Type 2 diabetes mellitus (T2D) substantially elevates the risk of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Cardiovascular remodeling, often termed diabetic cardiomyopathy, occurs early in T2D and progresses gradually. Exercise intolerance is an early symptom of heart failure and a prognostic indicator in T2D. The mechanisms behind exercise intolerance in HFpEF are complex, involving both cardiovascular (cardiac remodeling, diastolic dysfunction, left atrial hypertrophy, arterial stiffness, microvascular dysfunction) and peripheral factors (sarcopenia, frailty). While short-term improvements in cardiovascular remodeling and exercise tolerance are seen after interventions like acute weight loss or bariatric surgery, these are not always feasible. Evidence on the predictors and outcomes of T2D remission, including mortality, cardiovascular events, and functional capacity, is limited. The American Diabetes Association has called for research on the impact of T2D remission beyond weight loss and glycemia. A previous cohort study showed improved cardiovascular risk profiles in remission, but cardiac structure, function, and exercise capacity were not assessed. This study aimed to evaluate the medium-term effects of T2D remission on cardiovascular structure, function, and exercise capacity using MRI and cardiopulmonary exercise testing, comparing individuals with autonomous remission (self-directed lifestyle changes) to those with active T2D and healthy controls.

Existing literature highlights the strong association between type 2 diabetes and an increased risk of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Studies have shown that cardiovascular remodeling, a key feature of diabetic cardiomyopathy, begins early in the disease course and progresses insidiously. Exercise intolerance is recognized as a significant early symptom and prognostic marker in T2D and HFpEF. While the pathophysiology of exercise intolerance in HFpEF is not fully understood, it is believed to involve a combination of both cardiovascular and peripheral factors. Short-term studies have demonstrated improvements in cardiovascular function and exercise tolerance following interventions like acute weight loss or bariatric surgery. However, a significant gap remains in the understanding of the long-term impacts of T2D remission on cardiovascular health. Previous research has indicated a link between T2D remission and improved cardiovascular risk profiles, yet the effects on cardiac structure, function, and exercise capacity remain largely uninvestigated, motivating this study to bridge this knowledge gap.

Three hundred individuals with T2D and 45 healthy controls were recruited into the PREDICT study (NCT03132129) between May 2018 and March 2022. Twenty-five participants who had achieved autonomous T2D remission were identified. Remission was defined as HbA1c < 6.5% for ≥3 months without glucose-lowering therapy. Propensity score matching (1:4 for remission vs. active T2D, 1:1 for remission vs. controls) was used to minimize bias, based on age, sex, ethnicity, and time of exposure to T2D. Assessments included fasting plasma samples for renal and lipid profiles, glycaemia, and cardiac enzymes; insulin, leptin, and adiponectin quantification; multi-parametric magnetic resonance imaging (MRI) for left ventricular (LV) mass, volumes, perfusion, myocardial extracellular volume (ECV), late gadolinium enhancement, hepatic and pancreatic fat; cardiac computed tomography for coronary calcium scoring; echocardiography for diastolic function (E/e'); and a cardiopulmonary exercise test (CPET) for peak VO2 and VE/VCO2 slope. Data analysis involved descriptive statistics and appropriate statistical tests (independent sample t-test, Mann-Whitney, Chi-square/Fisher's exact tests), with Bonferroni correction for multiple testing (p = 0.025).

The study included 25 individuals in T2D remission, 100 with active T2D, and 25 non-T2D controls. Average T2D exposure was less than six years, and remission duration was 4.2 ± 2.5 years. Those in remission showed a more favorable metabolic profile: lower triglycerides, lower leptin-adiponectin ratio, better insulin homeostasis, and higher HDL cholesterol compared to those with active T2D. Hepatic steatosis was significantly lower in remission. There were no significant differences in cardiovascular structure or function between those in remission and those with active T2D. However, concentric remodeling was increased in the remission group compared to controls (higher LV mass:volume ratio). A trend toward higher peak VO2 was observed in remission compared to active T2D (p = 0.051), and the VE/VCO2 slope was significantly lower in remission compared to active T2D and similar to controls. Despite improvements in metabolic risk profile and ventilatory response to exercise, there were no significant differences in cardiac structure or function measures on MRI or echocardiography between individuals in remission and those with active T2D. Significantly, 82% of those in remission exhibited impaired fasting glucose.

This study provides novel insights into the impact of autonomous T2D remission on cardiovascular health, going beyond glycemic control and weight loss. The findings confirm improvements in the metabolic risk profile in remission (lower triglycerides, improved insulin homeostasis, lower leptin-adiponectin ratio, higher HDL), along with a more favorable ventilatory response to exercise. However, the lack of improvement in cardiovascular structure and function, particularly the persistence of concentric remodeling, is notable and suggests that achieving remission may not automatically lead to cardiac reverse remodeling. The high prevalence of impaired fasting glucose in the remission group (82%) raises questions about the current definition of remission and the potential need for more refined classifications, perhaps incorporating fasting glucose levels. The findings could support the concept of 'post-diabetes' and/or the need for further categorization of remission. The persistent cardiovascular risk, despite metabolic improvements, highlights the importance of ongoing risk factor management in this population. Potential mechanisms for the lack of cardiac reverse remodeling might involve 'metabolic memory'—persistent detrimental effects on the cardiovascular system, independent of glycaemia.

This study demonstrates that while T2D remission is associated with improved metabolic risk profiles and ventilatory efficiency during exercise, it doesn't guarantee improvements in cardiovascular structure or function. Concentric left ventricular remodeling persists. These findings underscore the need for continued and focused risk factor control in individuals who achieve T2D remission. Further long-term studies are essential to fully understand the long-term cardiovascular risk in this growing patient population and to refine the definition and categorization of T2D remission.

The relatively small sample size and the overrepresentation of White Europeans are limitations that may affect the generalizability of the findings. The cross-sectional design limits causal inferences. Future research should address these limitations by including larger and more diverse cohorts in longitudinal studies to better understand the long-term effects of T2D remission on cardiovascular health.