What a General Practitioner Needs to Know About Gliflozins

Introduction

In patients with type 2 diabetes, cardiovascular (CV) diseases are the most common cause of death. With the advent of new antidiabetic drugs in the past 20 years, studies verifying their CV safety have started to be required during their registration. After the CV neutrality of dipeptidyl peptidase-4 (DPP-4) inhibitors was proven, studies showing even the CV benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2i, i.e., gliflozins) inhibitors were published. Studies with gliflozins unexpectedly demonstrated their significant impact on reducing the risk of hospitalization for heart failure and their nephroprotective effects.

Mechanisms of Action of Gliflozins

The primary mechanism of action of gliflozins is the induction of glycosuria accompanied by osmotic diuresis. Glycosuria leads to a decrease in blood glucose levels and improves diabetes compensation. The mechanism of non-glycemic effects of gliflozins is not yet fully understood. From a cardioprotective perspective, a possible explanation is the change in the utilization of energy substrates by the myocardium or hemodynamic changes due to osmotic diuresis. In heart failure, the affectation of the transmembrane transporter NHE1 (Na⁺/H⁺ exchanger) in cardiomyocytes may play a role, even in patients without diabetes. Nephroprotection is attributed to the favorable effect on the tubuloglomerular feedback in the nephron.

Effects of Gliflozins on Glycemic Control

For the treatment of type 2 diabetes, four substances from the SGLT2i group are currently approved in the Czech Republic: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Their effect on reducing glycated hemoglobin (HbA_1c) after 24-26 weeks of treatment varies depending on the active substance and its dose, ranging from a decrease of 0.66% to 1.16%.

In the Czech Republic, gliflozins are reimbursed for the indication of type 2 diabetes treatment in combination with metformin and/or insulin in patients with HbA_1c > 60 mmol/mol, prescribed by a diabetologist, endocrinologist, or internist. It is also possible to use fixed combinations of SGLT2i with metformin.

Non-Glycemic Effects of Gliflozins

Empagliflozin, canagliflozin, and dapagliflozin have shown significant reductions in the risk of hospitalization for heart failure and in renal composite outcomes (including decline in renal function measured by eGFR, end-stage renal failure, or death from renal causes) compared to placebo. Empagliflozin and canagliflozin have also shown significant reductions in composite CV outcomes (including CV death, non-fatal myocardial infarction, or non-fatal stroke) and empagliflozin has demonstrated reductions in CV and overall mortality.

The Position of SGLT2i in Diabetes Treatment Recommendations

The latest update of the Czech diabetes treatment recommendations from December 2020 already considers new evidence. The recommendation to treat high-risk patients with type 2 diabetes using GLP-1RA or SGLT2i, because they reduce the risk of CV events or CV mortality or have favorable effects on heart failure or renal functions, remains unchanged. The main change is the recommendation to consider their use regardless of HbA_1c levels, as the beneficial non-glycemic effects of these classes of modern antidiabetics are independent of hyperglycemia and HbA_1c value. Another significant change is the shift of recommended cardioprotective drugs into primary prevention in patients with multiple risk factors. In high-risk patients, early combination therapy of metformin and another antidiabetic with proven cardioprotective or nephroprotective effects can be considered. The decision on initial combination therapy for newly diagnosed type 2 diabetes should be consensual across various specialties.

The American Diabetes Association (ADA) 2022 guidelines recommend gliflozins in the following cases:

• In patients with type 2 diabetes with established atherosclerotic cardiovascular disease or high CV risk, and further in patients with heart failure, especially with reduced ejection fraction of the left ventricle (LVEF), to reduce the risk of hospitalizations for heart failure, CV events, and CV mortality.
• In patients with type 2 diabetes with chronic kidney disease to reduce the risk of progression of renal disease, hospitalizations for heart failure, CV events, and CV mortality.
• Patients with lower limb ulcers or high risk of amputation should be treated with gliflozins only after careful shared decision-making and discussion of the risks and benefits of this therapy, along with comprehensive patient education on foot care and amputation prevention.

Gliflozins in Non-DM2 Indications

Gliflozins also appeared in the new recommendations of the European Society of Cardiology (ESC). Since 2021, dapagliflozin and empagliflozin have been recommended for the treatment of heart failure with reduced LVEF in patients with or without diabetes to prevent hospitalizations for heart failure and reduce mortality. Both drugs have reimbursement established for this indication in the Czech Republic. In the EU, both are also approved for the treatment of heart failure with preserved ejection fraction, with empagliflozin expected to soon receive reimbursement for this indication in the Czech Republic.

In patients with chronic kidney disease, gliflozins significantly slow kidney failure, contribute to preventing heart failure, and reduce mortality. For this indication, dapagliflozin is currently reimbursed for patients already treated with ACE inhibitors or sartans, or in those for whom this standard treatment is contraindicated.

Conclusion

As the number of studies increases, so does the amount of information that needs to be considered when choosing antidiabetic therapy for a specific patient. In patients with type 2 diabetes with comorbidities such as atherosclerotic cardiovascular disease or high-risk for it, heart failure, and chronic kidney disease, gliflozins with proven beneficial effects should always be considered regardless of HbA_1c value and preferred over antidiabetics that do not have these significant beneficial non-glycemic effects.

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Source: Prázný M. SGLT-2 Inhibitors and Their Application in Practice – Update 2022. Vnitřní lékařství 2022; 68 (2): 96-103.