Results From a Randomized, Open-Label, Crossover Study Evaluating the Effect of the Aldosterone Synthase Inhibitor Baxdrostat on the Pharmacokinetics of Metformin in Healthy Human Subjects.

BACKGROUND: Due to the high comorbidity of diabetes and hypertension, co-administration of metformin with anti-hypertensive drugs is likely. Baxdrostat is an aldosterone synthase inhibitor in development for the potential treatment of hypertension. In vitro data indicated that baxdrostat inhibits the multidrug and toxin extrusion 1 (MATE1) and MATE2-K renal transporters. Metformin is a MATE substrate, so this study assessed potential effects of baxdrostat on the pharmacokinetics of metformin. METHODS: Twenty-seven healthy volunteers received 1000 mg metformin alone and 1000 mg metformin in the presence of 10 mg baxdrostat in a randomized, crossover manner. Each treatment was separated by 10 or more days. Blood and urine samples were collected over a 3-day period after each treatment to measure plasma and urine concentrations of metformin. Safety was assessed by adverse events (AEs), physical examinations, electrocardiograms, vital signs, and clinical laboratory evaluations. RESULTS: There were no deaths, serious AEs, discontinuations due to treatment-emergent AEs, or noteworthy increases in AEs with either treatment, indicating that metformin and baxdrostat were well-tolerated when co-administered. Baxdrostat did not significantly affect plasma concentrations or renal clearance of metformin. CONCLUSION: The results of this study suggest that diabetic patients with hypertension receiving both metformin and baxdrostat are unlikely to require dose adjustment. REGISTRATION: ClinicalTrials.gov identifier no. NCT05526690.

Safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) during the month of Ramadan in patients with type 2 diabetes mellitus in Pakistani population-an observational study from a tertiary care center in Karachi.

BACKGROUND AND AIMS: Primary aim was to assess the safety of SGLT2-i in patients with Type 2 Diabetes Mellitus (T2D) in a real-life scenario during Ramadan by finding the frequency and severity of hypoglycemic/hyperglycemic events, dehydration, and Diabetic ketoacidosis (DKA). Secondary aim was to assess changes in glycated hemoglobin (HbA1c), weight and creatinine levels. METHODS: This prospective, observational, controlled cohort study was conducted at Aga Khan University Hospital, Karachi, Pakistan from March 15 to June 30, 2021. Participants were over 21 years of age, on stable doses of SGLT2-I, which was started at least 2 months before Ramadan. Endpoint assessments were done 1 month before and within 6 weeks after Ramadan. RESULTS: Of 102 participants enrolled, 82 completed the study. Most (52%) were males, with mean age 52.2 ± 9.5 years and average duration of T2D 11.2 ± 6.5 years. 63% were on Empagliflozin (mean dose; 14.8 ± 7.2 mg/day) whereas 37% were on Dapagliflozin (mean dose; 8.2 ± 2.7 mg/day). Six (7.3%) documented symptoms of hypoglycemia. However, no episode of severe hypoglycemia, hyperglycemia, dehydration, DKA, hospitalization or discontinuation of SGLT2i was reported. HbA1c changes were (7.7 ± 1.2% from 7.9 ± 2.3%, p 0.34), weight (78.4 ± 12.9 kgs from 78.9 ± 13.3, p 0.23) and eGFR (87.8 ± 27.9 from 94.3 ± 37.6, p < 0.001). The reasons of study participants drop outs were: six did not keep any fasts; four discontinued study participation for personal reasons; three were out of city and missed post Ramadan follow-up, two protocol violation and five could not be contacted for post-Ramadan follow up during the third wave of COVID-19. CONCLUSION: Results showed the safety of SGLT2i agents during Ramadan in the Pakistani population recommending it as a treatment option in adults with T2D, without any additional adverse events.

Trial of Hybrid Closed-Loop Control in Young Children with Type 1 Diabetes.

BACKGROUND: Closed-loop control systems of insulin delivery may improve glycemic outcomes in young children with type 1 diabetes. The efficacy and safety of initiating a closed-loop system virtually are unclear. METHODS: In this 13-week, multicenter trial, we randomly assigned, in a 2:1 ratio, children who were at least 2 years of age but younger than 6 years of age who had type 1 diabetes to receive treatment with a closed-loop system of insulin delivery or standard care that included either an insulin pump or multiple daily injections of insulin plus a continuous glucose monitor. The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. Secondary outcomes included the percentage of time that the glucose level was above 250 mg per deciliter or below 70 mg per deciliter, the mean glucose level, the glycated hemoglobin level, and safety outcomes. RESULTS: A total of 102 children underwent randomization (68 to the closed-loop group and 34 to the standard-care group); the glycated hemoglobin levels at baseline ranged from 5.2 to 11.5%. Initiation of the closed-loop system was virtual in 55 patients (81%). The mean (±SD) percentage of time that the glucose level was within the target range increased from 56.7±18.0% at baseline to 69.3±11.1% during the 13-week follow-up period in the closed-loop group and from 54.9±14.7% to 55.9±12.6% in the standard-care group (mean adjusted difference, 12.4 percentage points [equivalent to approximately 3 hours per day]; 95% confidence interval, 9.5 to 15.3; P<0.001). We observed similar treatment effects (favoring the closed-loop system) on the percentage of time that the glucose level was above 250 mg per deciliter, on the mean glucose level, and on the glycated hemoglobin level, with no significant between-group difference in the percentage of time that the glucose level was below 70 mg per deciliter. There were two cases of severe hypoglycemia in the closed-loop group and one case in the standard-care group. One case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In this trial involving young children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with a closed-loop system than with standard care. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; PEDAP ClinicalTrials.gov number, NCT04796779.).

Real-world safety and effectiveness of iGlarLixi in people with type 2 diabetes who fast during Ramadan: The SoliRam observational study.

BACKGROUND AND AIMS: To evaluate the safety and effectiveness of iGlarLixi in adults with type 2 diabetes (T2D) fasting during Ramadan. METHODS: SoliRam was a multinational, prospective, single-arm, real-world observational study conducted during Ramadan 2020 and 2021 in adults with T2D treated with iGlarLixi ≥3 months at study entry. The primary endpoint was the percentage of participants experiencing ≥1 episode of severe and/or symptomatic documented hypoglycemia (<70 mg/dL [<3.9 mmol/L]). RESULTS: Among the 409 eligible participants followed during Ramadan, 96.8% fasted for ≥25 days and 92.4% did not break fasting during Ramadan. Four participants broke their fast due to hypoglycemia. Minimal adjustments were seen in antihyperglycemic therapies from pre to during Ramadan. Documented symptomatic hypoglycemia was experienced by 1.0%, 2.3%, and 0.3% of participants, respectively, during the last month of pre-Ramadan, Ramadan, and first month post-Ramadan. Mean change in HbA1c from pre-to post-Ramadan periods was -0.75% (-8.2 mmol/mol), and participants with HbA1c <7% (<53 mmol/mol) increased from 7.9% pre-Ramadan to 28.6% post-Ramadan. CONCLUSIONS: iGlarLixi is an effective and well-tolerated therapy for people with T2D, including those who intend to fast during Ramadan, and is associated with a low risk of hypoglycemia; benefits were observed both during and after Ramadan.

Blood glucose control with different treatment regimens in type 2 diabetes patients hospitalized with COVID-19 infection: A retrospective study.

Coronavirus disease (COVID-19) is closely associated with hyperglycemia and a worse prognosis in patients with a previous diagnosis of type 2 diabetes mellitus. A few studies investigated the effects of diabetes treatment regimens in these patients during hospitalization. Here, we evaluate the impact of insulin and non-insulin therapy on glucose control in patients with type 2 diabetes admitted with COVID-19. This is a retrospective study including 359 COVID-19 patients with type 2 diabetes. Patients were divided into 2 groups according to diabetes treatment during hospitalization. The first group included patients treated with insulin only, and the second group patients treated with other antidiabetic agents with or without insulin. Average blood glucose was higher in the insulin-only treatment group (201 ± 66 mg/dL vs 180 ± 71 mg/dL, P = .004), even after excluding mechanically ventilated patients (192 ± 69 vs 169 ± 59 mg/dL, P = .003). In patients with moderate severity of COVID-19, average blood glucose was also significantly higher in the insulin-only treated group (197 ± 76 vs 168 ± 51 mg/dL, P = .001). Most patients (80%) in the combination treatment group received metformin. Moderately affected COVID-19 patients with type 2 diabetes could safely be treated with antihyperglycemic medications with or without insulin.

Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.

BACKGROUND: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. METHODS: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. RESULTS: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide. CONCLUSIONS: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).

Antidiabetic treatment and COVID-19 Outcomes: A population-based cohort study in primary health care in Catalonia during the first wave of the pandemic.

AIMS: To analyse if antidiabetic treatment was associated with better COVID-19 outcomes in type 2 diabetic patients, measured by hospital admission and mortality rates as severe outcomes. METHODS: Cohort study including COVID-19 patients registered in the Primary Care electronic records, in March-June 2020, comparing exposed to metformin in monotherapy with exposed to any other antidiabetic. DATA SOURCE: SIDIAP (Information System for Research in Primary Care), which captures clinical information of 5,8 million people from Catalonia, Spain. RESULTS: We included 31,006 diabetic patients infected with COVID-19, 43.7% previously exposed to metformin, 45.5% of them in monotherapy. 16.4% were admitted to hospital and 15.1% died. Users of insulin in monotherapy (OR 1.29, 95% CI 1.11-1.50), combined with metformin (OR 1.38, 1.13-1.69) or IDPP4 alone (OR 1.29, 1.03-1.63) had higher risk of severe outcomes than those in metformin monotherapy. Users of any insulin (OR 1.61, 1.32-1.97) or combined with metformin (OR 1.69, 1.30-2.20) had a higher risk of mortality. CONCLUSIONS: Patients receiving metformin monotherapy in our study showed a lower risk of hospitalization and death in comparison to those treated with other frequent antidiabetic agents. We cannot distinguish if better outcomes are related with the antidiabetic therapy or with other factors, such as metabolic control or interventions applied during the hospital admission.

Effect of Empagliflozin and Dapagliflozin on Ambulatory Arterial Stiffness in Patients with Type 2 Diabetes Mellitus and Cardiovascular Co-Morbidities: A Prospective, Observational Study.

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.

Metformin-associated Lactic Acidosis with Hypoglycemia during the COVID-19 Pandemic.

Metformin-associated lactic acidosis (MALA) is an extremely rare but life-threatening adverse effect of metformin treatment. The lifestyle changes associated with the coronavirus disease 2019 (COVID-19) pandemic may increase the potential risk of MALA development in patients with diabetes. We herein report a 64-year-old Japanese man taking a small dose of metformin who presented with MALA accompanied by hypoglycemia secondary to increased alcohol consumption triggered by lifestyle changes during the pandemic. Physicians should prescribe metformin judiciously to prevent MALA development and pay close attention to lifestyle changes in patients at risk for MALA during the COVID-19 pandemic.

Careful use to minimize adverse events of oral antidiabetic medications in the elderly.

INTRODUCTION: An increasing number of older patients has type 2 diabetes treated with different oral antidiabetic agents whose safety may raise concern considering some particularities of a heterogeneous elderly population. AREAS COVERED: This article discusses some characteristics of older patients that could increase the risk of adverse events, with a focus on hypoglycemia. It describes the most frequent and/or severe complications reported in the elderly in both randomized controlled trials and observational studies with metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporter type 2 inhibitors (gliflozins). EXPERT OPINION: Old patients may present comorbidities (renal impairment, vascular disease, heart failure, risk of dehydration, osteoporosis, cognitive dysfunction) that could increase the risk of severe adverse events. Sulfonylureas (and meglitinides) induce hypoglycemia, which may be associated with falls/fractures and cardiovascular events. Medications lacking hypoglycemia should be preferred. Gliptins appear to have the best tolerance/safety profile whereas gliflozins exert a cardiorenal protection. However, data are lacking in very old or frailty old patients so that caution and appropriate supervision of such patients are required. Taking advantage of a large choice of pharmacotherapies, personalized treatment is recommended based upon both drug safety profiles and old patient individual characteristics.

Development of a pharmacist-managed protocol for the transition from intravenous to subcutaneous insulin in critically ill adults.

PURPOSE: To evaluate the efficacy and safety of a pharmacist-managed protocol for transitioning critically ill patients from intravenous (IV) to subcutaneous insulin. METHODS: This single-center, retrospective, observational study included patients admitted to the medical or surgical/trauma intensive care unit who received a continuous infusion of IV insulin from January 2019 to April 2021. Patients were excluded if they were less than 18 years old, pregnant, or incarcerated or received IV insulin for the diagnosis of diabetic ketoacidosis, hyperglycemic hyperosmolar state, calcium channel blocker or ß-blocker overdose, or hypertriglyceridemia. The primary outcome was to evaluate the percentage of blood glucose (BG) concentrations within the target range of 70 to 150 mg/dL within 48 hours of the transition to subcutaneous insulin. Secondary outcomes included the percentage of BG concentrations within the goal range following transition at 0 to 12 hours and 12 to 24 hours, the incidence of hypo- and hyperglycemia, and the percentage of patients requiring dose adjustments after the initial transition. RESULTS: Pharmacists were able to achieve BG concentrations in the target range for 53% of transitions at 12 hours, 40% of transitions at 24 hours, and 47% of transitions at 48 hours. With respect to safety endpoints, the pharmacist-managed group had a low rate of hypoglycemia (1.0%) and no severe hypoglycemia. Hyperglycemia was reported for 28% of BG concentrations while severe hyperglycemia was reported for 27%. Pharmacists transitioned patients to an average of 63% of the 24-hour total daily dose of insulin as basal insulin. CONCLUSION: Pharmacists can effectively and safely transition critically ill patients from IV to subcutaneous insulin utilizing a standardized protocol.

Covid 19 May Limit the Use of Anti-hyperglycemic Agents. Does it Call for the Development of New Anti-hyperglycemic Agents?

Diabetes mellitus has been identified as a major risk factor for developing severe COVID 19 complications. In this review article, the efforts were directed to provide insights and the possible extent to which some diabetic pharmacological interventions may exacerbate COVID 19 or may not be idyllic options for COVID 19 patients. Articles reviewed were identified using the Google scholar database, and search was done using the English language. Anti-hyperglycemic is associated with undesirable effects including episodes of hypoglycemia, diarrhea, lactic acidosis, and increased risks of cardiovascular and hepatic hazards. These undesirable effects associated with the anti-hyperglycemic agents possess a threat of developing severe COVID19 complications Therefore, this calls for more studies to understand the extent of the risks these agents possess in diabetic COVID 19 patients. Almost all the anti-hyperglycemic agents have the potential to worsen COVID 19, despite their class. COVID 19 may limit the options in terms of available anti-hyperglycemic agents which may not heighten the risk of developing severe COVID 19 complications. The research towards the discovery and development of new compounds and also new therapeutic targets for hyperglycemia should be encouraged and welcome.

No effects of the COVID-19 pandemic on the prescription of insulin in Germany.

AIMS: The aim of the study was to investigate the change of insulin doses in Germany between 2017 and 2021. METHODS: This retrospective study used data from the longitudinal prescription LRx database (IQVIA) and included all patients with at least two insulin prescriptions per year in 2017-2021. Calculated daily dose (CDD) was assessed in 2017, 2018, 2019, 2020, and 2021, separately. RESULTS: The number of patients was comprised between 1,079,894 in 2021 and 1,132,839 in 2018. Median (interquartile range) CDD of basal insulin was relatively stable across the years and ranged between 27.9 (18.5-38.8) in 2021 and 28.3 (18.7-39.5) in 2020. In terms of short-acting insulin, median (interquartile range) CDD slightly decreased from 40.1 (28.2-54.3) in 2017 to 38.1 (27.2-52.2) in 2021. A slight decrease was also observed for mix insulin, from 39.4 (27.5-55.3) in 2017 to 37.9 (26.5-54.2) in 2021. These results were corroborated in most age and sex subgroups. CONCLUSIONS: COVID-19 had no substantial effects on insulin doses in Germany. Further data are warranted to corroborate or refute these findings in other settings and countries.

A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes.

Introduction: We report a case series of severe ketoacidosis after COVID-19 vaccination in a type 1 diabetes patients treated with insulin and an SGLT-2 inhibitor. Case Report: We present two cases of type 1 diabetes mellitus. One patient was treated with insulin therapy and an SGLT-2 inhibitor, and the other patient was treated with insulin therapy alone. Both patients became ill after coronavirus disease-2019 vaccination, making it difficult to continue their diet or insulin injections. On admission, they developed severe diabetic ketoacidosis. This is the first report of ketoacidosis after coronavirus disease-2019 vaccination. Conclusion: The vaccine should be carefully administered to type 1 diabetes patients receiving intensive insulin therapy and a sodium-glucose transporter due to the high risk ketoacidosis. It is important to instruct patients to drink sufficient fluids and to continue insulin injections when they become sick.