Effect of sotagliflozin as an adjunct to insulin therapy on blood pressure and arterial stiffness in adults with type 1 diabetes: A post hoc pooled analysis of inTandem1 and inTandem2

Objective: Evaluate the effect of sotagliflozin, a dual inhibitor of sodium glucose cotransporter (SGLT) 1 and 2, on arterial stiffness in patients with type 1 diabetes (T1D) treated with sotagliflozin as adjunct to optimized insulin therapy. Methods: In this post hoc analysis, indirect markers of arterial stiffness, including pulse pressure, mean arterial pressure (MAP), and double product, were calculated using observed systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse rate at 24 weeks using data from a pooled patient population from the inTandem1 and inTandem2 randomized controlled trials (n = 1575). Results: Baseline characteristics were similar among groups. Relative to placebo at Week 24, sotagliflozin 200 mg and 400 mg reduced SBP by 2.03 mm Hg (95% CI −3.30 to −0.75; p = 0.0019) and 2.85 mm Hg (−4.12 to −1.57; p < 0.0001), respectively. DBP decreased by 1.1 and 0.9 mm Hg, MAP by 1.4 and 1.6 mm Hg, and double product by 202.5 and 221.1 bpm × mm Hg, respectively (p < 0.05 for all). No increases in heart rate were observed. Conclusion: In adults with T1D, adding sotagliflozin to insulin significantly reduced blood pressure and other markers of arterial stiffness and vascular resistance

Impact of Diabetes on Work Cessation: Data from the GAZEL cohort study

International audienceOBJECTIVE: To measure the impact of diabetes on work cessation, i.e., on the risks of work disability, early retirement, and death while in the labor force. RESEARCH DESIGN AND METHODS: We used data from the GAZEL prospective cohort of 20,625 employees of the French national gas and electricity company "EDF-GDF." We identified 506 employees with diabetes and randomly selected 2,530 nondiabetic employed control subjects matched for major sociodemographic and occupational characteristics. Using a multistate Cox model, we estimated hazard ratios (HRs) comparing the risks of transition from employment to disability, retirement, and death over time between participants with versus without diabetes. RESULTS: Employment rate decreased more rapidly in participants with diabetes (51.9 and 10.1% at 55 and 60 years, respectively) compared with nondiabetic participants (66.5 and 13.4%, respectively). Participants with diabetes had significantly increased risks of transition from employment to disability (HR 1.7 [95% CI 1.0-2.9]), retirement (HR 1.6 [1.5-1.8]), and death (HR 7.3 [3.6-14.6]) compared with participants without diabetes. Between 35 and 60 years, each participant with diabetes lost an estimated mean time of 1.1 year in the workforce (95% CI 0.99-1.14) compared with a nondiabetic participant. CONCLUSIONS: Our results provide evidence for a profound negative impact of diabetes on workforce participation in France. Social and economic consequences are major for patients, employers, and society-a burden that is likely to increase as diabetes becomes more and more common in the working-aged population

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

The DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy (DURABLE) Trial: Comparing the durability of lispro mix 75/25 and glargine

OBJECTIVE This study compared the durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25: 75% insulin lispro protamine suspension/25% lispro) and once-daily insulin glargine, added to oral antihyperglycemic drugs in type 2 diabetes patients

IDegLira Improves Both Fasting and Postprandial Glucose Control as Demonstrated Using Continuous Glucose Monitoring and a Standardized Meal Test

Objective: IDegLira is a novel, fixed-ratio combination of the long-acting basal insulin, insulin degludec, and the long-acting glucagon-like peptide-1 analog liraglutide. We studied the effect of IDegLira versus its components on postprandial glucose (PPG) in type 2 diabetes. Methods: In this substudy, 260 (15.6%) of the original 1663 patients with inadequate glycemic control participating in a 26-week, open-label trial (DUAL I) were randomized 2:1:1 to once-daily IDegLira, insulin degludec or liraglutide. Continuous glucose monitoring (CGM) for 72 hours and a meal test were performed. Results: At week 26, IDegLira produced a significantly greater decrease from baseline in mean PPG increment (normalized iAUC0-4h) than insulin degludec (estimated treatment difference [ETD] -'12.79 mg/dl [95% CI: -'21.08; -'4.68], P =.0023) and a similar magnitude of decrease as liraglutide (ETD -'1.62 mg/dl [95% CI: -'10.09; 6.67], P =.70). CGM indicated a greater reduction in change from baseline in PPG increment (iAUC0-4h) for IDegLira versus insulin degludec over all 3 main meals (ETD -'6.13 mg/dl [95% CI: -'10.27, -'1.98], P =.0047) and similar reductions versus liraglutide (ETD -'1.80 mg/dl [95% CI: -'2.52, 5.95], P =.4122). Insulin secretion ratio and static index were greater for IDegLira versus insulin degludec (P =.048 and P =.006, respectively) and similar to liraglutide (P =.45 and P =.895, respectively). Conclusions: Once-daily IDegLira provides significantly better PPG control following a mixed meal test than insulin degludec. The improvement is at least partially explained by higher endogenous insulin secretion and improved beta cell function with IDegLira. The benefits of liraglutide on PPG control are maintained across all main meals in the combination

Use of Dipeptidyl Peptidase-4 Inhibitors and the Reporting of Infections: A Disproportionality Analysis in the World Health Organization VigiBase

OBJECTIVE - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS - A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS - We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9-2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6-17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS - This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism

One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial

AimsTo confirm, in a 26‐week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide (IDegLira) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes.MethodsInsulin‐naïve adults with type 2 diabetes randomized to once‐daily IDegLira, insulin degludec or liraglutide, in addition to metformin ± pioglitazone, continued their allocated treatment in this preplanned 26‐week extension of the DUAL I trial.ResultsA total of 78.8% of patients (1311/1663) continued into the extension phase. The mean glycated haemoglobin (HbA1c) concentration at 52 weeks was reduced from baseline by 1.84% (20.2 mmol/mol) for the IDegLira group, 1.40% (15.3 mmol/mol) for the insulin degludec group and 1.21% (13.2 mmol/mol) for the liraglutide group. Of the patients on IDegLira, 78% achieved an HbA1c of <7% (53 mmol/mol) versus 63% of the patients on insulin degludec and 57% of those on liraglutide. The mean fasting plasma glucose concentration at the end of the trial was similar for IDegLira (5.7 mmol/l) and insulin degludec (6.0 mmol/l), but higher for liraglutide (7.3 mmol/l). At 52 weeks, the daily insulin dose was 37% lower with IDegLira (39 units) than with insulin degludec (62 units). IDegLira was associated with a significantly greater decrease in body weight (estimated treatment difference, −2.80 kg, p < 0.0001) and a 37% lower rate of hypoglycaemia compared with insulin degludec. Overall, all treatments were well tolerated and no new adverse events or tolerability issues were observed for IDegLira.ConclusionsThese 12‐month data, derived from a 26‐week extension of the DUAL I trial, confirm the initial 26‐week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability