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Posted on Friday February 27, 2026 in Glucose and Insulin Dynamics
Toward Early Cardiometabolic Intervention in the Prevention of Cardiovascular Disease
An article by Dr Edward Leatham, Consultant Cardiologist © 2024 E.Leatham
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For decades, prediabetes has occupied an ambiguous clinical space — acknowledged as a risk state yet often excluded from aggressive therapeutic decision-making. Traditionally viewed as a metabolic precursor rather than a disease entity, prediabetes has been managed predominantly through lifestyle advice, with pharmacologic intervention reserved for progression to overt type 2 diabetes. However, contemporary cardiometabolic evidence challenges this passive paradigm.
From a cardiovascular standpoint, prediabetes is not merely a transitional glycemic classification; it represents a biologically active phase characterized by insulin resistance, endothelial dysfunction, low-grade inflammation, adipose tissue dysregulation, and early vascular injury. The implications for cardiologists are considerable. Cardiovascular risk emerges well before diagnostic glycemic thresholds are crossed, suggesting that waiting for overt diabetes may represent a missed therapeutic opportunity.¹
This editorial argues that prediabetes should be reframed as a legitimate therapeutic target within cardiovascular prevention, aligning contemporary metabolic pharmacology with the principles of early risk modification long established in cardiology.
Prediabetes — defined by impaired fasting glucose, impaired glucose tolerance, or mildly elevated HbA1c — reflects progressive dysregulation of glucose metabolism driven primarily by insulin resistance and declining beta-cell reserve. Importantly, this stage is already associated with measurable cardiovascular abnormalities:
Longitudinal observations have demonstrated that microvascular and macrovascular risk rises continuously across the glycemic spectrum rather than abruptly at diabetic thresholds.¹ This parallels experiences in hypertension and dyslipidemia, where risk modification occurs before arbitrary cutoffs are exceeded.
For preventive cardiology, this distinction is critical. Prediabetes frequently coexists with obesity, hypertension, dyslipidemia, and fatty liver disease, creating a clustered cardiometabolic phenotype that amplifies overall risk. The clinical reality is clear: many patients presenting to cardiology clinics with coronary disease, heart failure, or atrial arrhythmias already reside within this metabolic intermediary stage.
The Diabetes Prevention Program (DPP) established lifestyle modification as the most effective intervention for delaying progression to diabetes, reducing incidence by approximately 58% compared with placebo.² Weight reduction and increased physical activity remain foundational recommendations and align closely with guideline-directed cardiovascular prevention.
However, implementation challenges are substantial:
While lifestyle remains indispensable, reliance on behavioral intervention alone may underestimate the progressive biological momentum inherent in cardiometabolic disease. As in hypertension management, pharmacologic support becomes increasingly relevant when risk burden is high or progression persists despite non-pharmacologic measures.
Metformin remains the most extensively studied medication for prediabetes. Meta-analytic data demonstrate a significant reduction in progression to overt diabetes, particularly among younger individuals with obesity or higher baseline risk.³
From a cardiology perspective, metformin offers several practical advantages:
Yet metformin’s role is not without debate. Questions remain regarding whether it truly modifies disease trajectory or primarily delays the biochemical diagnosis while therapy is continued.³ Nevertheless, delaying diabetes onset itself may confer meaningful long-term cardiovascular benefit, particularly when cumulative glycemic exposure is considered.
Despite guideline support for selected high-risk patients, metformin remains underutilized in prevention pathways — reflecting therapeutic inertia rather than lack of evidence.
The last decade has witnessed a paradigm shift driven by cardiovascular outcomes trials demonstrating that certain glucose-lowering agents improve cardiovascular outcomes independent of glycemic effects. These findings have profound implications for prediabetes management.
The EMPA-REG OUTCOME trial fundamentally altered cardiovascular diabetology by demonstrating reductions in cardiovascular mortality and heart failure hospitalization with empagliflozin.⁴ Importantly, early separation of event curves suggested mechanisms extending beyond glucose lowering — including natriuresis, hemodynamic effects, myocardial energetics, and renal protection.
Although evidence specifically in prediabetes remains limited, the principle is transformative: cardiovascular benefit may derive from metabolic modulation rather than diabetes correction alone. This raises an important conceptual question for cardiologists — should intervention wait for diabetes when cardiovascular pathways are already active?
GLP-1 receptor agonists have demonstrated consistent cardiovascular benefit alongside weight reduction and metabolic improvement.
The LEADER trial showed liraglutide reduced major adverse cardiovascular events (MACE) in high-risk patients, reinforcing the role of incretin therapies beyond glycemic control.⁵
Semaglutide further extended this therapeutic class through superior weight loss and metabolic normalization. In obesity trials, substantial proportions of participants with baseline prediabetes reverted to normoglycemia during therapy, suggesting potential interruption of disease progression rather than simple glucose suppression.⁶
From a cardiology standpoint, this is especially relevant given the increasing recognition of obesity as a primary cardiovascular driver rather than a secondary comorbidity.
Tirzepatide, combining GIP and GLP-1 receptor agonism, represents a further evolution of cardiometabolic pharmacology. In large obesity trials, participants experienced profound weight loss exceeding 20%, accompanied by high rates of normalization of glycemic status among those with prediabetes.⁷
These outcomes suggest a potentially disease-modifying effect by targeting multiple levels of metabolic dysfunction:
For cardiologists, the implications are substantial. Treatments once considered “diabetes drugs” are increasingly functioning as cardiovascular risk-modifying therapies.
Cardiology has long embraced early intervention — treating LDL cholesterol before plaque rupture, controlling blood pressure before stroke, and managing heart failure before decompensation. Prediabetes challenges clinicians to apply the same logic to metabolism.
The central issue is not whether diabetes develops but whether cardiovascular disease progresses.
Prediabetes may represent the final stage at which:
Waiting for overt diabetes may therefore represent a lost opportunity for upstream prevention.
A pragmatic approach might include:
Low risk:
Intermediate risk:
High cardiovascular risk or established ASCVD:
This framework aligns with modern preventive cardiology, where risk clustering — rather than isolated laboratory thresholds — drives decision-making.
Several key questions remain unanswered:
Ongoing trials focusing on obesity, heart failure, and primary prevention may soon provide clarity. What is already evident, however, is that the boundaries between endocrinology and cardiology are dissolving into a unified field of cardiometabolic medicine.
Prediabetes should no longer be regarded as a passive observational state. It represents a biologically active phase in the continuum of cardiometabolic disease, during which cardiovascular risk is already measurable and potentially modifiable.
Lifestyle intervention remains foundational, and metformin provides a pragmatic pharmacologic option for selected high-risk individuals. Yet the emergence of agents such as empagliflozin, liraglutide, semaglutide, and tirzepatide signals a broader shift — from glycemic control toward comprehensive metabolic and cardiovascular risk modification.
For modern cardiology, the question is increasingly clear:
The goal is not simply to prevent diabetes — it is to prevent cardiovascular disease before metabolic dysfunction becomes irreversible.
Prediabetes may therefore represent one of the most important therapeutic windows in contemporary cardiovascular prevention.
¹ Rad Pour O, Dagogo-Jack S. Prediabetes as a Therapeutic Target.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395135/
² Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention.
https://www.nejm.org/doi/full/10.1056/NEJMoa012512
³ Lilly M, Godwin M. Treating prediabetes with metformin: systematic review and meta-analysis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669003/
⁴ Zinman B et al. Empagliflozin cardiovascular outcomes (EMPA-REG OUTCOME).
https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
⁵ Marso SP et al. Liraglutide and cardiovascular outcomes (LEADER trial).
https://www.nejm.org/doi/full/10.1056/NEJMoa1603827
⁶ Rubino D et al. Semaglutide and weight reduction in obesity (STEP program).
https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
⁷ Jastreboff AM et al. Tirzepatide once weekly for obesity (SURMOUNT-1).
https://www.nejm.org/doi/full/10.1056/NEJMoa2206038
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