Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly elevates the risk of cardiovascular disease (CVD). This article delves into the integration of GLP-1 RAs and SGLT2is in clinical practice, supported by real-world experiences and case studies.

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Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly elevates the risk of cardiovascular disease (CVD). Currently, 101 million Indians live with diabetes. From this, 90-95% have T2DM. Cardiovascular complications remain the leading cause of morbidity and mortality both in India and globally among individuals with T2DM. The CVD epidemic among Indians is marked by a greater risk burden, higher premature deaths, an earlier age of onset and higher mortality.

Recent advancements in pharmacotherapy, particularly the introduction of sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have transformed the therapeutic landscape by offering not only improved glycaemic control but also substantial cardiovascular and renal benefits.

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Understanding the Cardiovascular Implications of T2DM

T2DM is more than just a problem with glucose metabolism; it is inherently associated with heart failure, atherosclerosis, and chronic kidney disease (CKD). Hyperglycaemia, insulin resistance, dyslipidaemia, and systemic inflammation all work together to accelerate vascular damage. Glycaemic control was the main emphasis of traditional care; however, new research emphasises the importance of simultaneously tackling cardiovascular risk factors.

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Evolution and Clinical Evidence of GLP-1 RAs and SGLT2 Inhibitors

GLP-1 Receptor Agonists

The identification of the GLP-1 fragment GLP-1(7-37) and the successive development of more stable, long-acting GLP-1 analogues mark major advancements in the medical field. GLP-1 RAs, such as semaglutide, liraglutide, and dulaglutide, mimic the action of endogenous GLP-1, activating GLP-1R thereby increasing insulin secretion, suppressing glucagon release, and inducing satiety. Beyond glycaemic control, these agents have demonstrated significant cardiovascular and renal benefits.

Large cardiovascular outcome trials (CVOTs) have consistently demonstrated that GLP-1 RAs reduce major adverse cardiovascular events (MACE) in patients with T2D and established CVD. A meta-analysis of eight cardiovascular outcome trials (CVOTs), which involved over 60000 patients, concluded that GLP-1 RAs reduced major adverse cardiovascular events (MACE) by 14%, cardiovascular death by 13%, non-fatal stroke by 16%, and all-cause death by 12%.

SGLT2 Inhibitors

1. SGLT2is, including empagliflozin, dapagliflozin, and canagliflozin, bind to SGLT2 receptors, wherein they reduce glucose reabsorption in the renal proximal tubules, leading to increased excretion of glucose in urine (glycosuria).
2. This action of SGLT2 is free from the risk of hypoglycaemia. Notably, these agents exhibit cardiovascular and renal benefits independent of their glucose-lowering effects.
3. Moreover, they reduce preload and afterload, thereby reducing fluid overload, especially in heart failure patients.
4. They also exhibit pleiotropic advantages, which include blood pressure reduction, weight reduction, and some evidence also suggests a reduction in low-density lipoprotein cholesterol (LDL-c) and uric acid levels.
5. SGLT2 inhibitors have shown remarkable efficacy in improving heart failure outcomes (Emperor-REDUCED and Emperor-PRESERVED trials) as well as cardiovascular outcomes (Empa-REG trial) and also slowing the progression of CKD (Empa-KIDNEY trial).
6. A meta-analysis of 14 trials with over 97000 participants demonstrated that SGLT2 inhibitors reduced MACE by 11%, cardiovascular death or hospitalisation for heart failure by 22%, and hospitalisation for heart failure by 29%.

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Case Studies

Case Study 1: Ms. A – A 63-Year-Old Female with T2DM and Established CVD

Patient Profile: Ms. A, a 63-year-old female with a 12-year history of T2DM, presented with a recent myocardial infarction, estimated glomerular filtration rate (eGFR) of 65 mL/min/1.73 m², with a history of hypertension and dyslipidaemia. Her HbA1c was 8.3%.

Clinical Course: Despite optimal statin, ACE inhibitor, beta-blocker and metformin + sulfonylurea (SU) therapy, her glycaemic control and weight remained suboptimal. SGLT2 inhibitor therapy (empagliflozin) was initiated, resulting in modest HbA1c reduction and weight loss. However, further improvement was needed.

Intervention: A GLP-1 RA (semaglutide) was added while SU therapy was discontinued to avoid hypoglycaemia. GLP-1 RA was added for targeting further cardiovascular risk reduction and weight management. Over 18 months, the patient achieved:

• HbA1c reduction to 7.1%
• 6.8 kg weight reduction
• No further cardiovascular events
• Improved blood pressure and lipid profile

Discussion: This case demonstrates the benefits of GLP-1 RA and SGLT2-i therapy to further prevent and reduce cardiovascular complications. The patient experienced significant improvements in glycaemic and cardiovascular risk parameters, proving that these agents are beneficial in reducing MACE and heart failure risk independently and additively.

Case Study 2: Mr. Y – A 68-year-old male with T2DM and Heart Failure with reduced EF

Patient Profile: Mr Y, a 68-year-old male with a history of ischemic cardiomyopathy (LVEF 30%), type 2 diabetes (HbA1c 7.5%), CKD (eGFR 52 mL/min/1.73 m²), and NYHA Class III heart failure symptoms. He was on optimal guideline-directed medical therapy (telmisartan, bisoprolol, spironolactone, chlorthalidone, metformin).

Clinical Course: The patient had three heart failure hospitalisations in the previous year despite receiving the optimal treatment. He complained of exhaustion, fluctuating weight from volume overload, and chronic dyspnoea with little effort. LVEF of 30% was confirmed by echocardiography, and BNP was high at 850 pg/mL.

Intervention: Empagliflozin 10 mg daily was initiated, given his ongoing symptoms and hospitalisations despite standard therapy. Renal function and glycaemic control were monitored closely.

Outcomes: After six months of therapy:

• LVEF improved from 30% to 35%
• BNP decreased from 850 pg/mL to 400 pg/mL
• Heart failure hospitalisations reduced from 3/year to 0
• Weight decreased from 92 kg to 87 kg
• NYHA class improved from III to II
• eGFR remained stable (52 to 50 mL/min/1.73 m²)

Discussion: This case demonstrates the advantages of administering an SGLT2 inhibitor to a patient with T2DM and HFrEF. In line with the results of landmark trials, empagliflozin improved cardiac biomarkers, decreased hospitalisations, and alleviated symptoms. Even in patients with concomitant T2DM and CKD, the therapy was well tolerated, showed steady renal function, and had minimal side effects, confirming its significance as a cornerstone treatment for HFrEF.

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Practical Considerations in Clinical Practice

1. Patient Selection: Assess cardiovascular history, renal function, and individual risk factors.
2. Monitoring: Regularly monitor renal parameters, electrolytes, and glycaemic control.
3. Adverse Effects: Be vigilant for gastrointestinal symptoms with GLP-1 RAs and genitourinary infections with SGLT2is.
4. Cost and Accessibility: Consider the financial implications and ensure patient adherence.

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Disclaimer: The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Ranganathan Gopinath, MD, DNB Cardiology, is a Consultant Cardio Diabetologist in Erode.