Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial

IGTPAims: To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a randomized open-label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed-ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose-lowering drugs. Materials and Methods: In this exploratory analysis of LixiLan-L (N = 736), efficacy outcomes were assessed within population subgroups derived from the following baseline characteristics: glycated haemoglobin [HbA1c; <8%, ≥8% (<64, ≥64 mmol/mol)]; duration of T2DM (<10, ≥10 years); body mass index (<30, ≥30 kg/m2). Furthermore, the incidence of symptomatic hypoglycaemia with plasma glucose ≤3.9 mmol/L (≤70 mg/dL) was also analysed according to the same subgroups. Results: Compared with the iGlar treatment group, patients treated with iGlarLixi showed consistently greater reductions in HbA1c during the treatment period, with higher percentages of patients achieving the HbA1c target level of <7% (<53 mmol/mol) in all of the subpopulations tested (P < .0001 for all), having consistent mitigation of body weight gain and with no major differences in the incidence of hypoglycaemia. Conclusions: iGlarLixi consistently improved glycaemic control compared with iGlar in all baseline characteristic subgroups of patients with T2DM inadequately controlled with insulin, including difficult-to-treat subgroups of patients with long duration of diabetes, obesity and high HbA1c. Clinical trial number: NCT02058160 (clinicaltrials.gov)

Comparing Patch vs Pen Bolus Insulin Delivery in Type 2 Diabetes Using Continuous Glucose Monitoring Metrics and Profiles

OBJECTIVE: CeQur Simplicity™ (CeQur, Marlborough, MA) is a 3-day insulin delivery patch designed to meet mealtime insulin requirements. A recently reported 48-week, randomized, multicenter, interventional trial compared efficacy, safety and self-reported outcomes in 278 adults with type 2 diabetes (T2D) on basal insulin therapy who initiated and managed mealtime insulin therapy with a patch pump versus insulin pen. We assessed changes in key glycemic metrics among a subset of patients who wore a continuous glucose monitoring (CGM) device. METHODS: Study participants (patch, n = 49; pen, n = 48) wore a CGM device in masked setting during the baseline period and prior to week 24. Glycemic control was assessed using international consensus guidelines for percentage of Time In Range (%TIR: \u3e70% at 70-180 mg/dL), Time Below Range (%TBR: \u3c4% at \u3c70 mg/dL; \u3c1% at \u3c54 mg/dL), and Time Above Range (%TAR: \u3c25% at \u3e180 mg/dL; \u3c5% at \u3e250 mg/dL). RESULTS: Both the patch and pen groups achieved recommended targets in %TIR (74.1% ± 18.7%, 75.2 ± 16.1%, respectively) and marked reductions in %TAR \u3e180 mg/dL (21.1% ± 19.9%, 19.7% ± 17.5%, respectively) but with increased %TBR \u3c70 mg/dL (4.7% ± 5.2%, 5.1 ± 5.8, respectively), all P \u3c .0001. No significant between-group differences in glycemic improvements or adverse events were observed. CONCLUSIONS: CGM confirmed that the patch or pen can be used to safely initiate and optimize basal-bolus therapy using a simple insulin adjustment algorithm with SMBG. Preference data suggest that use of the patch vs pen may enhance treatment adherence

Implementation of Basal-Bolus Therapy in Type 2 Diabetes:A Randomized Controlled Trial Comparing Bolus Insulin Delivery Using an Insulin Patch with an Insulin Pen

Background: Barriers to mealtime insulin include complexity, fear of injections, and lifestyle interference. This multicenter, randomized controlled trial evaluated efficacy, safety, and self-reported outcomes in adults with type 2 diabetes, inadequately controlled on basal insulin, initiating and managing mealtime insulin with a wearable patch versus an insulin pen. Methods: Adults with type 2 diabetes (n = 278, age: 59.2 +/- 8.9 years), were randomized to patch (n = 139) versus pen (n = 139) for 48 weeks, with crossover at week 44. Baseline insulin was divided 1:1 basal: bolus. Using a pattern-control logbook, subjects adjusted basal and bolus insulin weekly using fasting and premeal glucose targets. Results: Glycated hemoglobin (HbA1c) change (least squares mean +/- standard error) from baseline to week 24 (primary endpoint) improved (P \u3c 0.0001) in both arms, -1.7% +/- 0.1% and -1.6% +/- 0.1% for patch and pen (-18.6 +/- 1.1 and -17.5 +/- 1.1 mmol/mol), and was maintained at 44 weeks. The coefficient of variation of 7-point self-monitoring blood glucose decreased more (P = 0.02) from baseline to week 44 for patch versus pen. There were no differences in adverse events, including hypoglycemia (three severe episodes per arm), and changes in weight and insulin doses. Subject-reported treatment satisfaction, quality of life, experience ratings at week 24, and device preferences at week 48 significantly favored the patch. Most health care providers preferred patch for mealtime insulin. Conclusions: Bolus insulin delivered by patch and pen using an algorithm-based weekly insulin dose titration significantly improved HbA1c in adults with type 2 diabetes, with improved subject and health care provider experience and preference for the patch

Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

Funding Information: This work was supported by grants from the National Institutes of Health (R01DK111529 and R01DK106076 to Y.-B.K.) and in part by Merit Review Award (I01CX00635) from the United States Department of Veterans Affairs Clinical Sciences Research and Development Service (R.R.H.), grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07049123 to J.A.S. and 2017R1A6A3A03003298 to W.-M.Y.), a grant from the Korean Diabetes Association (2017S-2 to J.A.S.), and a grant from Korea University (K1813091 to J.A.S.). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The Animal Metabolic Physiology Core (P30 DK057521 Barbara Kahn) performed in vivo glucose uptake. M.-C.K. is a recipient of a postdoctoral fellowship award from the American Diabetes Association (1-17-PDF-146), I.S.L. is a recipient of FCT fellowship from Portugal (SFRH/BD/71021/2010), and L.P.M is a recipient of São Paulo Research Foundation from Brazil (FAPESP 2013/ 14149-6). We would like to thank Barbara Kahn, Tony Hollenberg, and Terry Flier for helpful discussions, Odile Peroni for technical assistance on in vivo glucose uptake, Amira Klip for the C2C12-myc-Glut4 cell line, Sungman Cho for glucose uptake assays, Jin Sung Park for VLDL-secretion, Wendy Li for Immunofluorescent analysis, Zoltan Arany for myogenin-Cre transgenic mice, Inkyu Lee for ApoJ adenovirus, and Min Bon Hong for ApoJ recombinant protein. Publisher Copyright: © 2020, The Author(s).Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.publishersversionpublishe

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.