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In a 13-week, randomized trial involving persons 6 to 79 years of age with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction in the glycated hemoglobin level than standard care.

Insulin efsitora alfa (efsitora), a once-weekly basal insulin, has the potential to reduce the treatment burden of people with type 2 diabetes who require insulin. We aimed to assess the efficacy and safety of once-weekly efsitora compared with insulin glargine U100 in adults with type 2 diabetes treated with basal and prandial insulin. This phase 3, randomised, 26-week, parallel-design, open-label, treat-to-target, non-inferiority study was done at 78 outpatient clinics and hospitals in Argentina, Germany, India, Italy, Mexico, Spain, and the USA (including Puerto Rico). Participants with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0–10·0%) treated with basal and prandial insulin and up to three non-insulin glucose-lowering agents were randomly assigned (1:1) to efsitora or glargine U100, both with prandial insulin lispro. Randomisation was stratified by country, baseline HbA1c (<8% vs ≥8%; <63·9 mmol/mol vs ≥63·9 mmol/mol), and routine use of personal continuous glucose monitoring or flash glucose monitoring at randomisation (yes vs no). The primary endpoint was HbA1c change from baseline to week 26 (non-inferiority margin 0·4%). The completed trial is registered at ClinicalTrials.gov (NCT05462756). Between Aug 11, 2022, and Feb 27, 2024, 1037 study participants were screened and 730 were randomly assigned to efsitora (n=365) or glargine U100 (n=365). 369 (51%) of 730 participants were female and 361 (49%) were male, the mean participant age was 58·9 years (SD 10·5), and the mean participant BMI was 31·85 kg/m2 (SD 5·47). Using the treatment regimen estimand, the least-squares mean baseline HbA1c was 8·18% (SE 0·04; 65·9 mmol/mol [SE 0·47]) in the efsitora group and 8·18% (0·04; 65·9 mmol/mol [0·47]) in the glargine U100 group. At week 26, the least-squares mean HbA1c was 7·17% (SD 0·05; 54·8 mmol/mol [0·51]) in the efsitora group and 7·18 (0·05; 55·0 mmol/mol [0·51]) in the glargine U100 group. The change from baseline to week 26 using the treatment regimen estimand was –1·01 percentage points for the efsitora group and –1·00 percentage points for the glargine U100 group, indicating non-inferiority of efsitora versus glargine U100. Rates of overall and nocturnal level 2 (<54 mg/dL; 3·0 mmol/L) or level 3 (severe) hypoglycaemia during the treatment period were similar for efsitora versus glargine U100 (6·6 vs 5·9 events per patient-year of exposure, estimated rate ratio [ERR] 1·11, 95% CI 0·85–1·44; p=0·44; 0·67 vs 1·00 events per patient-year of exposure, ERR 0·67, 95% CI 0·44–1·01; p=0·058), respectively. Adverse event occurrence was similar between efsitora and glargine U100. Serious adverse events were reported by 25 (7%) of 365 participants in the efsitora group and 23 (6%) of 365 participants in the glargine U100 group. Efsitora showed non-inferior HbA1c reductions and similar rates of combined clinically significant or severe hypoglycaemia versus glargine U100 in participants with type 2 diabetes treated with basal and prandial insulin. These findings show that efsitora is a well tolerated and efficacious once-weekly alternative to daily basal insulin, with a reduced injection frequency, for the treatment of adults with type 2 diabetes. Eli Lilly and Company.

Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.

Objective Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM. Methods In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry. Results At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean − 8.1 mmHg [95%CI − 13.9 to − 2.4], p = 0.008) and diastolic BP (mean − 5.1 mmHg [− 9.0 to − 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout. Conclusion Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM. Trial Registration: ClinicalTrials.Gov NCT02194595.

Treating hyperglycemia in previously non-diabetic individuals with exogenous insulin immediately after kidney transplantation reduced the odds of developing Posttransplantation Diabetes Mellitus (PTDM) in our previous proof-of-concept clinical trial. We hypothesized that insulin-pump therapy with maximal insulin dosage during the afternoon would improve glycemic control compared to basal insulin and standard-of-care. In a multi-center, randomized, controlled trial testing insulin isophane for PTDM prevention, we added a third study arm applying continuous subcutaneous insulin lispro infusion (CSII) treatment. CSII was initiated in 24 patients aged 55±12 years, without diabetes history, receiving tacrolimus. The mean daily insulin lispro dose was 9.2±5.2 IU. 2.3±1.1% of the total insulin dose were administered between 00:00 and 6:00, 19.5±11.6% between 6:00 and 12:00, 62.3±15.6% between 12:00 and 18:00 and 15.9±9.1% between 18:00 and 24:00. Additional bolus injections were necessary in five patients. Mild hypoglycemia (52-60 mg/dL) occurred in two patients. During the first post-operative week glucose control in CSII patients was overall superior compared to standard-of-care as well as once-daily insulin isophane for fasting and post-supper glucose. We present an algorithm for CSII treatment in kidney transplant recipients, demonstrating similar safety and superior short-term efficacy compared to standard-of-care and once-daily insulin isophane.

We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine. •This was a 52-week extension of a previously reported 26-week study.•Albiglutide once weekly was compared with insulin lispro thrice daily.•Both treatments were added on to titrated insulin glargine.•Similar glycemic control was achieved with both treatments at week 52.•Albiglutide was associated with weight loss and less hypoglycemia but more GI events.

Background In Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine. Methods In three cohorts of patients with diabetes (type 1, type 2 insulin naïve, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures. Results In patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naïve patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine. Conclusions The lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012)

Background and Aims Few studies have evaluated long-term durability of glycemic control in older patients. The aim of this study was to compare durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25; 75 % insulin lispro protamine suspension, 25 % insulin lispro) and once-daily insulin glargine (GL) added to oral antihyperglycemic medications in older patients (≥65 years of age). Methods Patients were participants in the maintenance phase of the DURABLE trial. During the initiation phase, patients with type 2 diabetes were randomized to LM75/25 or GL. After 6 months, patients with hemoglobin A 1c (HbA 1c ) ≤7.0 % advanced to the 24-month maintenance phase. The primary objective was between-group comparison of duration of maintaining the HbA 1c goal in older patients (≥65 years of age). A similar analysis was conducted for older patients achieving HbA 1c  ≤6.5 % in the initiation phase. Results Median time of maintaining HbA 1c goal was longer in LM75/25 versus GL (19.6 versus 15.4 months, p  = 0.007) and more LM75/25 patients maintained goal versus GL (49.2 versus 30.4 %; p  = 0.003). HbA 1c reduction from baseline was greater in LM75/25 versus GL (−1.56 ± 0.10 versus −1.24 ± 0.11 %; p  = 0.003). Post-meal glucose was significantly lower in LM75/25 versus GL (158.86 ± 3.42 versus 171.67 ± 4.51 mg/dL; p  = 0.017). No differences were observed in overall and severe hypoglycemia. LM75/25 patients had higher daily insulin doses (0.41 ± 0.02 versus 0.32 ± 0.02 units/kg/day; p  < 0.001) and more weight gain (5.47 ± 0.49 versus 3.10 ± 0.53 kg; p  = 0.001). Similar results were generally obtained in older patients with HbA 1c  ≤6.5 %. Conclusions In our evaluation of older patients from a larger trial, LM75/25 appeared to provide longer durability of glycemic control, as well as a greater number of patients maintaining HbA 1c goal versus GL.

Prandial premixed therapy 3 times daily has been proposed recently for type 2 diabetes mellitus (T2DM) patients who fail to achieve glycemic control with commonly used premixed insulin analogs, insulin lispro mix 75/25 (LM75/25) and biphasic insulin aspart 70/30 (BIAsp70/30) BID. The aim of this work was to compare the efficacy and safety of 3-times daily insulin lispro mix 50/50 (TID group) with progressive titration of twice-daily LM75/25 or BIAsp70/30 (BID group) administered along with metformin in T2DM patients. This was an open-label, 16-week, multicenter, randomized, parallel trial. End point glycosylated hemoglobin (HbA 1c) was the primary efficacy measure; HbA 1c reduction from baseline to end point, percentage of patients reaching target HbA 1c (<7.0% and ≤6.5%), postprandial blood glucose (BG), and BG excursions after lunch were secondary measures. Safety was evaluated by collecting adverse events. A total of 302 patients with mean (SD) age 57.7 (9.27) years, diabetes duration 11.2 (6.47) years, HbA 1c 8.5% (1.23), fasting BG 184.0 (53.04) mg/dL, body weight 86.8 (14.79) kg, body mass index 31.7 (4.23) kg/m 2, and daily insulin dose ∼48 IU were randomized. No significant difference was observed in end point HbA 1c between the 2 groups. Seven-point BG profiles showed lower fasting and postbreakfast BG in the BID group but lower postlunch BG in the TID group. Daily insulin dose change was similar in both groups, with more weight gain in the TID group ( P = 0.0009). Overall hypoglycemic rates were similar in both groups, but nocturnal hypoglycemia was more frequent in the BID group ( P = 0.0063). In patients with T2DM who have not achieved adequate glycemic control with LM75/25 and BiAsp70/30 BID plus metformin and who are not candidates for basal bolus therapy, switching either to treatment with LM50/50 TID or to progressive titration of premix insulin analogs BID did not produce sufficient evidence of a difference of overall glycemic control between the 2 treatment groups. Short study duration and less intensive dose adjustments might have contributed to these results.