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Summary: Type 2 diabetes (T2D), obesity, and nonalcoholic fatty liver disease/nonalacoholic steatohepatitis (NAFLD/NASH) share mutual causalities. Medications that may offer clinical benefits to all three conditions are being developed. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are approved for the management of T2D and obesity and there is great interest in evaluating higher doses of available GLP‐1RAs and developing novel GLP‐1RA‐based co‐agonists to provide greater reductions in glycated hemoglobin (HbA1c) and body weight as well as modifying NAFLD/NASH complications in clinically meaningful ways. High‐dose GLP‐1RAs and multi‐hormonal strategies including GLP‐1R agonism have either already been approved or are in development for managing T2D, obesity, or NASH. We provide a mechanistic outline with a detailed summary of the available clinical data and ongoing trials that are adjudicating the impact of high‐dose GLP‐1RAs, unimolecular, and multimolecular GLP‐1R‐based co‐agonists in populations living with T2D, obesity, or NASH. The available trial findings are aligned with preclinical observations, showing clinical efficacy and safety thus providing optimism for the expansion of GLP‐1R‐based drug classes for managing the triad of T2D, obesity and NASH. Development, access, and wide‐spread utilization of these new therapeutic approaches will offer important opportunities to markedly improve the collective global burden of T2D, obesity, and NASH. [ABSTRACT FROM AUTHOR]

Introduction: A post hoc analysis of the PIONEER 1–5 and 8 trials assessed the clinically relevant composite endpoints of HbA1c (glycated haemoglobin) reduction ≥ 1% and body weight loss of ≥ 5% or ≥ 10% with orally administered semaglutide versus comparators. Methods: In the PIONEER trials, people with type 2 diabetes were randomised to orally administered semaglutide versus placebo (PIONEER 1, 4, 5 and 8), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3) and liraglutide (PIONEER 4) for 26–78 weeks. This analysis assessed the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% at week 26 and at end of treatment, and the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment. Results: Overall, 3506 people in PIONEER 1–5 and 8 were included. At week 26 and at end of treatment, odds of achieving the composite endpoint of an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% were significantly greater with orally administered semaglutide 14 mg than with placebo (PIONEER 1, 4, 5 and 8; all p < 0.0001), empagliflozin 25 mg (PIONEER 2, p < 0.0001), sitagliptin 100 mg (PIONEER 3, p < 0.0001) and liraglutide 1.8 mg (PIONEER 4, p < 0.0001). Odds of achieving the composite endpoint of HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment were also significantly greater with orally administered semaglutide versus comparators. Conclusion: In PIONEER 1–5 and 8, odds of achieving clinically relevant reductions in both HbA1c and body weight were significantly greater with orally administered semaglutide versus comparators. [ABSTRACT FROM AUTHOR]

Individuals can be sent to the Emergency Room (ER) for a variety of reasons. Our goal was to determine the differences in reasons and frequencies for visits to the ER between individuals with and without diabetes. This study was conducted by way of review of ER visit sheets over a three month period at tertiary care centre in Winnipeg, Canada. Examination of the control group (individuals without diabetes) revealed the most common documented reason for ER visits were cardiac complications (49.56%), hypertension (26.25%), renal conditions (15.34%), and neurological complications (5.90%). For the Type 1 diabetes group, reasons for visit to the ER were cardiac complications (33.33%), neurological complications (18.06%), and hypertension, nephropathy, DKA/glycemic control, and infectious diseases (all at 13.89%). Analyzing the documented diagnosis of type 2 individuals revealed similar trends to non-diabetic individuals. Cardiac complications (52.86%) dominated the reasons for admittance to the emergency room, followed by hypertension (32.36%), renal conditions (11.30%), neurological (4.32%), and DKA/glycemic control issues (0.42%), Type 2 diabetes patients presented with similar reasons for visit as patients without diabetes, and thus it appeared as though patients with Type 2 diabetes did not visit the ER primarily due to glycemic control issues. In type 1 diabetes patients, neurological and DKA/glycemic concerns were of higher occurrence than in patients with Type 2 or no diabetes. Cardiovascular, hypertension, and renal concerns constituted major reason for ER visit in all three groups. [ABSTRACT FROM AUTHOR]

Recent phase 3 clinical trials have evaluated the impact of adding sodium‐glucose co‐transporter (SGLT) inhibitors to the type 1 diabetes armamentarium. These trials studied SGLT2 inhibitors (dapagliflozin and empagliflozin) and a dual SGLT1 and SGLT2 inhibitor (sotagliflozin), and demonstrated that these oral non‐insulin antihyperglycaemic medications are able not only to improve glycaemic control, but also to reduce body weight and extend time in range without increasing rates of hypoglycaemia in type 1 diabetes. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes and the risk is increased when SGLT inhibitors are used in type 1 diabetes. To minimize the risk of DKA and still gain the multiple benefits, we developed the "STOP DKA Protocol ", an easily accessible and practical tool, that provides a risk mitigation strategy for reducing DKA in patients with type 1 diabetes being treated with SGLT inhibitors. [ABSTRACT FROM AUTHOR]

In the present multicentre, open‐label, prospective, phase III study, we evaluated the real‐world effectiveness and ease of use of nasal glucagon (NG) in the treatment of moderate/severe hypoglycaemic events (HEs) in adults with type 1 diabetes (T1D). Patients and caregivers were taught how to use NG (3 mg) to treat moderate/severe HEs, record the time taken to awaken or return to normal status, and measure blood glucose (BG) levels over time. Questionnaires were used to collect information about adverse events and ease of use of NG. In the efficacy analysis population, 69 patients experienced 157 HEs. In 95.7% patients, HEs resolved within 30 minutes of NG administration. In all the 12 severe HEs, patients awakened or returned to normal status within 15 minutes of NG administration without additional external medical help. Most caregivers reported that NG was easy to use. Most adverse events were local and of low to moderate severity. In this study, a single, 3‐mg dose of NG demonstrated real‐life effectiveness in treating moderate and severe HEs in adults with T1D. NG was well tolerated and easy to use. [ABSTRACT FROM AUTHOR]

Objective: This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes.Research Design and Methods: The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)-each with insulin detemir.Results: HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart-IAsp, mealtime, -0.15% [95% CI -0.23; -0.07], and postmeal, 0.04% [-0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L [95% CI -1.65; -0.71], -21.21 mg/dL [-29.65; -12.77]; P < 0.0001) and 2 h (-0.67 mmol/L [-1.29; -0.04], -12.01 mg/dL [-23.33; -0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose <3.1 mmol/L [56 mg/dL]) hypoglycemic episodes and safety profiles were similar between treatments.Conclusions: Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp. [ABSTRACT FROM AUTHOR]

The PIONEER phase 3 program investigated glycemic response and other efficacy endpoints in patients (pts) with type 2 diabetes randomized to the glucagon-like peptide-1 analog oral semaglutide (sema; 3, 7 or 14 mg once daily), placebo (pbo) or an active comparator (empagliflozin [empa] 25 mg, sitagliptin [sita] 100 mg or liraglutide [lira] 1.8 mg once daily). This post-hoc analysis of the PIONEER 1-5 and 8 trials evaluated the response of any reduction in HbA1c (%) and/or body weight (%), and a clinically relevant composite endpoint of HbA1c reduction ≥1% and body weight loss ≥5%, with oral sema 14 mg vs. comparators at the end of treatment (26-78 weeks). Across trials, any reduction in HbA1c was observed in higher proportions of pts with oral sema (89-95%) than with pbo (51-64%) or active comparators (82-88%). A simultaneous reduction in both HbA1c and body weight was seen in 72-86% of pts treated with oral sema (Figure). The composite of HbA1c reduction ≥1% and body weight loss ≥5% was achieved by 27-41% of pts with oral sema, 1-8% of pts with pbo, 11% with sita 100 mg, 18% with lira 1.8 mg, and 20% with empa 25 mg. Within each trial, the odds of achieving HbA1c reduction of ≥1% and body weight loss of ≥5% with oral sema 14 mg were significantly greater vs. all comparators (p<0.0001). These results demonstrate that oral sema 14 mg was more effective vs. comparators for providing any HbA1c reduction, or both an HbA1c reduction ≥1% and body weight loss ≥5%. Disclosure: K.M. Dungan: Advisory Panel; Self; Eli Lilly and Company, Elsevier. Research Support; Self; Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Nova Biomedical. Other Relationship; Self; UpToDate, Vizient Inc. C.L. Hertz: Employee; Self; Novo Nordisk A/S. L. Mellbin: Advisory Panel; Self; Amgen, AstraZeneca, Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. Research Support; Self; Bayer AG. Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk Foundation. M. Abildlund Nielsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. R. Sørrig: Employee; Self; Novo Nordisk A/S. V.C. Woo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. Funding: Novo Nordisk A/S [ABSTRACT FROM AUTHOR]

The SUSTAIN clinical trials demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide, a glucagon-like peptide 1 analog for the treatment of type 2 diabetes (T2D). SUSTAIN 9 investigated semaglutide 1.0 mg vs. placebo as add-on to a stable dose of sodium-glucose co transporter-2 inhibitor (SGLT2i) therapy, with or without metformin or a sulfonylurea. The primary and secondary endpoints were, respectively, change from baseline in HbA1c and body weight at week 30. In this post hoc analysis, SUSTAIN 9 data were analyzed by background SGLT2i (empagliflozin, canagliflozin, dapagliflozin or other [ipragliflozin, luseogliflozin and tofogliflozin; drugs available only in Japan]). In total, 302 subjects were randomized to semaglutide or placebo. Reductions in HbA1c and body weight were greater with semaglutide vs. placebo. There was no significant interaction between background SGLT2i and treatment effect (interaction p-value >0.05 for both endpoints), with a smaller observed weight reduction in the 'Other' group (Table). No safety concerns were identified when adding semaglutide to SGLT2i therapy. No diabetic ketoacidosis or lower limb amputation events occurred. In conclusion, in subjects with T2D already receiving an SGLT2i, semaglutide generally resulted in superior HbA1c and body weight reductions vs. placebo, regardless of background SGLT2i therapy. Disclosure: B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. V. Bhosekar: None. R.S. Busch: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; Bayer AG. Speaker's Bureau; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. Stock/Shareholder; Self; Amarin Corporation. I. Holst: Employee; Self; Novo Nordisk A/S. B. Ludvik: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Takeda Development Centre Europe Ltd. Research Support; Self; Akebia Therapeutics, Eli Lilly and Company, Novartis AG, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J. Thrasher: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Senseonics. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc. V.C. Woo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. A. Philis-Tsimikas: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc., Glooko, Inc., National Institute of Diabetes and Digestive and Kidney Diseases. Stock/Shareholder; Spouse/Partner; Ionis Pharmaceuticals, Inc., Novo Nordisk Inc. Funding: Novo Nordisk A/S [ABSTRACT FROM AUTHOR]

Purpose Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents available on the market. Regulator warnings and concerns regarding the risk of developing diabetic ketoacidosis (DKA), however, have dampened enthusiasm for the class despite the combined glycemic, blood pressure, and occasional weight benefits of SGLT2 inhibitors. With the goal of improving patient safety, a cross-Canada expert panel and writing group were convened to review the evidence to-date on reported SGLT2 inhibitor–related DKA incidents and to offer recommendations for preventing and recognizing patients with SGLT2 inhibitor–associated DKA. Methods Reports covering DKA events in subjects taking SGLT2 inhibitors that were published in PubMed, presented at professional conferences, or in the public domain from January 2013 to mid-August 2016 were reviewed by the group independently and collectively. Practical recommendations for diagnosis and prevention were established by the panel. Findings DKA is rarely associated with SGLT2 inhibitor therapy. Patients with SGLT2 inhibitor–associated DKA may be euglycemic (plasma glucose level <14 mmol/L). DKA is more likely in patients with insulin-deficient diabetes, including those with type 2 diabetes, and is typically precipitated by insulin omission or dose reduction, severe acute illness, dehydration, extensive exercise, surgery, low-carbohydrate diets, or excessive alcohol intake. SGLT2 inhibitor–associated DKA may be prevented by withholding SGLT2 inhibitors when precipitants develop, avoiding insulin omission or inappropriate insulin dose reduction, and by following sick day protocols as recommended. Implications Preventive strategies should help avoid SGLT2 inhibitor–associated DKA. All SGLT2 inhibitor–treated patients presenting with signs or symptoms of DKA should be suspected to have DKA and be investigated for DKA, especially euglycemic patients. If DKA is diagnosed, SGLT2 inhibitor treatment should be stopped, and the DKA should be treated with a traditional treatment protocol. [ABSTRACT FROM AUTHOR]