Low Risk Of Hypoglycemia Research Articles

A Real-World Study in Patients with Type 2 Diabetes Treated with Gliclazide Modified Release during Fasting in Gulf Cooperation Council Countries: An Analysis from the International DIA-RAMADAN Study

Introduction: The safety and effectiveness of gliclazide modified release (MR) in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan were previously published. Here, we carried out a regional analysis among patients living in Gulf Cooperation Council (GCC) countries. Patients and Methods: DIA-RAMADAN was a real-world, observational, international, noncomparative study conducted in nine countries that included >1200 T2DM adults receiving gliclazide MR for at least 90 days before inclusion. The study comprised 2 visits: at inclusion, 6–8 weeks before the start of Ramadan (V0) and 4–6 weeks after the end of Ramadan (V1). The primary endpoint was the proportion of patients reporting ≥1 symptomatic hypoglycemic event as collected using a patient diary. Changes in HbA1c, fasting plasma glucose (FPG), and weight were also analyzed. This manuscript represents data collected in GCC countries (Kuwait, Saudi Arabia, and United Arab Emirates). Results: Data from 161 patients were analyzed: mean (SD) age 56.8 (10.6) years, 30.4% women, body mass index 29.1 (3.7) kg/m2, T2DM disease duration 6.7 (3.3) years, baseline HbA1c 7.9% (0.8). The proportions of patients reporting ≥1 symptomatic hypoglycemic event or confirmed hypoglycemia during Ramadan were 4.3% and 0.6%, respectively. No cases of severe hypoglycemia were reported. Significant reductions in main variables were observed before the start of Ramadan (V0) and 4–6 weeks after the end of Ramadan (V1): HbA1c (from 7.9 [0.8] to 7.6 [0.7]%; p value <0.001), FPG (from 143.5 [24.3] to 137.9 [25.2] mg/dL; p value = 0.031), and weight (from 79.0 [73.0–86.0] to 78.0 [72.0–85.0] kg; p value = 0.018). Conclusions: These real-world data indicate that patients with T2DM treated with gliclazide MR during Ramadan in the selected GCC countries have a low risk of hypoglycemia and maintain glycemic control and weight while fasting.

Saudi Consensus for GLP-1 RAs Switching Guidance: Consensus Report

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide adequate glycemic control, weight reduction, low risk of hypoglycemia, and CV risk reduction. Their usage for type 2 DM (T2DM) is recommended mainly when hypoglycemia or weight gain should be considered, also, whenever initial therapy is failed. There are many recent updates in the treatment paradigm of T2DM. There are many types of GLP-1RAs, with a knowledge gap regarding switching between the different types. A Saudi task force gathered to develop an explicit, evidence-based consensus for switching between GLP-1RAs, when, why, and how? This article contains the expert panel’s recommendations as a contribution to complement the knowledge gap in this area from the national perspective. As an alternative to intensifying therapy, switching from one GLP-1RA to another has various advantages. Improvements in glycemic control, weight loss, adherence, and medications with established cardiovascular benefits are among them. Also, switching needs to be individualized upon many discussed factors like the dose of the previous GLP1-RA and gastrointestinal adverse effects. Discussion with patients about the why and how to switch is critical.

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future.

Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular morbidity and mortality, and cardiovascular diseases are the leading causes of death and disability in people with T2DM. Unfortunately, therapies strictly aimed at glycemic control have poorly contributed to a significant reduction in the risk of cardiovascular events. On the other hand, randomized controlled trials have shown that five glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and one exendin-based GLP-1 RA reduced atherosclerotic cardiovascular events in patients with diabetes at high cardiovascular risk. Furthermore, a meta-analysis including these six agents showed a reduction in major adverse cardiovascular events as well as all-cause mortality compared with placebo, regardless of structural homology. Evidence has also shown that some drugs in this class have beneficial effects on renal outcomes, such as preventing the onset of macroalbuminuria. In addition to lowering blood pressure, these drugs also favorably impacted on body weight in large randomized controlled trials as in real-world studies, a result considered a priority in T2DM management; these and other factors may justify the benefits of GLP-1 RAs upon the cardiovascular system, regardless of glycemic control. Finally, studies showed safety with a low risk of hypoglycemia and no increase in pancreatitis events. Given these benefits, GLP-1 RAs were preferentially endorsed in the guidelines of the European and American societies for patients with these conditions. This narrative review provides a current and comprehensive overview of GLP-1 RAs as cardiovascular and renal protective agents, far beyond their use as glucose-lowering drugs, supporting their effectiveness in treating patients with T2DM at high cardiovascular risk.

Fixed-Dose Combination of Dipeptidyl Peptidase-4 Inhibitors Plus Metformin in Patients with Type 2 Diabetes: A Review on Safety and Efficacy

There is a significant increase noted in the incidence and prevalence of Type 2 diabetes mellitus (T2DM). The global number of diabetic patients is projected by the International Diabetes Federation (IDF) to reach 552 million. T2DM disease has chronic and progressive nature. More than fifty percent of patients do not attain adequate glycemic control despite initial sufficient monotherapy. To maintain target glycated hemoglobin (HbA1c) levels (&lt;7%), dose adjustment and adoption of several diabetes therapies become necessary in many cases. Compared to monotherapy, a fixed drug combination of oral agents and metformin has proven to be more efficacious to maintain levels of blood glucose and HbA1c. The combination of dipeptidyl peptidase-4 inhibitors (DDPIs) and metformin has been explicated to effectively decrease HbA1c to a relatively higher degree compared to the use of either agent individually. This combination addresses various pathophysiological processes involved in T2DM pathogenesis. Additionally, the concerned combination is safe and associated with a lower risk of hypoglycemia. Moreover, it is well-tolerated and prescribed as an easy-to-use single pill to improve patient compliance. This review provides an overview of the pharmacology, efficacy, and safety of fixed drug combinations of DDPIs and metformin according to current practice.

Sitagliptin and Acute Pancreatitis: A Systematic Review and Meta-analysis

Background and Objectives: Sitagliptin is a dipepidyl peptidase inhibitor (DPP-4i) with gentle antidiabetic effects with a lower risk of hypoglycemia. The association with acute pancreatitis is controversial. The current meta-analysis aimed to assess the relationship of sitagliptin and acute pancreatitis.&#x0D; Methods: The literature in PubMed and Google Scholar was searched for relevant articles published in the last ten years up to September 2021. The keywords sitagliptins, DPP-4i, acute pancreatitis were used with the protean AND or OR. Among the 204 articles retrieved, 24 full-texts were assessed for eligibility and only five studies (Three from the USA, one from Asia, and one from Canada) met the inclusion criteria for the systematic review. The author name, year of publication, country, type of study, number of patients, and the duration of the study were reported.&#x0D; Results: There were five studies. The total number of patients were 729808 with 6459 events. The studies showed no increased rate of acute pancreatitis following sitagliptin use, odd ratio, 0.79, 95% CI, 0.29-2.15, a significant heterogeneity was observer, I2 for heterogeneity=98%, P-value, &lt;001, the P-value for overall effect was 0.65 and the chi-square, 160.15.&#x0D; Interpretation and Conclusion: Sitagliptin use is not associated with acute pancreatitis.

Abstract 9392: Cardiovascular, Metabolic and Safety Outcomes With Semaglutide by Age: A Post Hoc Analysis of SUSTAIN 6 and PIONEER 6

Introduction: For older patients with type 2 diabetes, treatments that minimize the risk of hypoglycemia and provide benefits in terms of comorbidities, while optimizing glycemic control, are particularly important. Semaglutide, a glucagon-like peptide-1 receptor agonist available as a once-weekly (OW) subcutaneous and once-daily oral formulation, reduces HbA 1c and body weight with a low risk of hypoglycemia. In addition, major adverse cardiovascular events (MACE) were reduced in SUSTAIN 6 (OW semaglutide; significant) and PIONEER 6 (oral semaglutide; not significant) vs placebo. The aim of this post hoc analysis was to evaluate cardiovascular (CV), metabolic and safety outcomes with semaglutide according to age. Methods: Subgroup analyses for semaglutide vs placebo by age as quartiles (≤60 years; &gt;60 years to ≤65; &gt;65 years to ≤70 years; &gt;70 years) were performed for pooled SUSTAIN 6 and PIONEER 6 data in relation to: CV (3-point and individual MACE components), metabolic (change in HbA 1c , body weight) and safety (severe hypoglycemia, serious adverse events [SAEs]) outcomes. Results: In patients treated with semaglutide (n=3,239) vs placebo (n=3,241), the reduction in MACE and individual components of MACE was consistent across age subgroups (p interaction &gt;0.05 for all; Table ). Minor heterogeneity for change in HbA 1c from baseline was observed with semaglutide vs placebo across the four age subgroups (p interaction =0.01). Weight reduction with semaglutide vs placebo did not differ across age subgroups. Semaglutide (vs placebo) did not result in an increase in severe hypoglycemia or SAEs in any of the age subgroups ( Table ). Conclusions: This post hoc combined analysis of SUSTAIN 6 and PIONEER 6 indicates that the CV and metabolic benefits and the safety profile of semaglutide (vs placebo) align with the drug class and were consistent across age subgroups.

Low risk of hypoglycemia and high efficacy of gliclazide MB: results of recent studies

Sulfonylureas are widely prescribed all over the world, mainly because of their high effectiveness. At the same time, the heterogeneity of the group is obvious, primarily in relation to the effect of drugs on the risk of developing hypoglycemic events. The review presents the results of new studies, including «Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after metformin monotherapy in patients with uncontrolled type 2 diabetes» and results of a model-based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes, confirming the higher efficacy of modified release gliclazide (gliclazide MB) compared to DPP-4, as well as a low risk of hypoglycemic conditions. The results of recent studies, as well as the results of the ADVANCE and ADVANCE-ON studies, suggest that gliclazide MB is safe to use as a second-line drug, especially in patients with chronic kidney disease.

The obesity paradox and hypoglycemia in critically ill patients

BackgroundA high body mass index (BMI) has been associated with decreased mortality in critically ill patients. This association may, in part, relate to the impact of BMI on glycemia. We aimed to study the relationship between BMI, glycemia and hospital mortality.MethodsWe included all patients with a recorded BMI from four large international clinical databases (n = 259,177). We investigated the unadjusted association of BMI with average glucose levels, mortality and hypoglycemia rate. We applied multivariate analysis to investigate the impact of BMI on hypoglycemia rate, after adjusting for glycemia-relevant treatments (insulin, dextrose, corticosteroids, enteral and parenteral nutrition) and key physiological parameters (previous blood glucose level, blood lactate, shock state, SOFA score).ResultsWe analyzed 5,544,366 glucose measurements. On unadjusted analysis, increasing BMI was associated with increasing glucose levels (average increase of 5 and 10 mg/dL for the 25–30, 30–35 kg/m2 BMI groups compared to normal BMI (18.5–25 kg/m2) patients). Despite greater hyperglycemia, increasing BMI was associated with lower hospital mortality (average decrease of 2% and 3.25% for the 25–30, 30–35 kg/m2 groups compared to normal BMI patients) and lower hypoglycemia rate (average decrease of 2.5% and 3.5% for the 25–30, 30–35 kg/m2 groups compared to normal BMI patients). Increasing BMI was significantly independently associated with reduced hypoglycemia rate, with odds ratio (OR) 0.72 and 0.65, respectively (95% CIs 0.67–0.77 and 0.60–0.71, both p < 0.001) when compared with normal BMI. Low BMI patients showed greater hypoglycemia rate, with OR 1.6 (CI 1.43–1.79, p < 0.001). The association of high BMI and decreased mortality did not apply to diabetic patients. Although diabetic patients had higher rates of hypoglycemia overall and higher glucose variability (p < 0.001), they also had a reduced risk of hypoglycemia with higher BMI levels (p < 0.001).ConclusionsIncreasing BMI is independently associated with decreased risk of hypoglycemia. It is also associated with increasing hyperglycemia and yet with lower mortality. Lower risk of hypoglycemia might contribute to decreased mortality and might partly explain the obesity paradox. These associations, however, were markedly modified by the presence of diabetes.Graphical

The Impact of Adding Prandial Insulin to a Basal Based Regimen with Insulin Glargine in Type 2 Diabetic Patients.

Background: Type 2 diabetes (T2D) is a progressive disease that should be managed with insulin in case of oral glucose lowering drugs (OGLDs) failure. If basal insulin is not sufficient, rapid acting insulin will be added before the largest meal. We assessed the impact of adding one prandial insulin to a basal based regimen and insulin glargine in patients with type 2 diabetes to measure the percentage of subjects achieving the HbA1c target by the end of 24 weeks of treatment in routine clinical practice. Methods: This study was a 24-week observational study of patients with T2D not adequately controlled with OGLDs and basal insulin, for whom the physician had decided to initiate prandial insulin. The study endpoint was assessed at visit 1 (baseline), visit 2 at week 12 (±1 week) and visit 3 at week 24 (±1 week). The percentage of patients who achieved HbA1c targets was assessed at week 24. Statistical analyses were performed using IBM SPSS for Windows v 19 (IBM, Armonk, New York, USA). Logistic regression analysis was used to detect predicting factors of achieving the HbA1c target by week 24. P<0.05 was considered as significant level. Results : Four hundred and eighteen patients with a mean±SD age of 56.24±9.85 years and a mean±SD duration of diabetes of 12.50±7.16 years were included. The median total daily dose of basal insulin was 24 units, while prandial insulin was started with 6 (4, 10) U/day, titrating up to 10 (8, 18) U/day at week 24. The daily dose of prandial insulin was the only factor that could significantly predict achieving targeted HbA1c by week 24 [OR: 1.04; 95% CI: 1.007,1.079; p-value: 0.019]. At week 24, 96 (22.9%) subjects achieved the HbA1c target with one prandial insulin. Conclusion : The results of our study suggest that “basal plus therapy” can lead to good glycemic control with a low risk of hypoglycemia and weight gain in patients with type 2 diabetes.

ARISE-a prospective, non-interventional, single-arm study assessing clinical parameters associated with the use of insulin degludec/insulin aspart in patients with type 2 diabetes in real-world settings: rationale and design.

PurposeIDegAsp, a co-formulation of long-acting basal (insulin degludec) and rapid-acting bolus (insulin aspart) insulin, provides separate prandial and basal glucose-lowering effects with relatively low risk of hypoglycaemia. Its efficacy and safety have been investigated in a large clinical trial programme (BOOST). We present the rationale and design of the ARISE study, which aims to assess glycaemic control and other clinical parameters associated with IDegAsp use in real world.MethodsARISE is a ~26-wk-long, prospective, non-interventional, single-arm study of patients with type 2 diabetes (T2D) initiating IDegAsp treatment. Approximately 1112 patients with T2D aged ≥18 years previously on anti-hyperglycaemic drugs except IDegAsp will be enroled across six countries from 15 Aug 2019 to 12 Nov 2020. IDegAsp treatment will be initiated at the physicians’ discretion and as per the local label. Key exclusion criteria include previous participation, or previous IDegAsp treatment. The primary and secondary endpoints are change in HbA1c from baseline (wk 0) to study end (wk 26–36) and the proportion of patients achieving the target HbA1c level of <7% at the study end, respectively. A mixed model for repeated measurements will analyse the primary endpoint.ConclusionBetween-country differences in the prescription patterns of glucose-lowering agents in people with T2D warrant examination of their clinical use in different geographical settings. The ARISE study is designed to assess the clinical use of IDegAsp from real world in six different countries. Findings from the ARISE study will supplement those of previous randomised controlled studies by establishing real-world evidence of IDegAsp use in the participating countries.Trial registrationClinicalTrials.gov, NCT04042441. Registered 02 August 2014, https://clinicaltrials.gov/ct2/show/NCT04042441

An update on the safety of insulin-GLP-1 receptor agonist combinations in type 2 diabetes mellitus

ABSTRACT Introduction Recent development of novel antidiabetic drugs with proven cardiovascular (CV) and renal benefit and positive effect on body weight enable to take a more complex approach toward the management of type 2 diabetes mellitus (T2DM). Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) utilize complementary mechanisms of action of their individual components and address multiple pathologies linked with T2DM at the same time. Areas covered There are currently three FRCs on the market: iGlarLixi (glargine and lixisenatide in 2 different formulations) and IDegLira (degludec and liraglutide). We provide an up-to-date review on the rationale for the use of FRCs and their current position in the management of T2DM. We discuss the available evidence from randomized controlled trials, post hoc analyses, indirect comparative studies and real-world data on their effect on glycemic control, risk of hypoglycemia, body weight, CV safety, and their safety profile. Expert opinion FRCs represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM. Their excellent glucose-lowering efficacy is complemented with lower risk of hypoglycemia in comparison to basal insulin, neutral effect on body weight and the lower risk of gastrointestinal adverse effects in comparison to GLP-1 receptor agonists.

Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

Management of Type 2 Diabetes Mellitus in a Patient with COVID-19: The Window of Insulin Glargine U300

Research on pharmacological therapies for the treatment and prevention of Coronavirus Disease 2019 (COVID-19) is limited in patients with Type 2 Diabetes Mellitus (T2DM). In this case, diabetes management of a 51-year-old male patient who was followed up and treated with COVID-19 diagnosis in the pandemic clinic is presented. While metformin (2000 mg/day) oral therapy was continued, insulin glargine U100 (IGlar100) was added to the treatment subcutaneously. In addition, enoxaparin, hydroxychloroquine, azithromycin were started to be administered to the patient. During follow-up, respiratory distress and tachypnea (26 breaths/min), high fever (38.3oC), increased CRP (42 mg/dL), and decreased oxygen saturation (91%) were detected. Favipiravir was added to the treatment, and metformin was stopped due to possible lactic acidosis risk. IGlar300 treatment with more potency effect and lower risk of hypoglycaemia was initiated while IGlar100 was discontinued. In the follow-ups, titration was provided with IGlar300 to keep fasting blood glucose between 100-140 mg/dL and postprandial one between 140-180 mg/dL. In the treatment for this purpose, a maximum of 34 units/day insulin was needed. Capillary blood sugar monitoring was revised every 12 hours and then once a day. As the infection was brought under control, the required dose of IGlar300 decreased to 14 units/day. After diabetes training with a video phonecall, he was discharged with metformin and IGlar300. IGlar300 may be effective against diabetes in the COVID-19 pandemic. In addition, a significant contribution can be made both to the treatment safety of the patient in a glycemic sense and to the safety of contamination by reduced contact of health care professionals.

Development and Validation of Novel RP-HPLC Method for the Simultaneous Determination of Remogliflozin and Vildagliptin in Bulk and in synthetic Mixture

Vildagliptin which is DPP-4 inhibitor and Remogliflozin which is SGLT2 inhibitor in single dose regimen lower blood glucose by separate, complementary mechanisms. Both are glucose dependent, accounting for the low risk of hypoglycaemia during treatment. There is no risk factors associated with this combination and moreover it is single dose regimen. The aim of the present study was to develop and validate a simple, rapid and reproducible gradient high performance reverse phase liquid chromatography method for the estimation of Remogliflozin and Vildagliptin in bulk drug sample and in synthetic mixture using Xterra® Waters C18 column (150 mm×4.6 mm, 5 µm) at 25°C with UV detection at 210 nm and for this gradient mode was used. The compounds were eluted gradiently at a flow rate of 1.0ml/min. The average retention times for Remogliflozin and Vildagliptin were 4.881 and 6.334 min, respectively. The calibration curves were linear (r2 =0.988) over the concentration range 10-200 µg/ml for Remogliflozin and 10-200 µg/ml for Vildagliptin. No spectral or chromatographic interferences from formulation excipients were found and hence it was successfully applied for the determination of Remogliflozin and Vildagliptin in bulk and in synthetic mixture. The accuracy of the proposed method was determined by recovery studies and found to be 98-101%. The proposed method was validated and results conformed to ICH parameters.

Antihyperglycemic and hypoglycemic activities of the aqueous leaf extract of Rubus Erlangeri Engl (Rosacea) in mice

BackgroundThe prevalence of diabetes mellitus is on the inexorable rise despite the promises of a wide range of conventional medications. Thus, there is a need to scientifically investigate plants for antidiabetic effect. MethodsAfter the Rubus Erlanrige Engl (Rosaceae) leaf has been decocted, the plant extract's antidiabetic activity was first investigated in vitro and then in vivo. The in vitro activity was assessed using 3, 5-Dinitrosalicylic acid, and 2,2-diphenyl-1-picrylhydrazine method for α-amylase inhibition and antioxidant effect respectively. On the other hand, the in vivo antidiabetic activity was carried out in normoglycemic, glucose loaded (2.5 g/kg) and single dose streptozotocin (200 mg/kg) induced diabetic mice. ResultsAcute toxicity study showed the extract is safe with ≥2 g/kg. The in vitro results demonstrated the extract has an IC50 of 7.34 ± 0.02 and 10.38 ± 0.0.62 μg/ml for antioxidant and α-amylase inhibition activity respectively. On the other hand, the in vivo study revealed that the extract significantly reduced blood glucose level following glucose loading. The extract did not, however, produce a significant reduction of glucose level in normal mice indicating low risk of hypoglycemia. The extract also significantly decreased blood glucose levels in streptozotocin-induced diabetic mice. In the single dose study, the extract lowered blood glucose level all except by lower dose at the 3rd and 4th h (p < 0.05). In repeated dose studies, the reduction in fasting blood glucose was significant with all doses of the extract from the 2nd week onwards. In addition, the extract produced less reduction in body weight after diabetic induction. ConclusionThe findings collectively indicate that the extract has an antidiabetic activity, with low risk of hypoglycemia, probably mediated by various secondary metabolites that act in synergy.

Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. Eli Lilly and Company.

Impact of a Single 36 Hours Prolonged Fasting Period in Adults With Type 1 Diabetes - A Cross-Over Controlled Trial.

Prolonged fasting has shown beneficial effects in healthy individuals and in people with chronic diseases. In type 1 diabetes, the effect or even the feasibility of fasting is unclear. We aimed to assess the impact and safety of prolonged fasting in adults with type 1 diabetes. Glycemia was assessed during overnight fasting (12 hours) vs. prolonged fasting (36 hours) via an intermittently-scanned continuous glucose monitoring system. Anthropometric data, metabolic and hormonal markers were compared between both trial arms. After each fasting period, a 75 g oral glucose tolerance test was performed and plasma glucose levels and hormones were assessed. Data were compared via paired t-tests and mixed-model regressions (p ≤ 0.05). Twenty individuals with type 1 diabetes (7 females) with a mean ± SD age of 35 ± 11 years, body mass index (BMI) 24.8 ± 2.8 kg/m2 and HbA1c 54 ± 7 mmol/mol were included. Hypoglycemia/hour (70 mg/dL; <3.9 mmol/L) was similar in both trial arms (12 hrs: 0.07 ± 0.06 vs. 36 hrs: 0.05 ± 0.03, p=0.21). Glycemic excursions during the oral glucose tolerance test were not different after the two fasting periods. Beta-hydroxybutyrate levels were higher after prolonged fasting (p=0.0006). Our study showed that people with type 1 diabetes can safely perform a 36 hours fasting period with a low risk of hypoglycemia and ketoacidosis.Clinical Trial RegistrationDRKS.de, identifier DRKS00016148.

A pH‐Triggered Self‐Unpacking Capsule Containing Zwitterionic Hydrogel‐Coated MOF Nanoparticles for Efficient Oral Exendin‐4 Delivery

Oral peptide or protein delivery is considered a revolutionary alternative to daily subcutaneous injection; however, major challenges remain in terms of impediments of the gastrointestinal environment and the intestinal epithelium consisting of mucus and the epithelial cell layer, leading to low bioavailability. To protect against gastrointestinal degradation and promote penetration across the intestinal mucosa, a pH-triggered self-unpacking capsule encapsulating zwitterionic hydrogel-coated metal-organic framework (MOF) nanoparticles is engineered. The MOF nanoparticles possess a high exendin-4 loading capacity, and the zwitterionic hydrogel layer imparts unique capability of permeation across the mucus layer and effective internalization by epithelial cells to the nano-vehicles. In addition to the gastro-resistant feature, the pH-responsive capsules are dissociated drastically in the intestinal environment due to the rapid generation of abundant CO2 bubbles, which triggers a sudden release of the nanoparticles. After oral administration of the capsules containing exendin-4-loaded nanoparticles into a diabetes rat model, markedly enhanced plasma exendin-4 levels are achieved for over 8 h, leading to significantly increased endogenous insulin secretion and a remarkable hypoglycemic effect with a relative pharmacological availability of 17.3%. Owing to the low risk of hypoglycemia, this oral exendin-4 strategy will provide a vast potential for daily and facile diabetes treatment.

Sodium-Glucose Transporter Inhibition in Adult and Pediatric Patients with Type 1 Diabetes Mellitus.

Adjunctive therapies to insulin for treatment of type 1 diabetes mellitus (T1D) have gained popularity in efforts to achieve glycemic targets, and sodium-glucose transporter (SGLT) inhibitors are an appealing option due to associated weight loss, low risk of hypoglycemia, and improved cardiorenal outcomes seen in persons with type 2 diabetes mellitus. The increased risk of diabetic ketoacidosis (DKA), including euglycemic DKA, has led many to be wary of their use in T1D, especially given limited pediatric data and data regarding cardiorenal protection in this population. The phase 3 trials of these agents in T1D have yielded lower HbA1c, decreased total daily insulin dose, and small but significant weight loss with no increase in hypoglycemia. These trials also reported increased risks of genital mycotic infection and DKA. SGLT inhibitors have been approved as adjunctive therapy to insulin in adults with T1D in Europe and Japan, but the United States Food and Drug Administration has rejected similar applications. Although approaches to mitigate the risk of DKA have been developed, no randomized trials using such tools have been conducted. More research is needed to minimize the risk of DKA and to better evaluate the cardiorenal impact of these agents in persons with T1D.

Profile of Ipragliflozin, an Oral SGLT-2 Inhibitor for the Treatment of Type 2 Diabetes: The Evidence to Date.

BackgroundSodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel class of pharmacotherapeutics for type 2 diabetes management that work by reducing renal reabsorption of glucose. Ipragliflozin is a potent, selective SGLT-2 inhibitor used for the management of type 2 diabetes.ObjectiveThe primary aim of this review is to summarize the available evidence on the efficacy and safety of ipragliflozin for the management of type 2 diabetes. We also review the discovery, pharmacokinetic, and pharmacodynamic profile of ipragliflozin.MethodsTo inform our review, we searched MEDLINE, International Pharmaceutical s, and Embase to identify relevant papers to ipragliflozin use in type 2 diabetes. Clinical trial registries were also searched.ResultsFindings from randomized clinical trials demonstrate that compared to placebo, ipragliflozin significantly reduces glucose as measured via Hemoglobin A1c and fasting plasma glucose levels. Ipragliflozin is also associated with weight reduction and an improvement in some, but not all, cardiovascular risk markers. Ipragliflozin has a favourable safety profile with a low risk of hypoglycemia and the rates of common adverse events are not significantly different than placebo. Limited data are available to assess rare and long-term adverse effects.ConclusionCurrent evidence shows that ipragliflozin is an effective therapeutic option for the management of glucose control in type 2 diabetes. However, no cardiovascular outcome trials have been conducted to date. Real-world observational studies are still needed to accurately capture any possible rare or long-term adverse events.