Impact of the Remission of Type 2 Diabetes on Cardiovascular Structure and Function, Exercise Capacity and Risk Profile: A Propensity Matched Analysis

Type 2 diabetes mellitus (T2D) confers an excess risk of heart failure, often with heart failure with preserved ejection fraction (HFpEF). T2D-related cardiovascular remodeling (diabetic cardiomyopathy) develops early and progresses insidiously. Exercise intolerance is an early symptom of heart failure and a prognostic indicator in T2D. Mechanisms underlying exercise intolerance in HFpEF likely include both cardiovascular (diastolic dysfunction, left atrial hypertrophy, arterial stiffness, microvascular dysfunction) and peripheral factors (sarcopenia, frailty). Although short-term improvements in cardiovascular remodeling and exercise tolerance have been shown after acute weight loss (low-calorie diet or bariatric surgery), such interventions are not feasible for all. There is a lack of evidence regarding predictors and medical outcomes, including functional capacity, after T2D remission; the ADA has called for data on the impact of remission beyond weight loss and glycaemia. Prior work has shown improved cardiovascular risk profile with remission, but not changes in cardiac structure, function, or exercise capacity. This study aimed to assess medium-term effects of autonomous (self-directed, non-surgical) T2D remission on cardiovascular structure and function by MRI and exercise capacity by CPET, compared with matched people with active T2D and with healthy controls.

The background highlights that T2D is associated with HFpEF and early diabetic cardiomyopathy characterized by diastolic dysfunction and concentric remodeling. Exercise intolerance predicts outcomes in T2D and HFpEF. Prior interventions (low-calorie diets, bariatric surgery) can yield short-term improvements in cardiovascular phenotypes and exercise tolerance, but generalizability is limited. The ADA consensus emphasized the need for research on remission beyond weight loss and glycaemia. A recent cohort linked T2D remission to an improved cardiovascular risk profile but did not evaluate cardiac structure, function, or exercise capacity. The study also references mechanistic frameworks including microvascular dysfunction in HFpEF and the twin-cycle hypothesis linking ectopic fat (particularly hepatic and pancreatic fat) to T2D pathophysiology.

Design and participants: Prospective case-control analysis within the PREDICT study (NCT03132129), a cross-sectional study recruiting 300 adults with T2D and 45 healthy controls from May 2018 to March 2022 in Leicester, UK. Twenty-five participants had autonomous remission (self-directed diet and/or exercise; no medical intervention). Remission definition: HbA1c < 48 mmol/mol (6.5%) for ≥3 months off glucose-lowering therapy. Ethics approval (17/WM/0192), informed consent obtained. Matching: To estimate the effect of remission, propensity score matching was used. T2D remission cases were matched 1:4 to active T2D (n = 100) by age, sex, ethnicity, and time since T2D diagnosis using nearest-neighbour matching. They were also matched 1:1 to non-T2D controls (n = 25) by age, sex, and ethnicity. Total analyzed: 150 participants. Assessments (same-day): - Blood tests: renal and lipid profiles, full blood count, glycaemia, cardiac biomarkers (NT-proBNP, high-sensitivity troponin). Insulin and leptin by multiplex (Luminex); adiponectin by ELISA. - Cardiac MRI (3T, Siemens): LV mass and volumes, adenosine stress/rest perfusion, extracellular volume (ECV), late gadolinium enhancement (LGE). Hepatic and pancreatic fat quantified using HepaFat (Resonance Health). Images analyzed blinded using CVi42. Myocardial perfusion reserve (MPR) computed as stress/rest myocardial blood flow ratio. - Cardiac CT: coronary artery calcium (Agatston) and epicardial adipose tissue volume (QFat deep learning). - Echocardiography: diastolic function and LV filling pressures (E/e') per ASE guidelines (iE33 S5-1), by accredited operators. - Cardiopulmonary exercise testing (CPET): one-minute incremental bicycle protocol with expired gas analysis; outcomes included peak VO2 and VE/VCO2 slope (regression of ventilation vs CO2 production). Statistical analysis: Descriptive statistics summarized groups. Novel measures compared using independent t-test, Mann–Whitney U, or chi-square/Fisher’s exact as appropriate. Bonferroni-adjusted significance threshold p = 0.025 per comparison (remission vs active T2D; remission vs control). Analyses performed in IBM SPSS v26.

- Cohort: 150 participants (25 remission, 100 active T2D, 25 controls). Mean T2D duration < 6 years in T2D groups; remission duration 4.2 ± 2.5 years. Only active T2D participants used glucose-lowering therapy. - Risk profile: Despite lower statin use in remission, triglycerides were lower and HDL cholesterol higher than active T2D. The leptin:adiponectin ratio was lower in remission vs active T2D. Active T2D showed a more adverse inflammatory profile. - Glycaemia: In remission, >80% had impaired fasting glucose; 22% had fasting glucose in the diabetes range; 28% of controls had IFG. - Ectopic fat: Hepatic fat markedly lower in remission vs active T2D (median 3.20% [2.20, 7.33] vs 9.40% [4.80, 15.20], significant). Trends toward lower pancreatic fat and epicardial adipose tissue in remission vs active T2D (p ≈ 0.10). Ectopic fat depots were comparable between remission and controls. - Blood pressure: 24 h ambulatory BP and antihypertensive use similar between T2D groups; systolic BP was higher in remission vs controls. - Cardiac structure/function (MRI/echo): No significant differences between remission and active T2D in LV mass, volumes, EF, strain, diastolic indices, ECV, MPR, or LGE. Compared with controls, remission showed evidence of concentric remodeling: LV mass/volume ratio higher (0.88 ± 0.10 vs 0.80 ± 0.10; p < 0.025). MPR and ECV were not significantly different among groups. - Exercise capacity (CPET): Trend toward higher peak VO2 in remission vs active T2D (22.20 ± 7.05 vs 19.16 ± 4.90 mL/kg/min; p = 0.051). VE/VCO2 slope significantly lower in remission vs active T2D (27.74 ± 3.95 vs 30.52 ± 5.46; p < 0.0025), and similar to controls (27.09 ± 4.57). Overall: Remission associated with improved metabolic risk factors and ventilatory efficiency during exercise but without detectable reverse cardiac remodeling compared with active T2D; concentric remodeling persisted vs controls.

Autonomous remission of T2D was linked to a more favorable cardiometabolic profile, including lower triglycerides, reduced leptin–adiponectin ratio, improved insulin homeostasis, higher HDL cholesterol, and lower hepatic fat, with trends toward lower pancreatic and epicardial adipose tissue. Ventilatory efficiency during exercise (VE/VCO2 slope), a prognostic marker in heart failure, improved to a level comparable to controls, and peak VO2 tended to be higher. Despite these benefits, cardiac MRI and echocardiography revealed no differences in structural or functional indices between remission and active T2D, and concentric remodeling remained more pronounced in remission compared with non-T2D controls. These findings suggest that remission alone may not induce cardiac reverse remodeling, indicating persistent cardiovascular risk and the need for ongoing risk factor management. Potential explanations include metabolic memory, whereby prior hyperglycaemia induces sustained oxidative stress and downstream pathogenic pathways even after normalization of HbA1c, and possibly alterations in pathways such as Sirtuin 1 signaling implicated in hypertrophy, fibrosis, and inflammation. Microvascular dysfunction (MPR) differences were not observed, potentially reflecting a later-stage phenomenon in T2D-related HFpEF pathophysiology. Continued surveillance and targeted interventions may be necessary to modify residual cardiac remodeling and risk.

T2D remission is associated with improvements in metabolic risk profile and ventilatory response to exercise but not with measurable improvements in cardiac structure or function. Evidence of persistent concentric remodeling suggests residual cardiovascular risk. This growing patient population requires continued attention to comprehensive risk factor control and further research to determine long-term cardiovascular outcomes and strategies to achieve cardiac reverse remodeling.

Strengths include detailed, same-day multimodal phenotyping with state-of-the-art MRI, blinded image analysis and biochemistry, and propensity score matching to enhance analytical power. Limitations include small sample size and overrepresentation of White European participants, limiting generalizability. The cross-sectional nature within a prospective study framework precludes causal inference; larger and more diverse cohorts with longitudinal follow-up are needed.