Pharmacokinetics and Pharmacodynamics of Therapeutic Doses of Basal Insulins NPH, Glargine, and Detemir After 1 Week of Daily Administration at Bedtime in Type 2 Diabetic Subjects: A randomized cross-over study

OBJECTIVE-To compare the pharmacokinetics and pharmacodynamics of NPH, glargine, and detemir insulins in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS-This study used a single-blind, three-way, cross-over design. A total of 18 type 2 diabetic subjects underwent a euglycemic clamp for 32 h after a subcutaneous injection of 0.4 units/kg at 2200 h of either NPH, glargine, or detemir after 1 week of bedtime treatment with each insulin. RESULTS-The glucose infusion rate area under the curve(0-32 h) was greater for glargine than for detemir and NPH (1,538 +/- 688; 1,081 +/- 785; and 1,170 +/- 703 mg/kg, respectively; P 150 mg/dL. CONCLUSIONS-Compared with NPH and detemir, glargine provided greater metabolic activity and superior glucose control for up to 32 h.Lucidi, P.; Porcellati, F.; Rossetti ., P.; Candeloro, P.; Cioli, P.; Marzotti, S.; Andreoli, AM.... (2011). Pharmacokinetics and pharmacodynamics of therapeutic doses of basal insulins NPH, glargine, and detemir after 1 week of daily administration at bedtime in type 2 diabetic subjects: a randomized cross-over study. Diabetes Care. 34(6):1312-1314. doi:10.2337/dc10-1911S1312131434

Protective Effects of Home T2DM Treatment with Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Co-transporter-2 Inhibitors Against Intensive Care Unit Admission and Mortality in the Acute Phase of the COVID-19 Pandemic: A Retrospective Observational Study in Italy

Introduction: Type 2 diabetes mellitus (T2DM) is a relevant risk factor for severe forms of COVID-19 (SARS coronavrus 2 [SARS-CoV-2] disease 2019), and calls for caution because of the high prevalence of T2DM worldwide and the high mortality rates observed in patients with T2DM who are infected with SARS-CoV-2. People with T2DM often take dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1ras), or sodium-glucose co-transporter-2 inhibitors (SGLT-2is), all of which have clear anti-inflammatory effects. The study aimed to compare (i) the severity and duration of hospital stay between patients with T2DM categorized by pre-hospitalization drug class utilization and (ii) the COVID-19-related death rates of those three groups.Methods: We designed an observational, retrospective, multi-center, population-based study and extracted the hospital admission data from the health care records of 1916 T2DM patients over 18 years old who were previously on GLP-1ra, SGLT-2i, or DPP-4i monotherapy and were hospitalized for COVID-19 (diagnosis based on ICD.9/10 codes) between January 2020 and December 2021 in 14 hospitals throughout Italy. We analyzed general data, pre-admission treatment schedules, date of admission or transfer to the intensive care unit (ICU) (i.e., the index date; taken as a marker of increased COVID-19 disease severity), and death (if it had occurred). Statistics analyzed the impact of drug classes on in-hospital mortality using propensity score logistic regressions for (i) those admitted to intensive care and (ii) those not admitted to intensive care, with a random match procedure used to generate a 1:1 comparison without diabetes cohort replacement for each drug therapy group by applying the nearest neighbor method. After propensity score matching, we checked the balance achieved across selected variables if a balance was ever achieved. We then used propensity score matching between the three drug classes to assemble a sample in which each patient receiving an SGLT-2i was matched to one on a GLP-1ra, and each patient on a DPP-4i was matched to one on a GLP-1ra, adjusting for covariates. We finally used GLP-1ras as references in the logistic regression.Results: The overall mortality rate (MR) of the patients was 14.29%. The MR in patients with COVID was 53.62%, and it was as high as 42.42% in the case of associated T2DM, regardless of any glucose-lowering therapy. In those on DPP-4is, there was excess mortality; in those treated with GLP-1ras and SGLT-2is, the death rate was significantly lower, i.e., almost a quarter of the overall mortality observed in COVID-19 patients with T2DM. Indeed, the odds ratio (OR) in the logistic regression resulted in an extremely high risk of in-hospital death in individuals previously treated with DPP-4is [incidence rate (IR) 4.02, 95% confidence interval (CI) 2.2-5.7) and only a slight, nonsignificantly higher risk in those previously treated with SGLT-2is (IR 1.42, 95% CI 0.6-2.1) compared to those on GLP-1ras. Moreover, the longer the stay, the higher the death rate, which ranged from 22.3% for <= 3-day stays to 40.3% for 4- to 14-day stays (p < 0.01 vs. the former) and 77.4% for over-14-day stays (p < 0.001 vs. both the others).Discussion: Our data do not support a protective role of DPP-4is; indeed, this role has already been questioned due to previous observations. However, the data do show a strong protective effect of SGLT-2is and GLP-1ras.Beyond lowering circulating glucose levels, those two drug classes were found to exert marked anti-phlogistic effects: SGLT-2is increased adiponectin and reduced urate, leptin, and insulin concentrations, thus positively affecting overall low-grade inflammation, and GLP-1ras may also greatly help at the lung tissue level, meaning that their extra-glycemic effects extend well beyond those acknowledged in the cardiovascular and renal fields.Conclusions: The aforedescribed observational clinical data relating to a population of Italian inpatients with T2DM suggest that GLP-1ras and SGLT-2is can be considered antidiabetic drugs of choice against COVID-19, and might even prove beneficial in the event of any upcoming pandemic that has life-threatening effects on the pulmonary and cardiovascular systems

Shape of the OGTT glucose curve and risk of impaired glucose metabolism in the EGIR-RISC cohort

Objective. To study whether the shape of the oral glucose tolerance test (OGTT)-glucose curve is a stable trait over time; it is associated with differences in insulin sensitivity, beta-cell function and risk of impaired fasting glucose (IFG) and glucose tolerance (IGT) in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Methods. OGTT-glucose curve shape was classified as monophasic, biphasic, triphasic and anomalous in 915 individuals. Oral glucose insulin sensitivity (OGIS), Matsuda insulin sensitivity index (ISI) and beta-cell function were assessed at baseline and 3 years apart. Results. The OGTT-glucose curve had the same baseline shape after 3 years in 540 people (59%; kappa = 0.115; p < 0.0001). Seventy percent of the participants presented with monophasic OGTT-glucose curve shape at baseline and after 3 years (percent positive agreement 0.74). Baseline monophasic shape was associated with significant increased risk of IFG (OR 1.514; 95% CI 1.084-2.116; p = 0.015); biphasic shape with reduced risk of IGT (OR 0.539; 95% CI 0.310-0.936) and triphasic shape with reduced risk of IFG (OR 0.493; 95% CI 0.228-1.066; P = 0.043) after 3 years. Increased risks of IFG (OR 1.509; 95% CI 1.008-2.260; p = 0.05) and IGT (OR 1.947; 95% CI 1.085-3.494; p = 0.02) were found in people who kept stable monophasic morphology over time and in switchers from biphasic to monophasic shape (OR of IGT = 3.085; 95% CI 1.377-6.912; p = 0.001). Conclusion. After 3 years follow-up, the OGTT-glucose shape was stable in 59% of the RISC cohort. Shapes were associated with different OGIS and beta-cell function; persistence over time of the monophasic shape and switch from biphasic to monophasic shape with increased risk of impaired glucose metabolism. (C) 2017 Elsevier Inc. All rights reserved

Renal function markers and insulin sensitivity after 3 years in a healthy cohort, the EGIR-RISC study

International audienceBACKGROUND:People with chronic renal disease are insulin resistant. We hypothesized that in a healthy population, baseline renal function is associated with insulin sensitivity three years later.METHODS:We studied 405 men and 528 women from the European Group for the study of Insulin Resistance - Relationship between Insulin Sensitivity and Cardiovascular disease cohort. Renal function was characterized by the estimated glomerular filtration rate (eGFR) and by the urinary albumin-creatinine ratio (UACR). At baseline only, insulin sensitivity was quantified using a hyperinsulinaemic-euglycaemic clamp; at baseline and three years, we used surrogate measures: the Matsuda insulin sensitivity index (ISI), the HOmeostasis Model Assessment of Insulin Sensitivity (HOMA-IS). Associations between renal function and insulin sensitivity were studied cross-sectionally and longitudinally.RESULTS:In men at baseline, no associations were seen with eGFR, but there was some evidence of a positive association with UACR. In women, all insulin sensitivity indices showed the same negative trend across eGFR classes, albeit not always statistically significant; for UACR, women with values above the limit of detection, had higher clamp measured insulin sensitivity than other women. After three years, in men only, ISI and HOMA-IS showed a U-shaped relation with baseline eGFR; women with eGFR> 105 ml/min/1.73m2 had a significantly higher insulin sensitivity than the reference group (eGFR: 90-105 ml/min/1.73m2). For both men and women, year-3 insulin sensitivity was higher in those with higher baseline UACR. All associations were attenuated after adjusting on significant covariates.CONCLUSIONS:There was no evidence to support our hypothesis that markers of poorer renal function are associated with declining insulin sensitivity in our healthy population

Shape of the OGTT glucose curve and risk of impaired glucose metabolism in the EGIR-RISC cohort

Objective To study whether the shape of the oral glucose tolerance test (OGTT)-glucose curve is a stable trait over time; it is associated with differences in insulin sensitivity, f-cell function and risk of impaired fasting glucose (IFG) and glucose tolerance (IGT) in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Methods OGTT-glucose curve shape was classified as monophasic, biphasic, triphasic and anomalous in 915 individuals. Oral glucose insulin sensitivity (OGIS), Matsuda insulin sensitivity index (ISI) and f-cell function were assessed at baseline and 3\ua0years apart. Results The OGTT-glucose curve had the same baseline shape after 3\ua0years in 540 people (59%; \u3ba\ua0=\ua00.115; p\ua0<\ua00.0001). Seventy percent of the participants presented with monophasic OGTT-glucose curve shape at baseline and after 3\ua0years (percent positive agreement 0.74). Baseline monophasic shape was associated with significant increased risk of IFG (OR 1.514; 95% CI 1.084\u20132.116; p\ua0=\ua00.015); biphasic shape with reduced risk of IGT (OR 0.539; 95% CI 0.310\u20130.936) and triphasic shape with reduced risk of IFG (OR 0.493; 95% CI 0.228\u20131.066; P\ua0=\ua00.043) after 3\ua0years. Increased risks of IFG (OR 1.509; 95% CI 1.008\u20132.260; p\ua0=\ua00.05) and IGT (OR 1.947; 95% CI 1.085\u20133.494; p\ua0=\ua00.02) were found in people who kept stable monophasic morphology over time and in switchers from biphasic to monophasic shape (OR of IGT\ua0=\ua03.085; 95% CI 1.377\u20136.912; p\ua0=\ua00.001). Conclusion After 3\ua0years follow-up, the OGTT-glucose shape was stable in 59% of the RISC cohort. Shapes were associated with different OGIS and f-cell function; persistence over time of the monophasic shape and switch from biphasic to monophasic shape with increased risk of impaired glucose metabolism

Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin?

Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field

Comparison of pharmacokinetics and dynamics of the long acting insulin analogues glargine and detemir at steady state in type 1 diabetes: a double-blind, randomised, cross-over study

OBJECTIVE—To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 ± 10 years, BMI 22.4 ± 1.6 kg/m2, and A1C 7.2 ± 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study). RESEARCH DESIGN AND METHODS—Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was >150 mg/dl). RESULTS—With glargine, plasma glucose remained at 103 ± 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose <180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P < 0.001). Estimated total insulin activity (GIR area under the curve [AUC]0–end of GIR) was 1,412 ± 662 and 915 ± 225 mg/kg (glargine vs. detemir, P < 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P < 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids0–24 h 11 ± 1.7 vs. 8 ± 2.8 mmol/l, respectively, P < 0.001). CONCLUSIONS—Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12–24 h. Abbreviations: AUC, area under the curve • FFA, free fatty acid • GIR, glucose infusion rate • IIR, intravenous insulin infusion rate • IV, intravenous • SC, subcutaneou