The arrival of sodium-glucose cotransporter type 2 (SGLT2) inhibitors has ushered in a new era in the management of cardiometabolic diseases. These innovative agents, initially developed for glycaemic control in type 2 diabetes, have unexpectedly demonstrated significant cardiovascular benefits, revolutionising cardiologists’ approach to the prevention and treatment of heart failure and cardiovascular events.1
SGLT2 inhibitors exert their cardioprotective effect through several proposed mechanisms. Primarily, by inhibiting the SGLT2 in the proximal renal tubules, these agents promote urinary glucose excretion, leading to reductions in serum glucose levels, body weight, and blood pressure.1,2 Additionally, SGLT2 inhibitors are thought to drive cardiovascular benefits by promoting natriuresis and diuresis, reducing preload and afterload on the heart.1,2 They also appear to improve myocardial energetics, reduce oxidative stress and inflammation, and exert favourable effects on cardiac remodelling and vascular function.1,2
The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial was a watershed moment that sparked cardiologists’ interest in the potential cardiac benefits of SGLT2 inhibitors.3 This landmark study demonstrated that dapagliflozin, initially developed for glycaemic control in diabetes, remarkably reduced the risk of worsening heart failure and cardiovascular death in patients with reduced ejection fraction.3,4 Building upon the ground-breaking EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, which unveiled the cardiovascular protective effects of empagliflozin, and the CANVAS (Canagliflozin Cardiovascular Assessment Study) trial highlighting canagliflozin’s cardiovascular safety, DAPA-HF created a paradigm shift.5 Subsequent trials, such as DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction), and EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction), further solidified the cardiorenal benefits of SGLT2 inhibitors, extending their promise to heart failure with preserved ejection fraction and chronic kidney disease.5 This cumulative evidence has persuaded cardiologists worldwide to embrace SGLT2 inhibitors as a strong addition to their therapeutic armamentarium.
The implications of these findings are far-reaching, offering hope to patients grappling with the debilitating effects of heart failure and the ever-present threat of cardiovascular complications.3–5
Adoption
The integration of SGLT2 inhibitors into cardiovascular care has been rapidly advancing across healthcare systems worldwide. Many international guidelines, including those from the American Heart Association (AHA), European Society of Cardiology (ESC), and National Institute for Health and Care Excellence (NICE), now recommend SGLT2 inhibitors for the treatment of heart failure and cardiovascular risk reduction in specific patient populations. However, their widespread adoption has been tempered by cost concerns.6,7 Policymakers are grappling with the economic implications of providing access to these novel agents, weighing their upfront costs against the potential long-term savings from reduced hospitalisations and improved outcomes.7 Comprehensive cost-effectiveness analyses are being explored to facilitate sustainable access while managing healthcare expenditures responsibly.6,7 Overcoming these economic barriers and aligning policies to support appropriate SGLT2 inhibitor use will be critical to fully unlocking their transformative potential in cardiovascular care globally.
Potential
The potential of SGLT2 inhibitors in the realm of cardiovascular management has ignited a flurry of research curiosity and anticipation. Ongoing studies are actively investigating the efficacy of these agents in novel therapeutic indications, such as heart failure with preserved ejection fraction, and expanding their potential applications beyond diabetes management.8,9 Additionally, researchers are delving deeper into the intricate molecular mechanisms underlying the observed cardioprotective effects, aiming to unravel the complex interplay of cellular pathways involved.10,11
Long-term follow-up studies are crucial to assess the durability and safety profile of SGLT2 inhibitors over extended periods, particularly in high-risk patient populations. Exploring potential synergies with other therapeutic modalities through combination therapies is another area of possible investigation, with the goal of optimising treatment outcomes. Furthermore, the identification of biomarkers or genetic factors that influence individual responses could pave the way for personalised treatment strategies, maximising efficacy while minimising adverse effects. As these research endeavours progress, the anticipated insights will shape the future landscape of cardiovascular management with SGLT2 inhibitors. However, as we embrace the potential of SGLT2 inhibitors in cardiology, it is imperative that we remain vigilant in our assessment of their safety profile.12
Precautions
While the cardiovascular benefits of SGLT2 inhibitors are significant, we must exercise caution and diligence in our understanding of their potential risks and adverse effects.12 Concerns, such as the risk of genital mycotic infections, euglycaemic diabetic ketoacidosis, and the initial decline in renal function, highlight the need for comprehensive patient education, careful monitoring, and judicious patient selection.12,13 Furthermore, the possibility of volume depletion, hypotension, and the initially reported, yet controversial, risk of lower limb amputations, underscore the importance of individualised risk–benefit assessments and proactive management strategies.13
As clinicians, we must stay up-to-date with the evidence surrounding SGLT2 inhibitors, critically evaluating both their strengths and limitations. We need to engage in open and transparent discussions with our patients, ensuring that they are fully informed about the potential risks and benefits, empowering them to make informed decisions about their care.
Collaboration between healthcare professionals, researchers, regulatory authorities, and the pharmaceutical industry is vital to foster a culture of safety and vigilance. Robust surveillance, in vivo evidence generation, and ongoing clinical research are essential to refine our understanding of the long-term safety implications of SGLT2 inhibitor use in cardiology.
New frontiers
As we stride into this new frontier of cardiovascular care, a resounding call to action reverberates: we must prioritise robust post-marketing surveillance and expand clinical research horizons for SGLT2 inhibitors. Diligent monitoring will help identify long-term safety patterns, while broader trials addressing diverse populations and novel applications will unlock invaluable insights. Only through a strong commitment to evidence generation can we harness the full potential of SGLT2 inhibitors in cardiovascular care, fortifying our arsenal against cardiometabolic diseases while upholding patient safety.
In embracing SGLT2 inhibitors for cardiovascular care, we must balance efficacy against risks. Clinicians should educate patients and monitor regularly to mitigate risks. Ongoing studies will provide crucial long-term safety data. This vigilant approach, coupled with continued research, can redefine cardiovascular care and improve outcomes for cardiometabolic patients.
Key messages
- Sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated robust cardiovascular benefits, but also have important safety risks, such as diabetic ketoacidosis and genital infections
- As use expands to broader populations, clinicians must carefully select appropriate patients, provide counselling on risks, and diligently monitor for reported complications
- A balanced perspective is needed – embracing the cardiac promise while exercising vigilance through prudent patient selection, risk stratification, and monitoring
Conflicts of interest
None declared.
Funding
None.
References
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