Utilizing synchronous care to improve cardiovascular and renal health among patients with type 2 diabetes: Proof-of-concept results from the DECIDE-CV clinical programme.

AIM: The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline-directed medical therapy (GDMT). METHODS: We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE-CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, renin-angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline-to-last-visit change in surrogate laboratory biomarkers. RESULTS: The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin-to-creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium-glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon-like peptide 1 receptor agonists (from 8% to 45%), renin-angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin-to-creatinine ratio and N-terminal proB-type natriuretic peptide levels significantly dropped from baseline (p < .05 for all). CONCLUSIONS: Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers.

Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial.

AIM: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. METHODS: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. RESULTS: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). CONCLUSION: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

Glucagon-like peptide-1 receptor agonists as adjunctive treatment for type 1 diabetes: Renewed opportunities through tailored approaches?

Exogenous insulin has been the mainstay treatment for individuals living with type 1 diabetes (T1D). Although there has been tremendous growth in both pharmacological and technological advancements, insulin monotherapy has proven to be insufficient for maintaining optimal glycaemic targets for most adults with T1D. At present, there is still no breakthrough for the treatment of T1D. Adjunctive pharmacotherapies might therefore complement insulin management to achieve better glycaemic control, while possibly offering additional benefits. Recent interest in re-purposing glucagon-like peptide-1 receptor agonists (GLP-1RAs), a leading antihyperglycaemic medication class approved for type 2 diabetes, has prompted the field to seek extended potential for the T1D population. The adjunctive use of GLP-1RAs has been at the forefront of T1D research, albeit with some conflicting trial findings to date. However, the potential of GLP-1 agonism for T1D may have been underestimated, possibly from missed opportunities or categorized effects. Moreover, some GLP-1RAs have demonstrated extra-pancreatic potential with emerging multi-organ protection involving the heart, kidneys, liver and brain in varied cohorts, which may bode well for the growing T1D profile of comorbid complications. This narrative review aims to summarize and critically appraise the current evidence-based literature from large-scale randomized controlled trials and closed-loop system pilot studies that examined GLP-1RAs as adjunctive therapy for T1D. Furthermore, we outline uncharted opportunities with GLP-1 agonism using versatile approaches in selected T1D populations that may inspire and re-direct future research in this field.

Alleviating carbohydrate counting with a FiASP-plus-pramlintide closed-loop delivery system (artificial pancreas): Feasibility and pilot studies.

AIM: To assess whether a FiASP-and-pramlintide closed-loop system has the potential to replace carbohydrate counting with a simple meal announcement (SMA) strategy (meal priming bolus without carbohydrate counting) without degrading glycaemic control compared with a FiASP closed-loop system. MATERIALS AND METHODS: We conducted a 24-hour feasibility study comparing a FiASP system with full carbohydrate counting (FCC) with a FiASP-and-pramlintide system with SMA. We conducted a subsequent 12-day outpatient pilot study comparing a FiASP-and-placebo system with FCC, a FiASP-and-pramlintide system with SMA, and a FiASP-and-placebo system with SMA. Basal-bolus FiASP-and-pramlintide were delivered at a fixed ratio (1 U:10 µg). Glycaemic outcomes were measured, surveys evaluated gastrointestinal symptoms and diabetes distress, and participant interviews helped establish a preliminary coding framework to assess user experience. RESULTS: Seven participants were included in the feasibility analysis. Time spent in 3.9-10 mmol/L was similar between both interventions (81%-84%). Four participants were included in the pilot analysis. Time spent in 3.9-10 mmol/L was similar between the FiASP-and-placebo with FCC and FiASP-and-pramlintide with SMA interventions (70%), but was lower in the FiASP-and-placebo with SMA intervention (60%). Time less than 3.9 mmol/L and gastrointestinal symptoms were similar across all interventions. Emotional distress was moderate at baseline, after the FiASP-and-placebo with FCC and SMA interventions, and fell after the FiASP-and-pramlintide with SMA intervention. SMA reportedly afforded participants flexibility and reduced mealtime concerns. CONCLUSIONS: The FiASP-and-pramlintide system has the potential to substitute carbohydrate counting with SMA without degrading glucose control.

Reducing the need for carbohydrate counting in type 1 diabetes using closed-loop automated insulin delivery (artificial pancreas) and empagliflozin: A randomized, controlled, non-inferiority, crossover pilot trial.

AIM: To assess whether adding empagliflozin to closed-loop automated insulin delivery could reduce the need for carbohydrate counting in type 1 diabetes (T1D) without worsening glucose control. MATERIALS AND METHODS: In an open-label, crossover, non-inferiority trial, 30 adult participants with T1D underwent outpatient automated insulin delivery interventions with three random sequences of prandial insulin strategy days: carbohydrate counting, simple meal announcement (no carbohydrate counting) and no meal announcement. During each sequence of prandial insulin strategies, participants were randomly assigned empagliflozin (25 mg/day) or not, and crossed over to the comparator. Mean glucose for carbohydrate counting without empagliflozin (control) was compared with no meal announcement with empagliflozin (in the primary non-inferiority comparison) and simple meal announcement with empagliflozin (in the conditional primary non-inferiority comparison). RESULTS: Participants were aged 40 ± 15 years, had 27 ± 15 years diabetes duration and HbA1c of 7.6% ± 0.7% (59 ± 8 mmol/mol). The system with no meal announcement and empagliflozin was not non-inferior (and thus reasonably considered inferior) to the control arm (mean glucose 10.0 ± 1.6 vs. 8.5 ± 1.5 mmol/L; non-inferiority p = .94), while simple meal announcement and empagliflozin was non-inferior (8.5 ± 1.4 mmol/L; non-inferiority p = .003). Use of empagliflozin on the background of automated insulin delivery with carbohydrate counting was associated with lower mean glucose, corresponding to a 14% greater time in the target range. While no ketoacidosis was observed, mean fasting ketones levels were higher on empagliflozin (0.22 ± 0.18 vs. 0.13 ± 0.11 mmol/L; p < .001). CONCLUSIONS: Empagliflozin added to automated insulin delivery has the potential to eliminate the need for carbohydrate counting and improves glycaemic control in conjunction with carbohydrate counting, but does not allow for the elimination of meal announcement.

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

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/1.73m2 , 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/m2 ) 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.

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

AIMS/HYPOTHESIS: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). METHODS: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. RESULTS: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. CONCLUSIONS/INTERPRETATION: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Personalized insulin dosing using reinforcement learning for high-fat meals and aerobic exercises in type 1 diabetes: a proof-of-concept trial.

In type 1 diabetes, high-fat meals require more insulin to prevent hyperglycemia while meals followed by aerobic exercises require less insulin to prevent hypoglycemia, but the adjustments needed vary between individuals. We propose a decision support system with reinforcement learning to personalize insulin doses for high-fat meals and postprandial aerobic exercises. We test this system in a single-arm 16-week study in 15 adults on multiple daily injections therapy (NCT05041621). The primary objective of this study is to assess the feasibility of the novel learning algorithm. This study looks at glucose outcomes and patient reported outcomes. The postprandial incremental area under the glucose curve is improved from the baseline to the evaluation period for high-fat meals (378 ± 222 vs 38 ± 223 mmol/L/min, p = 0.03) and meals followed by exercises (-395 ± 192 vs 132 ± 181 mmol/L/min, p = 0.007). The postprandial time spent below 3.9 mmol/L is reduced after high-fat meals (5.3 ± 1.6 vs 1.8 ± 1.5%, p = 0.003) and meals followed by exercises (5.3 ± 1.2 vs 1.4 ± 1.1%, p = 0.003). Our study shows the feasibility of automatically personalizing insulin doses for high-fat meals and postprandial exercises. Randomized controlled trials are warranted.

Simple meal announcements and pramlintide delivery versus carbohydrate counting in type 1 diabetes with automated fast-acting insulin aspart delivery: a randomised crossover trial in Montreal, Canada.

BACKGROUND: In type 1 diabetes, carbohydrate counting is the standard of care to determine prandial insulin needs, but it can negatively affect quality of life. We developed a novel insulin-and-pramlintide closed-loop system that replaces carbohydrate counting with simple meal announcements. METHODS: We performed a randomised crossover trial assessing 14 days of (1) insulin-and-pramlintide closed-loop system with simple meal announcements, (2) insulin-and-placebo closed-loop system with carbohydrate counting, and (3) insulin-and-placebo closed-loop system with simple meal announcements. Participants were recruited at McGill University Health Centre (Montreal, QC, Canada). Eligible participants were adults (aged ≥18 years) and adolescents (aged 12-17 years) with type 1 diabetes for at least 1 year. Participants were randomly assigned in a 1:1:1:1:1:1 ratio to a sequence of the three interventions, with faster insulin aspart used in all interventions. Each intervention was separated by a 14-45-day wash-out period, during which participants reverted to their usual insulin. During simple meal announcement interventions, participants triggered a prandial bolus at mealtimes based on a programmed fixed meal size, whereas during carbohydrate counting interventions, participants manually entered the carbohydrate content of the meal and an algorithm calculated the prandial bolus based on insulin-to-carbohydrate ratio. Two primary comparisons were predefined: the percentage of time in range (glucose 3·9-10·0 mmol/L) with a non-inferiority margin of 6·25% (non-inferiority comparison); and the mean Emotional Burden subscale score of the Diabetes Distress Scale (superiority comparison), comparing the insulin-and-placebo system with carbohydrate counting minus the insulin-and-pramlintide system with simple meal announcements. Analyses were performed on a modified intention-to-treat basis, excluding participants who did not complete all interventions. Serious adverse events were assessed in all participants. This trial is registered on ClinicalTrials.gov, NCT04163874. FINDINGS: 32 participants were enrolled between Feb 14, 2020, and Oct 5, 2021; two participants withdrew before study completion. 30 participants were analysed, including 15 adults (nine female, mean age 39·4 years [SD 13·8]) and 15 adolescents (eight female, mean age 15·7 years [1·3]). Non-inferiority of the insulin-and-pramlintide system with simple meal announcements relative to the insulin-and-placebo system with carbohydrate counting was reached (difference -5% [95% CI -9·0 to -0·7], non-inferiority p<0·0001). No statistically significant difference was found in the mean Emotional Burden score between the insulin-and-pramlintide system with simple meal announcements and the insulin-and-placebo system with carbohydrate counting (difference 0·01 [SD 0·82], p=0·93). With the insulin-and-pramlintide system with simple meal announcements, 14 (47%) participants reported mild gastrointestinal symptoms and two (7%) reported moderate symptoms, compared with two (7%) participants reporting mild gastrointestinal symptoms on the insulin-and-placebo system with carbohydrate counting. No serious adverse events occurred. INTERPRETATION: The insulin-and-pramlintide system with simple meal announcements alleviated carbohydrate counting without degrading glucose control, although quality of life as measured by the Emotional Burden score was not improved. Longer and larger studies with this novel approach are warranted. FUNDING: Juvenile Diabetes Research Foundation.