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Chronic kidney disease in type 1 diabetes: translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes.
Sridhar, VS, Limonte, CP, Groop, PH, Heerspink, HJL, Pratley, RE, Rossing, P, Skyler, JS, Cherney, DZI
Diabetologia. 2024;(1):3-18
Abstract
Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.
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Racial differences in measures of glycemia in the Vitamin D and Type 2 Diabetes (D2d) Study: a secondary analysis of a randomized trial.
LeBlanc, ES, Pittas, AG, Nelson, J, Chatterjee, R, Rasouli, N, Rhee, MK, Pratley, RE, Desouza, CV, Neff, LM, Peters, AM, et al
BMJ open diabetes research & care. 2024;(1)
Abstract
INTRODUCTION Understanding how race may influence the association between A1c and glycemia can improve diabetes screening. We sought to determine whether, for a given A1c level, glucose levels during an oral glucose tolerance test (OGTT) differed by race. RESEARCH DESIGN AND METHODS From data collected at 22 US clinical sites, we conducted a cross-sectional study of concurrently measured A1c and OGTT and observational longitudinal follow-up of the subset with high-risk pre-diabetes. Numerical integration methods were used to calculate area under the glycemic curve (AUCglu) during OGTT and least squares regression model to estimate A1c for a given AUCglu by race, controlling for potential confounders. RESULTS 1016 black, 2658 white, and 193 Asian persons at risk of diabetes were included in cross-sectional analysis. Of these, 2154 with high-risk pre-diabetes were followed for 2.5 years. For a given A1c level, AUCglu was lower in black versus white participants. After adjustment for potential confounders, A1c levels for a given AUCglu quintile were 0.15-0.20 and 0.02-0.19 percentage points higher in black and Asian compared with white participants, respectively (p<0.05). In longitudinal analyses, black participants were more likely to be diagnosed with diabetes by A1c than white participants (28% vs 10%, respectively; p<0.01). Black and Asian participants were less likely to be diagnosed by fasting glucose than white participants (16% vs 15% vs 37%, respectively; p<0.05). Black participants with A1c levels in the lower-level quintiles had greater increase in A1c over time compared with white participants. CONCLUSIONS Use of additional testing beyond A1c to screen for diabetes may better stratify diabetes risk in the diverse US population.
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Weight management in young adults with type 1 diabetes: The advancing care for type 1 diabetes and obesity network sequential multiple assignment randomized trial pilot results.
Igudesman, D, Crandell, J, Corbin, KD, Zaharieva, DP, Addala, A, Thomas, JM, Casu, A, Kirkman, MS, Pokaprakarn, T, Riddell, MC, et al
Diabetes, obesity & metabolism. 2023;(3):688-699
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Abstract
AIMS: Co-management of weight and glycaemia is critical yet challenging in type 1 diabetes (T1D). We evaluated the effect of a hypocaloric low carbohydrate, hypocaloric moderate low fat, and Mediterranean diet without calorie restriction on weight and glycaemia in young adults with T1D and overweight or obesity. MATERIALS AND METHODS We implemented a 9-month Sequential, Multiple Assignment, Randomized Trial pilot among adults aged 19-30 years with T1D for ≥1 year and body mass index 27-39.9 kg/m2 . Re-randomization occurred at 3 and 6 months if the assigned diet was not acceptable or not effective. We report results from the initial 3-month diet period and re-randomization statistics before shutdowns due to COVID-19 for primary [weight, haemoglobin A1c (HbA1c), percentage of time below range <70 mg/dl] and secondary outcomes [body fat percentage, percentage of time in range (70-180 mg/dl), and percentage of time below range <54 mg/dl]. Models adjusted for design, demographic and clinical covariates tested changes in outcomes and diet differences. RESULTS Adjusted weight and HbA1c (n = 38) changed by -2.7 kg (95% CI -3.8, -1.5, P < .0001) and -0.91 percentage points (95% CI -1.5, -0.30, P = .005), respectively, while adjusted body fat percentage remained stable, on average (P = .21). Hypoglycaemia indices remained unchanged following adjustment (n = 28, P > .05). Variability in all outcomes, including weight change, was considerable (57.9% were re-randomized primarily due to loss of <2% body weight). No outcomes varied by diet. CONCLUSIONS Three months of a diet, irrespective of macronutrient distribution or caloric restriction, resulted in weight loss while improving or maintaining HbA1c levels without increasing hypoglycaemia in adults with T1D.
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Newer Glucose-Lowering Therapies in Older Adults with Type 2 Diabetes.
Bilal, A, Pratley, RE
Endocrinology and metabolism clinics of North America. 2023;(2):355-375
Abstract
Diabetes is prevalent in older adults and older adults with diabetes are more likely to have multiple comorbidities. It is, therefore, important to personalize diabetes management in this group. Newer glucose-lowering drugs, including dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can be safely used in older patients and are preferred choices in many cases due to their safety, efficacy, and low risk of hypoglycemia.
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Statistically Adjusting for Wear Time in Randomized Trials of Continuous Glucose Monitors as a Complement to Intent-to-Treat and As-Treated Analyses: Application and Evaluation in Two Trials.
Weinstein, JM, Berkowitz, SA, Pratley, RE, Shah, KS, Kahkoska, AR
Diabetes technology & therapeutics. 2023;(7):457-466
Abstract
Background: Randomized trials of continuous glucose monitoring (CGM) often estimate treatment effects using standard intent-to-treat (ITT) analyses. We explored how adjusting for CGM-measured wear time could complement existing analyses by estimating the effect of receiving and using CGM 100% of the time. Methods: We analyzed data from two 6-month CGM trials spanning diverse ages, the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) and CGM Intervention in Teens and Young Adults with Type 1 Diabetes (CITY) Studies. To adjust the ITT estimates for CGM use, as measured by wear time, we used an instrumental variable (IV) approach with the treatment assignment as an instrument. Outcomes included (1) time in range ([TIR] 70-180 mg/dL), time below range ([TBR] ≤70 mg/dL), and time above range ([TAR] ≥250 mg/dL). We estimated outcomes based on CGM use in the last 28 days of the trial and the full trial. Findings: In the WISDM study, the wear time rates over the 28-day window and full trial period were 93.1% (standard deviation [SD]: 20.4) and 94.5% (SD: 11.9), respectively. In the CITY study, the wear time rates over the 28-day window and full trial period were 82.2% (SD: 26.5) and 83.1% (SD: 21.5), respectively. IV-based estimates for the effect of CGM on TIR, TBR, and TAR suggested greater improvements in glycemic management than the ITT counterparts. The magnitude of the differences was proportional to the level of wear time observed in the trials. Interpretation: In trials of CGM use, the effect of variable wear time is non-negligible. By providing adherence-adjusted estimates, the IV approach may have additional utility for individual clinical decision-making.
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Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study.
Corbin, KD, Pittas, AG, Desouza, C, Grdinovac, KK, Herzig, KH, Kashyap, SR, Kim, SH, Nelson, J, Rasouli, N, Vickery, EM, et al
Journal of diabetes and its complications. 2023;(6):108475
Abstract
AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD. METHODS Cross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)]. RESULTS Eighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis. CONCLUSIONS The predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.
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Ertugliflozin Delays Insulin Initiation and Reduces Insulin Dose Requirements in Patients With Type 2 Diabetes: Analyses From VERTIS CV.
Dagogo-Jack, S, Frederich, R, Liu, J, Cannon, CP, Shi, H, Cherney, DZI, Cosentino, F, Masiukiewicz, U, Gantz, I, Pratley, RE
The Journal of clinical endocrinology and metabolism. 2023;(8):2042-2051
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Abstract
CONTEXT VERTIS CV evaluated the cardiovascular safety of ertugliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE The aim of these analyses was to assess the insulin requirements of VERTIS CV patients over the trial duration. METHODS Patients received ertugliflozin 5 mg, 15 mg, or placebo once daily; mean follow-up was 3.5 years. Time to insulin initiation in patients who were insulin naïve at baseline, change in insulin dose in patients receiving baseline insulin, and hypoglycemia incidence in both patient groups were assessed. RESULTS In VERTIS CV, mean duration of type 2 diabetes was 13.0 years; glycated hemoglobin was 8.2%. Among 4348 (53%) insulin-naïve patients, the likelihood of insulin initiation was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: hazard ratio [HR] 0.70, 95% CI 0.58-0.84; ertugliflozin 15 mg: HR 0.64, 95% CI 0.53-0.78). Time to insulin initiation was delayed with ertugliflozin; the estimated delay in reaching a 10% cumulative incidence of new insulin initiations vs placebo was 399 days with ertugliflozin 5 mg and 669 days with ertugliflozin 15 mg. Among 3898 (47%) patients receiving baseline insulin, the likelihood of requiring a ≥20% increase in insulin dose was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: HR 0.62, 95% CI 0.52-0.75; ertugliflozin 15 mg: HR 0.51, 95% CI 0.41-0.62). The incidence of hypoglycemia events was not increased with ertugliflozin treatment. CONCLUSION In VERTIS CV patients, ertugliflozin reduced the likelihood of insulin initiation, delayed the time to insulin initiation by up to ∼1.8 years, and reduced insulin dose requirements vs placebo, without increasing hypoglycemia events.
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An Overview of Diet and Physical Activity for Healthy Weight in Adolescents and Young Adults with Type 1 Diabetes: Lessons Learned from the ACT1ON Consortium.
Bishop, FK, Addala, A, Corbin, KD, Muntis, FR, Pratley, RE, Riddell, MC, Mayer-Davis, EJ, Maahs, DM, Zaharieva, DP
Nutrients. 2023;(11)
Abstract
The prevalence of overweight and obesity in young people with type 1 diabetes (T1D) now parallels that of the general population. Excess adiposity increases the risk of cardiovascular disease, which is already elevated up to 10-fold in T1D, underscoring a compelling need to address weight management as part of routine T1D care. Sustainable weight management requires both diet and physical activity (PA). Diet and PA approaches must be optimized towards the underlying metabolic and behavioral challenges unique to T1D to support glycemic control throughout the day. Diet strategies for people with T1D need to take into consideration glycemic management, metabolic status, clinical goals, personal preferences, and sociocultural considerations. A major barrier to weight management in this high-risk population is the challenge of integrating regular PA with day-to-day management of T1D. Specifically, exercise poses a substantial challenge due to the increased risk of hypoglycemia and/or hyperglycemia. Indeed, about two-thirds of individuals with T1D do not engage in the recommended amount of PA. Hypoglycemia presents a serious health risk, yet prevention and treatment often necessitates the consumption of additional calories, which may prohibit weight loss over time. Exercising safely is a concern and challenge with weight management and maintaining cardiometabolic health for individuals living with T1D and many healthcare professionals. Thus, a tremendous opportunity exists to improve exercise participation and cardiometabolic outcomes in this population. This article will review dietary strategies, the role of combined PA and diet for weight management, current resources for PA and glucose management, barriers to PA adherence in adults with T1D, as well as findings and lessons learned from the Advancing Care for Type 1 Diabetes and Obesity Network (ACT1ON).
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Associations of Dietary Intake with the Intestinal Microbiota and Short-Chain Fatty Acids Among Young Adults with Type 1 Diabetes and Overweight or Obesity.
Igudesman, D, Crandell, JL, Corbin, KD, Hooper, J, Thomas, JM, Bulik, CM, Pence, BW, Pratley, RE, Kosorok, MR, Maahs, DM, et al
The Journal of nutrition. 2023;(4):1178-1188
Abstract
BACKGROUND Diet, a key component of type 1 diabetes (T1D) management, modulates the intestinal microbiota and its metabolically active byproducts-including SCFA-through fermentation of dietary carbohydrates such as fiber. However, the diet-microbiome relationship remains largely unexplored in longstanding T1D. OBJECTIVES We evaluated whether increased carbohydrate intake, including fiber, is associated with increased SCFA-producing gut microbes, SCFA, and intestinal microbial diversity among young adults with longstanding T1D and overweight or obesity. METHODS Young adult men and women with T1D for ≥1 y, aged 19-30 y, and BMI of 27.0-39.9 kg/m2 at baseline provided stool samples at baseline and 3, 6, and 9 mo of a randomized dietary weight loss trial. Diet was assessed by 1-2 24-h recalls. The abundance of SCFA-producing microbes was measured using 16S rRNA gene sequencing. GC-MS measured fecal SCFA (acetate, butyrate, propionate, and total) concentrations. Adjusted and Bonferroni-corrected generalized estimating equations modeled associations of dietary fiber (total, soluble, and pectins) and carbohydrate (available carbohydrate, and fructose) with microbiome-related outcomes. Primary analyses were restricted to data collected before COVID-19 interruptions. RESULTS Fiber (total and soluble) and carbohydrates (available and fructose) were positively associated with total SCFA and acetate concentrations (n = 40 participants, 52 visits). Each 10 g/d of total and soluble fiber intake was associated with an additional 8.8 μmol/g (95% CI: 4.5, 12.8 μmol/g; P = 0.006) and 24.0 μmol/g (95% CI: 12.9, 35.1 μmol/g; P = 0.003) of fecal acetate, respectively. Available carbohydrate intake was positively associated with SCFA producers Roseburia and Ruminococcus gnavus. All diet variables except pectin were inversely associated with normalized abundance of Bacteroides and Alistipes. Fructose was inversely associated with Akkermansia abundance. CONCLUSIONS In young adults with longstanding T1D, fiber and carbohydrate intake were associated positively with fecal SCFA but had variable associations with SCFA-producing gut microbes. Controlled feeding studies should determine whether gut microbes and SCFA can be directly manipulated in T1D.
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Cardiorenal outcomes, kidney function, and other safety outcomes with ertugliflozin in older adults with type 2 diabetes (VERTIS CV): secondary analyses from a randomised, double-blind trial.
Pratley, RE, Cannon, CP, Cherney, DZI, Cosentino, F, McGuire, DK, Essex, MN, Lawrence, D, Jones, PLS, Liu, J, Adamsons, I, et al
The lancet. Healthy longevity. 2023;(4):e143-e154
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Abstract
BACKGROUND VERTIS CV was a randomised, double-blind, placebo-controlled, parallel-group, multicentre cardiovascular outcomes trial that evaluated the cardiovascular efficacy and safety of ertugliflozin in adults with type 2 diabetes and atherosclerotic cardiovascular disease. The primary objective of VERTIS CV was to show non-inferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke). The analyses reported here aimed to assess cardiorenal outcomes, kidney function, and other safety outcomes with ertugliflozin in older adults with type 2 diabetes and atherosclerotic cardiovascular disease compared with younger participants. METHODS VERTIS CV was done at 567 centres in 34 countries. Participants (aged ≥40 years) with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned (1:1:1) to once-daily ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo in addition to background standard-of-care treatment. Random assignment was done with the use of an interactive voice-response system. The study outcomes were major adverse cardiovascular events, hospitalisation for heart failure or cardiovascular death, cardiovascular death, hospitalisation for heart failure, prespecified kidney composite outcomes, kidney function, and other assessments of safety. Cardiorenal outcomes, kidney function, and safety outcomes were evaluated by baseline age (≥65 years and <65 years [prespecified] and ≥75 years and <75 years [post hoc]). The study is registered with ClinicalTrials.gov, NCT01986881. FINDINGS Between Dec 13, 2013, and July 31, 2015, and between June 1, 2016, and April 14, 2017, 8246 adults with type 2 diabetes and atherosclerotic cardiovascular disease were recruited to the study and randomly assigned. 2752 patients were assigned to ertugliflozin 5 mg, 2747 patients to ertugliflozin 15 mg, and 2747 patients to placebo. 8238 participants received at least one dose of ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo. 4145 (50·3%) of 8238 participants were aged 65 years and older, including 903 (11·0%) participants aged 75 years and older. 5764 (70·0%) of 8238 participants were male and 2474 (30·0%) were female, and 7233 (87·8%) of 8238 participants were White, 497 (6·0%) were Asian, 235 (2·9%) were Black, and 273 (3·3%) were classified as other. The mean estimated glomerular filtration rate (eGFR) was lower and the type 2 diabetes duration longer for those aged 65 years and older versus those younger than 65 years, and for those aged 75 years and older versus those younger than 75 years. Cardiovascular outcomes were more common in the older age subgroups than in the younger age subgroups. Similar to the overall VERTIS CV cohort, ertugliflozin did not increase the risk of major adverse cardiovascular events, cardiovascular death or hospitalisation for heart failure, cardiovascular death alone, or the kidney composite outcome (using doubling of serum creatinine, dialysis or transplantation, or kidney death), and reduced the risk of hospitalisation for heart failure and the exploratory kidney composite outcome (using a 40% sustained eGFR decrease, dialysis or transplantation, or kidney death) in the older age subgroups (pinteraction>0·05 for outcomes assessed). A slower decline in eGFR and a smaller increase in the urine albumin-to-creatinine ratio were observed over time in all age subgroups taking ertugliflozin compared with placebo. Across age subgroups, safety outcomes were consistent with the known profile of ertugliflozin. INTERPRETATION The effects of ertugliflozin on cardiorenal outcomes, kidney function, and safety outcomes were generally similar across age subgroups. These results have the potential to help clinical decision making by providing a longer-term evaluation of the cardiorenal safety and overall tolerability of ertugliflozin in a large population of older adults. FUNDING Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA in collaboration with Pfizer Inc, New York, NY, USA.