Publications by authors named "Harpreet S Bajaj"

39 Publications

Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial.

Lancet Diabetes Endocrinol 2021 09 21;9(9):563-574. Epub 2021 Jul 21.

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

Background: Semaglutide is an effective treatment for type 2 diabetes; however, 20-30% of patients given semaglutide 1·0 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea.

Methods: We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (≥18 years) with inadequately controlled type 2 diabetes (HbA 8·0-10·0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2·0 mg or 1·0 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162.

Findings: Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58·0 years [SD 10·0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2·0 mg (n=480 [50%]) or 1·0 mg (n=481 [50%]); 462 (96%) patients in the semaglutide 2·0 mg group and 471 (98%) in the semaglutide 1·0 mg group completed the trial. Mean baseline HbA was 8·9% (SD 0·6; 73·3 mmol/mol [SD 6·9]) and BMI was 34·6 kg/m (SD 7·0). Mean change in HbA from baseline at week 40 was -2·2 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (estimated treatment difference [ETD] -0·23 percentage points [95% CI -0·36 to -0·11]; p=0·0003; trial product estimand) and -2·1 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (ETD -0·18 percentage points [-0·31 to -0·04]; p=0·0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was -6·9 kg with semaglutide 2·0 mg and -6·0 kg with semaglutide 1·0 mg (ETD -0·93 kg [95% CI -1·68 to -0·18]; p=0·015; trial product estimand) and -6·4 kg with semaglutide 2·0 mg and -5·6 kg with semaglutide 1·0 mg (ETD -0·77 kg [-1·55 to 0·01]; p=0·054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2·0 mg group and 148 [31%] in the 1·0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2·0 mg and 25 (5%) participants given semaglutide 1·0 mg. Three deaths were reported during the trial (one in the semaglutide 1·0 mg group and two in the semaglutide 2·0 mg group).

Interpretation: Semaglutide 2·0 mg was superior to 1·0 mg in reducing HbA, with additional bodyweight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control.

Funding: Novo Nordisk.
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http://dx.doi.org/10.1016/S2213-8587(21)00174-1DOI Listing
September 2021

Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial.

Diabetes Care 2021 08 28;44(8):1894-1897. Epub 2021 Jun 28.

Department of Renal Medicine, University College London, London, U.K.

Objective: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.

Research Design And Methods: We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m, and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.

Results: Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent ( for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.

Conclusions: Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.
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http://dx.doi.org/10.2337/dc21-0300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385469PMC
August 2021

Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial.

Lancet Diabetes Endocrinol 2021 08 18;9(8):484-490. Epub 2021 Jun 18.

St John's Medical College, St John's National Academy of Health Sciences, Bangalore, India.

Background: Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes.

Methods: The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006).

Interpretation: Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S2213-8587(21)00115-7DOI Listing
August 2021

Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial.

Diabetes Care 2021 Apr 19. Epub 2021 Apr 19.

Dallas Diabetes Research Center, Dallas, TX.

Objective: Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine U100 (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and one or more oral glucose-lowering medications.

Research Design And Methods: This multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal insulin-treated (total daily dose 10-50 units) people with type 2 diabetes (HbA 7.0-10.0% [53.0-85.8 mmol/mol]) to icodec with an initial 100% loading dose (in which only the first dose was doubled [icodec LD]), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. Primary end point was percent time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]) during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary end points included HbA, adverse events (AEs), and hypoglycemia.

Results: Estimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; = 54), 66.0% (icodec NLD; = 50), and 65.0% (IGlar U100; = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points [95% CI 1.8-13.9%]). Mean HbA reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% (54.4 mmol/mol icodec LD) and 7.4% (57.6 mmol/mol icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.

Conclusions: Switching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.
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http://dx.doi.org/10.2337/dc20-2877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323191PMC
April 2021

Extended-release naltrexone/bupropion and liver health: Pooled, post hoc analysis from four randomized controlled trials.

Diabetes Obes Metab 2021 03 13;23(3):861-865. Epub 2021 Jan 13.

Bausch Health, Laval, Quebec, Canada.

Sustained weight loss improves liver histology in non-alcoholic fatty liver disease. This post hoc analysis of four phase III, 56-week, randomized controlled trials investigated if extended-release naltrexone and bupropion (NB) affects alanine aminotransferase (ALT) and Fibrosis-4 (FIB-4) index in adults with overweight or obesity. Two thousand and seventy-three subjects (NB = 1310; placebo = 763; 79.0% female; 81.6% Caucasian) had baseline mean weight 101 kg, body mass index 36.2 kg/m , ALT 26.9 IU/L and FIB-4 0.79. At 56 weeks, NB-treated subjects experienced more weight loss than placebo (8.7 vs. 3.2 kg, respectively, P < .0001). Weight loss, independent of treatment, was associated with improved ALT and FIB-4 (P < .0001). There was a significant independent effect of NB on change from baseline for FIB-4 (P < .0001), but not for ALT (P = .54). Categorical ALT response (from above to within normal ranges: 10-40 IU/L for men; 7-35 IU/L for women) and achievement of 25% and 50% reduction in ALT were greater for NB versus placebo, and independently affected by weight loss (P < .0001), but not treatment. NB-associated weight loss may improve liver health by normalizing ALT values for those with high baseline levels.
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http://dx.doi.org/10.1111/dom.14284DOI Listing
March 2021

Assessing the Effect of Quality-Improvement Strategies for Organization of Care in Type 2 Diabetes Outcomes in Adults: Aim-Strait.

Can J Diabetes 2021 Jun 1;45(4):319-326.e5. Epub 2020 Oct 1.

Merck Canada Inc., Kirkland, Quebec, Canada.

Objectives: To observe the effect of an organization-of-care improvement process on the achievement of therapeutic goals for people with type 2 diabetes mellitus (T2DM).

Methods: This single-arm cohort study analyzed the electronic medical records of patients with T2DM in 5 primary care practices in Ontario, Canada, before and 2 years after implementation of an individualized quality-improvement program. The primary outcome was the change in glycated hemoglobin (A1C) between baseline and follow up, with secondary analyses including change in other metabolic parameters, medication patterns and clinic visits. Prespecified subgroup analysis of patients with baseline values above guideline therapeutic targets was performed.

Results: In the overall population of 1,886 patients, A1C improved from 7.1% (baseline) to 7.0% (follow up) (p<0.001); low-density lipoprotein-cholesterol (LDL-C) improved from 2.1 to 1.9 mmol/L (p<0.001); and diastolic blood pressure (BP) improved from 75 to 74 mmHg (p<0.001), with no significant change observed in systolic BP. Of those patients who were above guideline-recommended therapeutic targets at baseline, improvements were observed at follow-up: A1C 8.3±1.3% to 7.8±1.3% (p<0.001), LDL-C 2.9±0.7 mmol/L to 2.4±0.9 mmol/L (p<0.001), systolic BP 144±11 to 134±16 mmHg (p<0.001) and diastolic BP 80±10 to 75±11 mmHg (p<0.001), with the percentages of patients achieving target at follow up being 32% for A1C, 40% for LDL-C and 49% for systolic BP. Overall, 22% of patients achieved all 3 targets at baseline compared to 28% at follow up (p<0.001).

Conclusions: The implementation of an organization-of-care improvement program in primary care was associated with improved metabolic control, which was most pronounced in patients with baseline levels above guideline-recommended therapeutic targets.
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http://dx.doi.org/10.1016/j.jcjd.2020.09.019DOI Listing
June 2021

Prise en charge du diabète de type 2 en soins primaires durant la pandémie de la COVID-19.

Can Fam Physician 2020 10;66(10):e264-e267

Médecin de famille à l'Hôpital Women's College et professeur agrégé au DMFC de l'Université de Toronto.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571665PMC
October 2020

Managing type 2 diabetes in primary care during COVID-19.

Can Fam Physician 2020 10;66(10):745-747

Family physician at Women's College Hospital and Associate Professor in the DFCM at the University of Toronto.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571649PMC
October 2020

Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment.

N Engl J Med 2020 11 22;383(22):2107-2116. Epub 2020 Sep 22.

From the Dallas Diabetes Research Center at Medical City, Dallas (J.R.); LMC Diabetes and Endocrinology, Brampton (H.S.B.), Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto (H.S.B.), and LMC Diabetes and Endocrinology, Vaughan (R.G.) - all in Ontario, Canada; the Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (A.J.); Southern New Hampshire Diabetes and Endocrinology, Nashua (R.S.); and Novo Nordisk, Søborg, Denmark (K.B., M.V.H., T.J.).

Background: It is thought that a reduction in the frequency of basal insulin injections might facilitate treatment acceptance and adherence among patients with type 2 diabetes. Insulin icodec is a basal insulin analogue designed for once-weekly administration that is in development for the treatment of diabetes.

Methods: We conducted a 26-week, randomized, double-blind, double-dummy, phase 2 trial to investigate the efficacy and safety of once-weekly insulin icodec as compared with once-daily insulin glargine U100 in patients who had not previously received long-term insulin treatment and whose type 2 diabetes was inadequately controlled (glycated hemoglobin level, 7.0 to 9.5%) while taking metformin with or without a dipeptidyl peptidase 4 inhibitor. The primary end point was the change in glycated hemoglobin level from baseline to week 26. Safety end points, including episodes of hypoglycemia and insulin-related adverse events, were also evaluated.

Results: A total of 247 participants were randomly assigned (1:1) to receive icodec or glargine. Baseline characteristics were similar in the two groups; the mean baseline glycated hemoglobin level was 8.09% in the icodec group and 7.96% in the glargine group. The estimated mean change from baseline in the glycated hemoglobin level was -1.33 percentage points in the icodec group and -1.15 percentage points in the glargine group, to estimated means of 6.69% and 6.87%, respectively, at week 26; the estimated between-group difference in the change from baseline was -0.18 percentage points (95% CI, -0.38 to 0.02, P = 0.08). The observed rates of hypoglycemia with severity of level 2 (blood glucose level, <54 mg per deciliter) or level 3 (severe cognitive impairment) were low (icodec group, 0.53 events per patient-year; glargine group, 0.46 events per patient-year; estimated rate ratio, 1.09; 95% CI, 0.45 to 2.65). There was no between-group difference in insulin-related key adverse events, and rates of hypersensitivity and injection-site reactions were low. Most adverse events were mild, and no serious events were deemed to be related to the trial medications.

Conclusions: Once-weekly treatment with insulin icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily insulin glargine U100 in patients with type 2 diabetes. (Funded by Novo Nordisk; NN1436-4383 ClinicalTrials.gov number, NCT03751657.).
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http://dx.doi.org/10.1056/NEJMoa2022474DOI Listing
November 2020

The effects of recreational cannabis use on glycemic outcomes and self-management behaviours in people with type 1 and type 2 diabetes: a rapid review.

Syst Rev 2020 08 17;9(1):187. Epub 2020 Aug 17.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, 209 Victoria Street, East Building, Toronto, ON, M5B 1W8, Canada.

Background: Recent surveys of Canadian cannabis users reflect increasing consumption rates, some of whom may have diabetes. However, healthcare providers have limited information resources on the effects of recreational cannabis in people with diabetes. This rapid review was commissioned by Diabetes Canada to synthesize available evidence to guide recommendations for care of people 13 years of age and older who live with diabetes.

Methods: PubMed, Embase and PsycINFO databases were searched from January 2008 to January 2019. Study selection, data abstraction and quality appraisal were completed by pairs of reviewers working independently and discrepancies were resolved by a third reviewer with pilot tests completed before each stage to ensure consistency. Data collected from included studies were tabulated and summarized descriptively.

Results: The search resulted in 1848 citations of which 59 publications were selected for screening, resulting in six observational studies (2 full-text articles and 4 conference abstracts) that met the pre-defined criteria for inclusion. Five studies reported higher glycated hemoglobin (HbA1c) in people with type 1 diabetes (T1D) who consumed recreational cannabis. In one study, students aged 17 to 25 years living with T1D self-reported poorer glycemic control and higher HbA1c when smoking cannabis. In one study of adults with T1D, cannabis use within the previous 12 months was associated with almost double the risk of diabetic ketoacidosis compared with no cannabis use (odds ratio [OR] 1.98; confidence interval [CI] [95% CI] 1.01-3.91). Risks for peripheral arterial occlusion and myocardial infarction were found to be higher in people with type 2 diabetes (T2D) who consumed recreational cannabis, and worse renal parameters were also reported in two separate studies of T1D and T2D.

Conclusions: Recreational cannabis use may negatively impact diabetes metabolic factors and self-management behaviours in people with T1D. In people with T2D, recreational cannabis may increase risks for peripheral arterial occlusion, myocardial infarction and renal disease. However, the evidence base of this rapid review was limited to six observational studies of poor to fair methodological quality, and thus, further robust, higher quality research is required to confirm the potential impact of cannabis on diabetes.

Systematic Review Registration: PROSPERO CRD42019122829.
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http://dx.doi.org/10.1186/s13643-020-01411-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433109PMC
August 2020

Burden of nonalcoholic fatty liver disease in Canada, 2019-2030: a modelling study.

CMAJ Open 2020 Apr-Jun;8(2):E429-E436. Epub 2020 Jun 9.

Division of Gastroenterology and Hepatology (Swain, Shaheen), Cumming School of Medicine, University of Calgary, Calgary, Alta.; Division of Gastroenterology (Ramji), University of British Columbia, Vancouver, BC; Toronto Centre for Liver Disease (Patel), University Hospital Network, Toronto, Ont.; Division of Gastroenterology and Hepatology (Sebastiani), McGill University Health Centre, Montréal, Que.; LAIR Centre (Tam), Vancouver, BC; Division of Gastroenterology (Marotta), Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ont.; Toronto Liver Centre (Elkhashab), Toronto, Ont.; LMC Diabetes and Endocrinology Brampton (Bajaj), Brampton, Ont.; Leadership Sinai Centre for Diabetes (Bajaj), Mount Sinai Hospital, Toronto, Ont.; Center for Disease Analysis Foundation (Estes, Razavi), Lafayette, Colo.

Background: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) account for a growing proportion of liver disease cases, and there is a need to better understand future disease burden. We used a modelling framework to forecast the burden of disease of NAFLD and NASH for Canada.

Methods: We used a Markov model to forecast fibrosis progression from stage F0 (no fibrosis) to stage F4 (compensated cirrhosis) and subsequent progression to decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver-related death among Canadians with NAFLD from 2019 to 2030. We used historical trends for obesity prevalence among adults to estimate longitudinal changes in the number of incident NAFLD cases.

Results: The model projected that the number of NAFLD cases would increase by 20% between 2019 and 2030, from an estimated 7 757 000 cases to 9 305 000 cases. Increases in advanced fibrosis cases were relatively greater, as the number of model-estimated prevalent stage F3 cases would increase by 65%, to 357 000, and that of prevalent stage F4 cases would increase by 95%, to 195 000. Estimated incident cases of hepatocellular carcinoma and decompensated cirrhosis would increase by up to 95%, and the number of annual NAFLD-related deaths would double, to 5600.

Interpretation: Increasing rates of obesity translate into increasing NAFLD-related cases of cirrhosis and hepatocellular carcinoma and related mortality. Prevention efforts should be aimed at reducing the incidence of NAFLD and slowing fibrosis progression among those already affected.
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http://dx.doi.org/10.9778/cmajo.20190212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286622PMC
February 2021

Goal achievement of HbA1c and LDL-cholesterol in a randomized trial comparing colesevelam with ezetimibe: GOAL-RCT.

Diabetes Obes Metab 2020 10 18;22(10):1722-1728. Epub 2020 Jun 18.

LMC Diabetes & Endocrinology, Toronto, Ontario, Canada.

Aim: To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D).

Materials And Methods: GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed.

Results: Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (P  < .001, P = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively.

Conclusions: Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam.
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http://dx.doi.org/10.1111/dom.14084DOI Listing
October 2020

Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial.

J Am Soc Nephrol 2020 05;31(5):1128-1139

The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.

Background: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).

Methods: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m) and linear mixed effects models to analyze the effects on eGFR slope.

Results: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m; between-group difference 2.61 ml/min per 1.73 m).

Conclusions: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.

Clinical Trial Registry Name And Registration Number: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.
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http://dx.doi.org/10.1681/ASN.2019111168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217416PMC
May 2020

Cardiovascular and renal benefits of dapagliflozin in patients with short and long-standing type 2 diabetes: Analysis from the DECLARE-TIMI 58 trial.

Diabetes Obes Metab 2020 07 12;22(7):1122-1131. Epub 2020 Mar 12.

Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Aim: To investigate whether the cardiovascular and renal benefits observed with dapagliflozin in the DECLARE-TIMI 58 trial are also observed in patients with short and long-standing diabetes.

Materials And Methods: This post hoc analysis studied the dual primary efficacy endpoints, a composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) and major adverse cardiovascular events (MACE; CVD, myocardial infarction [MI], ischaemic stroke) by diabetes duration.

Results: Of the 17 160 patients, 3836 had diabetes duration of ≤5 years, 4731 >5-10 years, 3952 >10-15 years, 2433 >15-20 years and 2206 >20 years. Dapagliflozin reduced the risk of CVD/HHF by a similar amount across diabetes duration subgroups, ranging from HR 0.79 (0.58-1.06) in patients with diabetes duration of ≤5 years to 0.75 (0.55-1.03) in those patients with diabetes duration of >20 years (interaction trend P-value 0.76). Hazard ratios (HRs) for MACE ranged from 1.08 (0.87-1.35) in patients with diabetes duration of ≤5 years to 0.67 (0.52-0.86) in those patients with diabetes duration of >20 years (interaction trend P-value 0.004). This was driven by greater reductions in the risk of MI and ischaemic stroke with dapagliflozin in patients with long-standing diabetes (interaction trend P-values 0.019 and 0.015, respectively). The duration-based MACE heterogeneity was apparent in those with or without a history of prior MI and in those with multiple risk factors. The renal-specific outcome was reduced with dapagliflozin with HRs ranging from 0.79 (0.47-1.34) in patients with diabetes duration of ≤5 years to 0.42 (0.25-0.72) in those patients with diabetes duration of >20 years (interaction trend P-value 0.084).

Conclusions: Dapagliflozin reduced the risk of CVD/HHF consistently, regardless of diabetes duration, whereas the treatment effect for MACE differed by duration subgroups, with significant reductions with dapagliflozin in patients with long-standing diabetes.
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http://dx.doi.org/10.1111/dom.14011DOI Listing
July 2020

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

Diabetologia 2020 04 27;63(4):698-710. Epub 2020 Jan 27.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Aims/hypothesis: A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.

Methods: This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0-5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.

Results: Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.

Conclusions/interpretation: There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.

Trial Registration: ClinicalTrials.gov NCT03078478 FUNDING: This trial was funded by Novo Nordisk (Bagsvaerd, Denmark).
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http://dx.doi.org/10.1007/s00125-019-05080-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054369PMC
April 2020

Patient Reported Outcomes following initiation of Glucagon-like peptide-1 Receptor agonists in patients with type 2 Diabetes in a specialist endocrinology practice of the LMC diabetes registry: The PROGRESS-Diabetes study.

Diabetes Res Clin Pract 2019 Oct 22;156:107820. Epub 2019 Aug 22.

LMC Diabetes & Endocrinology, Toronto, ON, Canada. Electronic address:

Aims: To compare patient-reported outcomes and clinical outcomes in patients who initiated dulaglutide or liraglutide as part of usual clinical therapy.

Methods: This observational study enrolled adults with type 2 diabetes who initiated dulaglutide or liraglutide between April 2017 and January 2018. A prospective patient cohort completed questionnaires at baseline and at their usual follow-up visit three to six months later. Clinical outcomes were assessed in a post-hoc retrospective analysis using propensity score matching.

Results: In the per-protocol analysis, 146 dulaglutide and 79 liraglutide patients had similar significant improvements in diabetes treatment satisfaction scores (dulaglutide 9.6 ± 1.1, p < 0.001; liraglutide 10.6 ± 1.4, p < 0.001) and follow-up scores for diabetes device satisfaction. Only dulaglutide had significant improvements in medication adherence scores. In the overall cohort, 754 matched patients showed similar reductions in A1C (dulaglutide -0.8% [9 mmol/mol]; liraglutide -0.7% [8 mmol/mol]). Liraglutide patients had a greater reduction in weight than those initiating dulaglutide (-2.8 kg vs. -1.8 kg; p < 0.001).

Conclusions: Patients who initiated dulaglutide or liraglutide in a real-world specialist practice had similar improvements in diabetes medication satisfaction and diabetes device satisfaction. Only dulaglutide patients had significant improvements in medication adherence scores. Both treatment cohorts had similar patterns of A1C change, and liraglutide had significantly greater weight loss, which are similar to findings from clinical trials.
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http://dx.doi.org/10.1016/j.diabres.2019.107820DOI Listing
October 2019

Diabetes Canada Position Statement on Recreational Cannabis Use in Adults and Adolescents With Type 1 and Type 2 Diabetes.

Can J Diabetes 2019 Aug 29;43(6):372-376. Epub 2019 May 29.

Diabetes Canada Professional Section Executive, Toronto, Ontario, Canada; CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.

Objective: Pursuant to the legalization of recreational cannabis in Canada, a rapid review was undertaken to develop a position statement concerning the effects of cannabis consumption on Canadians living with diabetes.

Methods: An expert committee of 1 adult endocrinologist and 1 pediatric endocrinologist, with the help of coauthors, collaborated to develop the position statement using the same evidence-based principles as the Diabetes Canada Clinical Practice Guidelines (with the exception of an independent methods review). A rapid review was conducted by researchers with the Strategic Patient-Oriented Research Evidence Alliance. The scope of the review was limited to evaluating the effects of recreational cannabis use on: 1) metabolic factors and diabetes complications, and 2) diabetes self-management behaviors in people ≥13 years of age. An informed person with diabetes, Canadian health-care providers and scientific advisors performed independent external reviews.

Results: The review found a limited amount of published or presented literature for the review questions, with gaps in direct evidence linking cessation of cannabis use to improved outcomes in diabetes. However, there were sufficient data to begin developing recommendations for type 1 and type 2 diabetes about education, counseling and management related to recreational cannabis usage.

Conclusions: This is the first attempt in the world to generate an evidence-based guidance document on the topic of recreational cannabis use and diabetes. It provides guidance for health-care providers, so that they can assist and counsel Canadians living with diabetes on recreational cannabis. Further, higher quality research is required to provide more robust and evidence-informed guidance.
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http://dx.doi.org/10.1016/j.jcjd.2019.05.010DOI Listing
August 2019

CANadian CAnagliflozin REgistry: Patient-Reported Outcomes of Canagliflozin in the Treatment of Type 2 Diabetes Mellitus in Canadian Clinical Practice.

Can J Diabetes 2019 Oct 16;43(7):464-471. Epub 2019 Apr 16.

LMC Diabetes & Endocrinology, Brampton, Ontario, Canada.

Objectives: To describe patient-reported outcomes (PROs) after initiation of treatment with canagliflozin (CANA) for type 2 diabetes mellitus (T2DM) in a real-world Canadian setting.

Methods: CANadian CAnagliflozin REgistry (CanCARE) is a prospective, observational, single-arm, real-world Canadian study of the effectiveness and safety of CANA for the treatment of T2DM in 527 subjects. PRO measures were collected in CanCARE using the Current Health Satisfaction Questionnaire (CHES-Q) at baseline and after 3, 6 and 12 months of CANA treatment to examine patient satisfaction regarding weight and overall health. Associations between changes in satisfaction with weight, systolic blood pressure (SBP) and glycated hemoglobin (A1C) levels were also investigated.

Results: Proportion of patients satisfied with their body weight and overall health increased from 22.1% and 26.9% at baseline to 32.4% and 49.2% after 12 months of CANA treatment, respectively. Satisfaction rates also increased on CHES-Q domains representing physical and emotional health. Correlations were found between improvement in satisfaction with body weight and weight loss (r=-0.29; p<0.01) and between improvements in satisfaction with overall health and weight loss (r=-0.13; p=0.03) and SBP (r=-0.17; p<0.01), but not with changes in A1C level.

Conclusions: Treatment with CANA is associated with improvements in satisfaction with body weight and overall health, which may be important drivers of patient self-management and hold the potential to positively influence long-term outcomes in T2DM.
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http://dx.doi.org/10.1016/j.jcjd.2019.04.004DOI Listing
October 2019

Post hoc efficacy and safety analysis of insulin glargine/lixisenatide fixed- ratio combination in North American patients compared with the rest of world.

BMJ Open Diabetes Res Care 2019 21;7(1):e000581. Epub 2019 Mar 21.

Eastern Virginia Medical School, Norfolk, Virginia, USA.

Objective: To assess the efficacy and safety of iGlarLixi (titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide) in patients with type 2 diabetes (T2D) living in North America (NA; USA and Canada) compared with the rest of the world (RoW).

Research Design And Methods: Post hoc analysis included patient-level data from 509 sites/centers across two phase III trials: LixiLan-O (NCT02058147; insulin-naive patients; NA, n=371; RoW, n=796) and LixiLan-L (NCT02058160; inadequately controlled patients on basal insulin; NA, n=196; RoW, n=535). Efficacy outcomes were: change from baseline to Week 30 in glycated hemoglobin (HbA1c), postprandial glucose (PPG), PPG excursions, fasting plasma glucose (FPG) and body weight; proportion of patients achieving HbA1c <42 mmol/mol (<7.0%); proportion of patients achieving composite endpoint: HbA1c <42 mmol/mol (<7.0%), no weight gain or symptomatic hypoglycemia (blood glucose ≤3.9 mmol/L (≤70 mg/dL)). Safety endpoints included incidence of documented symptomatic hypoglycemia and gastrointestinal (GI) adverse events.

Results: Significantly larger reductions (p≤0.003) in HbA1c from baseline to Week 30 were achieved with iGlarLixi, compared with iGlar or lixisenatide, in NA and RoW patients in LixiLan-O (iGlarLixi vs iGlar: -0.31 and -0.29, respectively; iGlarLixi vs lixisenatide: -0.84 and -0.69, respectively) and in LixiLan-L (iGlarLixi vs iGlar: -0.5 and -0.51, respectively). Documented symptomatic hypoglycemia was similar between NA and RoW patients. iGlarLixi resulted in significant weight benefits versus iGlar (change from baseline -1.58 and -1.29 kg for NA and RoW patients, respectively; p0.001). GI adverse events were similar for iGlarLixi and iGlar, but significantly higher for lixisenatide.

Conclusions: iGlarLixi improved glycemic parameters versus iGlar or lixisenatide alone in both NA and RoW patients, with beneficial weight effects versus iGlar. iGlarLixi treatment responses, hypoglycemia risk and GI adverse events in NA patients were comparable with patients in the RoW.

Trial Registry: Clinicaltrials.gov NCT02058147 and NCT02058160.
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http://dx.doi.org/10.1136/bmjdrc-2018-000581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501856PMC
April 2020

CANadian CAnagliflozin REgistry: Effectiveness and safety of canagliflozin in the treatment of type 2 diabetes mellitus in Canadian clinical practice.

Diabetes Obes Metab 2019 03 5;21(3):691-699. Epub 2018 Dec 5.

LMC Diabetes and Endocrinology, Brampton, Ontario, Canada.

Aim: There is limited information concerning the effects of canagliflozin (CANA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i) in a real-world clinical setting in Canada. CanCARE is a 12-month, prospective, observational analysis to demonstrate the effectiveness and safety of CANA in usual clinical practice in Canada.

Materials And Methods: SGLT2i-naïve adult patients with type 2 diabetes mellitus (T2DM) (n = 527) on a stable antihyperglycemic agent (AHA) regimen with glycated hemoglobin (A1C) ≥ 7%, an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m , were initiated on CANA as part of their usual treatment approach, and were followed for a period of 12 months. The primary effectiveness objective was the mean change in HbA1c from baseline to 6 and 12 months.

Results: Significant improvement from baseline in mean HbA1c levels were observed at 6 months (-0.90%; 95% CI, -1.02, -0.78) and at 12 months (-1.04%; 95% CI, -1.15, -0.92), regardless of duration of diabetes or background AHA treatment regimen. Similarly, significant decreases in systolic blood pressure (-4.65 mm Hg); body weight (-3.24 kg), waist circumference (-2.91 cm) and body mass index (-1.15 kg/m ) were observed at 12 months. Additionally, 40.5% of patients achieved the double endpoint (≥0.5% HbA1c reduction and ≥ 3% weight loss), while 24.3% of patients achieved the triple composite endpoint (≥0.5% HbA1c reduction, ≥3% weight loss and ≥ 4 mm Hg systolic blood pressure reduction). No unexpected adverse events were reported.

Conclusion: CANA provided sustained clinically meaningful improvements in cardiometabolic parameters in this study in a real-world setting, confirming findings from randomized controlled trials.
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http://dx.doi.org/10.1111/dom.13573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667918PMC
March 2019

SGLT2 inhibitors: practical considerations and recommendations for cardiologists.

Curr Opin Cardiol 2018 11;33(6):676-682

Division of Cardiac Surgery, St. Michael's Hospital, Toronto.

Purpose Of Review: To address common concerns regarding sodium-glucose cotransporter 2 (SGLT2) inhibitor use for patients with type 2 diabetes mellitus (T2DM) in cardiovascular practice.

Recent Findings: SGLT2 inhibitors provide glycemic control and improve cardiovascular and renal endpoints in T2DM. Cardiovascular outcome trials have demonstrated sustained cardiovascular, heart failure and renal benefits independent of glycemic control, which persist down to an eGFR of 30 ml/min/1.73 m. SGLT2 inhibitors can be safely administered alongside common diuretics, and routine monitoring of renal function is advised at initiation of therapy, particularly for patients on loop diuretics. Mild initial reductions in eGFR are expected, usually stabilizing over time. The most common adverse effect noted with SGLT2 inhibitors is genital mycotic infections, primarily in women. Less common, but concerning effects associated with canagliflozin include increased risk of fractures and lower limb amputations, particularly in patients with previous amputation history. Overall, SGLT2 inhibitors are well tolerated and effective adjuncts to diabetic treatment, for which the benefits seem to outweigh the risks.

Summary: The care of patients with T2DM requires an interdisciplinary team approach, within which the role of cardiologists is expanding. SGLT2 inhibitors are an encouraging treatment option for achieving glycemic control, whilst also improving cardiovascular and renal outcomes.
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http://dx.doi.org/10.1097/HCO.0000000000000561DOI Listing
November 2018

Glucagon-like peptide-1 receptor agonists and cardiovascular protection in type 2 diabetes: a pathophysiology-based review of clinical implications.

Curr Opin Cardiol 2018 11;33(6):665-675

King Saud University, Riyadh.

Purpose Of Review: Cardiovascular outcome trials (CVOT) with glucagon-like peptide-1 receptor agonists (GLP-1 RA) have had variable results to date: with two CVOTs being positive and two concluding neutrality/safety results for primary cardiovascular outcome. Mechanistic insights delving into the pathophysiologic mechanisms that may link certain GLP-1 RA to cardioprotection may help define the application of this medication class in clinical practice based on the evidence of the CVOT data. We discuss the various mechanisms that have been postulated from animal and preclinical human studies to help explain the benefits observed in CVOTs with GLP-1 RA.

Recent Findings: Cardiovascular benefits of GLP-1 may be dependent on the complex interactions of this incretin hormone with the atherosclerotic pathways, either through its direct actions on the cardiovascular system or indirectly through intermediary actions on metabolism, energy transfer, inflammation or thrombosis. An indirect metabolic action of GLP-1 RA, via an initial step of achieving glucose homeostasis or balancing inter-organ energy metabolism, leading to favorable downstream effects on the inflammation-thrombosis pathways, finally impacting atherosclerosis, appears compelling.

Summary: In addition to their metabolic benefits, specific GLP-1 RA medications offer cardiovascular protection in high-risk type 2 diabetes. Further mechanistic studies and clinical trials in lower cardiovascular risk populations may help cement the place of this class of medications across the spectrum of type 2 diabetes.
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http://dx.doi.org/10.1097/HCO.0000000000000562DOI Listing
November 2018

Aspirin Increases the Risk of Nondiagnostic Yield of Fine-Needle Aspiration and Biopsy of Thyroid Nodules.

Eur Thyroid J 2018 Jun 16;7(3):129-132. Epub 2018 May 16.

LMC Diabetes and Endocrinology, Brampton, Ontario, Canada.

Background: The link between the diagnostic yield of thyroid fine-needle aspiration and biopsy (FNAB) in patients taking antithrombotic or anticoagulant medications (AT/AC) remains poorly characterized.

Objectives: We studied the risk of obtaining a nondiagnostic sample with ultrasound-guided thyroid FNAB in patients taking AT/AC medications.

Methods: This is a retrospective cohort study using medical rec-ords of 556 patients who underwent thyroid FNAB. All cytology samples were reported using the Bethesda classification. For patients with a nondiagnostic cytology, logistic regression was used to calculate OR for patients taking AT/AC medications. Multivariate regression was used to adjust for potential confounding variables including age, cystic ultrasound features, presence of eggshell calcifications, number of passes performed, cystic aspirate on FNAB, and position of the nodule.

Results: Out of 556 patients, cytology results were available for 547 patients. Of these, 46 subjects were taking aspirin and 1 was on warfarin. Among the entire cohort, 17.5% of the subjects had a nondiagnostic cytology. Among the patients on AT/AC medications, 34% had a nondiagnostic result compared to 16% for those not taking them (OR = 2.70, = 0.003). The subgroup of patients taking aspirin had similarly higher odds of a nondiagnostic cytology (OR = 2.78, = 0.002). These differences remained statistically significant after multivariate adjustment.

Conclusions: This is the first study to demonstrate a 3-fold independently greater risk of a nondiagnostic FNAB cytology in patients taking aspirin. Our results highlight the importance of evaluating the need for continuation of aspirin in patients undergoing thyroid FNAB as this may impact the diagnostic yield of the procedure.
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http://dx.doi.org/10.1159/000488451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047498PMC
June 2018

Biomarkers of vascular injury and endothelial dysfunction after recent glucose intolerance in pregnancy.

Diab Vasc Dis Res 2018 09 5;15(5):449-457. Epub 2018 Jun 5.

1 Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON, Canada.

Objective: Women with gestational diabetes mellitus and milder gestational impaired glucose intolerance have elevated future risks of type 2 diabetes and cardiovascular disease. However, it is unclear whether they show postpartum evidence of vascular injury/dysfunction, an early event in the natural history of cardiovascular disease.

Methods: In total, 337 women underwent a glucose challenge test and oral glucose tolerance test in pregnancy, yielding four gestational glucose tolerance groups: gestational diabetes mellitus, gestational impaired glucose intolerance, abnormal glucose challenge test with normal glucose tolerance on the oral glucose tolerance test and normal glucose challenge test with normal glucose tolerance. At 3 years postpartum, they underwent repeat oral glucose tolerance test (on which 69 women had pre-diabetes/diabetes) and measurement of the following serum markers of vascular injury/dysfunction: thrombomodulin, E-selectin, P-selectin, intercellular adhesion molecule-3 and vascular cell adhesion molecule-1.

Results: At 3 years postpartum, mean adjusted vascular cell adhesion molecule-1 was the only vascular marker that differed across the previous gestational glucose tolerance groups. On multiple linear regression analysis, each strata of gestational dysglycaemia was an independent predictor of lower vascular cell adhesion molecule-1 at 3 years postpartum (gestational diabetes mellitus: p = 0.005; gestational impaired glucose intolerance: p = 0.003; abnormal glucose challenge test normal glucose tolerance: p = 0.0008), as was current pre-diabetes/diabetes ( p = 0.01).

Conclusion: Dysregulation of vascular cell adhesion molecule-1 may be an early event in the natural history of cardiovascular disease in women with recent glucose intolerance in pregnancy.
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http://dx.doi.org/10.1177/1479164118779924DOI Listing
September 2018

Targets for Glycemic Control.

Can J Diabetes 2018 04;42 Suppl 1:S42-S46

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http://dx.doi.org/10.1016/j.jcjd.2017.10.030DOI Listing
April 2018

Glucose Lowering Strategies for Cardiac Benefits: Pathophysiological Mechanisms.

Physiology (Bethesda) 2018 05;33(3):197-210

Leadership Sinai Centre for Diabetes, Mount Sinai Hospital , Toronto, Ontario , Canada.

Recent trials in Type 2 diabetes (T2D) have shown cardiovascular benefits with specific GLP-1 receptor agonists and SGLT2 inhibitors. We discuss the landscape of outcome trials in T2D from a pathophysiology viewpoint, review current knowledge gaps in underlying mechanisms, propose a caloric fuel routing hypothesis, and highlight areas of future research.
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http://dx.doi.org/10.1152/physiol.00004.2018DOI Listing
May 2018

Antihyperglycemic agents and cardiovascular outcomes: recent insights.

Curr Opin Cardiol 2017 Sep;32(5):642-650

aLMC Diabetes & Endocrinology, Brampton bLeadership Sinai Centre for Diabetes cLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto dDivision of Endocrinology and Metabolism, University of Toronto eDivision of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital fDivision of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.

Purpose Of Review: To summarize cardiovascular outcome trials (CVOTs) with antihyperglycemic agents conducted since 2008 US Food and Drug Administration guidance.

Recent Findings: A series of large CVOTs since 2008 have included patients with type 2 diabetes (T2D), who are otherwise treated according to standard of care. After the initial trials with incretin agents demonstrated cardiovascular safety, two recent CVOTs with currently available antihyperglycemic agents - EMPA-REG OUTCOME with empagliflozin and LEADER with liraglutide - show a significant reduction of the primary composite outcome, including a significant difference in the cardiovascular death end-point in both trials [EMPA-REG OUTCOME: hazard ratio = 0.62, confidence interval (CI) = 0.49-0.77, P < 0.001 and LEADER: hazard ratio = 0.78, CI = 0.66-0.93, P = 0.007]. Number needed to treat to prevent one cardiovascular death of 46 and 77 for empagliflozin and liraglutide, respectively, over 3 years is comparable with other currently employed evidence-based cardioprotective strategies. In addition, EMPA-REG OUTCOME trial had a robust reduction in hospitalization for heart failure (hazard ratio = 0.65, CI = 0.50-0.85, P = 0.002).

Summary: New-generation CVOTs are shifting the focus in the treatment of T2D to the prevention of cardiovascular morbidity and mortality.
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http://dx.doi.org/10.1097/HCO.0000000000000435DOI Listing
September 2017
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