDITION 4 was a 6‐month, multicentre, randomized, open‐label phase 3 study. People with T1DM who completed the 6 months continued randomized Gla‐300 or Gla‐100 once daily, morning or evening, for a further 6 months.ResultsAmong 549 participants randomized, 444 completed the 12‐month study period (Gla‐300, 80%; Gla‐100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the 2 treatment groups (difference, 0.02 [95% CI, −0.13 to 0.17]) %‐units [0.2 (−1.5 to 1.9) mmol/mol]), to a mean of 7.86 %‐units (62.4 mmol/mol) in both groups. For morning vs evening injection, there was no difference in HbA1c change over 12 months for Gla‐100, but a significantly larger decrease in HbA1c was observed in the Gla‐300 morning group than in the Gla‐300 evening group (difference, −0.25 [−0.47 to −0.04] %‐units [−2.7 (−5.2 to −0.4) mmol/mol]). Mean glucose from the 8‐point SMPG profiles decreased from baseline, and was similar between the 2 treatment groups. Basal insulin dose was 20% higher with Gla‐300 than with Gla‐100, while hypoglycaemia event rates, analysed at night, over 24 hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups.ConclusionsIn T1DM, Gla‐300 provides glucose control comparable to that of Gla‐100, and can be given at any time of day.

Three further cardiovascular (CV) outcome studies of glucose-lowering drugs (linagliptin, albiglutide and dapagliflozin) have recently been published, adding to the twelve earlier within-class studies. The linagliptin study (CARMELINA) recruited people with renal disease as well as prior CV events and confirms the overall CV safety (and other safety) of the dipeptidylpeptidase-4 (DPP4) inhibitors, with no heart failure risk associated with this agent. However, taken together with the findings from two previous studies of DPP4 inhibitors (sitagliptin and saxagliptin), the three DPP4 inhibitor CV outcome trials (CVOTs) have highlighted a safety signal regarding risk of pancreatitis. Like CARMELINA, the albiglutide study (Harmony Outcome) had a very high CV event rate. Despite being a short duration study, albiglutide showed strong superiority for reduction in the major adverse CV events (MACE) composite in people with extant cardiovascular disease (CVD), in line with the earlier studies on the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide. Positive effects can be detected for all these medications from before 12 months and continue for the whole study duration. No new safety issues for albiglutide are identified and the lack of a pancreatitis or a pancreatic cancer signal for this class is now clear. For the sodiumglucose cotransporter-2 (SGLT2) inhibitor class, the DECLARE-TIMI 58 study (of dapagliflozin) clearly indicates strong protection for heart failure in those with CVD, and probably in those with no prior CVD. There is also strong protection against renal decline with dapagliflozin, with similar risk estimates in DECLARE as previously reported for empagliflozin and canagliflozin. However, findings for MACE outcomes with dapagliflozin are not concordant with the empagliflozin and canagliflozin studies, and are not convincingly superior across class and for the longer term. Care is required when prescribing the SGLT2 inhibitor class of medications to people with foot vascular issues or prior amputation, and to insulin users in regard of ketoacidosis. In summary, taking into account the findings from these new studies, it is suggested that a GLP-1RA should be offered to all people with CVD and type 2 diabetes, and SGLT2 inhibitors should be prescribed for those at high risk of heart failure or with progressive decline in eGFR. DPP4 inhibitors are a safe choice within the glucose-lowering stepped algorithm. Keywords Cardiovascular outcomes. Glucose-lowering medications. Review. Type 2 diabetes mellitus Abbreviations ACS Acute coronary syndrome CV Cardiovascular CVD Cardiovascular disease CVOT Cardiovascular outcome trial DPP4 Dipeptidylpeptidase-4 FDA US Food and Drugs Administration GLP-1RA GLP-1 receptor agonist MACE Major adverse cardiovascular events MI Myocardial infarction SGLT2 Sodium-glucose cotransporter-2

Aims: To estimate the relative treatment effect between the fixed-ratio combinations iGlarLixi and IDegLira (glucagon-like peptide 1 receptor agonist with basal insulin) in people with type 2 diabetes inadequately controlled on a glucagon-like peptide 1 receptor agonist. Materials and Methods: A systematic literature review of randomized controlled trials followed by an indirect treatment comparison was performed to compare the efficacy and safety of the available fixed-ratio combinations. Main outcomes were glycated haemoglobin (HbA1c) change and target achievement [<6.5% and <7.0% (<48 and <53 mmol/mol)], fasting plasma glucose, self-monitored plasma glucose, body weight, and incidence and rate of hypoglycaemia. Results: From 4850 abstracts screened, 78 qualified for full-text article review and two randomized controlled trials were included. Baseline characteristics were similar in the two studies. The mean difference at 26 weeks between IDegLira and iGlarLixi was −0.36 (95% credible intervals −0.58, −0.14) % [−3.9 (−6.3, −1.5) mmol/mol] for HbA1c and −1.0 (−1.6, −0.4) mmol/L for fasting plasma glucose. No significant differences were found in HbA1c target attainment, preprandial or postprandial selfmonitored plasma glucose, or body weight change. Formal comparisons of hypoglycaemia were limited by differences in definitions between the studies: in non-sulphonylurea users, incidence was 28% for IDegLira ('confirmed' at ≤3.1 mmol/ L); for iGlarLixi, incidence was 9% ('documented symptomatic' at <3.0 mmol/L). Conclusions: Results of this indirect treatment comparison using two studies suggest iGlarLixi and IDegLira appear to offer similar benefits for HbA1c target achievement. However, the findings suggest differences in other glycaemia results and hypoglycaemia, which may reflect differences in study design and titration approaches. * At time study was conducted.

The regulation of liver and skeletal muscle glycogen synthase by plasma insulin and glucose has not been investigated in vivo at physiological blood glucose concentrations. We have, therefore, used the glucose clamp technique to investigate the effects of these variables independently in rats. Short-term streptozocin-(0.15 g/kg) diabetic animals were used in addition to normal rats to avoid endogenous insulin secretion during hyperglycemic clamps. In normal and diabetic animals, 3 h of hyperinsulinemia without change in blood glucose concentrations caused only a small increase in liver glycogen synthase activity (+34%), whereas hyperglycemic clamps at 6.0 and 10.0 mmol/L resulted in marked increases (+268 and +394% of basal, P less than 0.001). Liver glycogen concentrations at the end of the clamps reflected these changes. In skeletal muscle, glycogen synthase was increased by +58% by the euglycemic hyperinsulinemic clamp and was not increased significantly further by hyperglycemia. Similarly, muscle glycogen concentration increased with the 4.0-mmol/L clamp but during the hyperglycemic clamps was only raised more in direct proportion to blood glucose concentrations. The results confirm that blood glucose concentration is the major short-term regulator of glycogen synthase activity in the liver but that insulin is of prime importance in skeletal muscle.

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