Cardiorenal Benefits of Dapagliflozin: An Overview

Abstract

Dapagliflozin, a selective sodium–glucose co-transporter 2 (SGLT2) inhibitor, is widely used for the management of type 2 diabetes mellitus (T2DM) and has demonstrated significant renal and cardiovascular benefits beyond glycemic control. By blocking glucose and sodium reabsorption in the proximal convoluted tubule, it promotes glycosuria, reduces plasma glucose, and restores tubuloglomerular feedback, thereby lowering intraglomerular pressure and preventing hyperfiltration injury. Pharmacologically, it is well absorbed orally, highly protein-bound, undergoes UGT1A9-mediated hepatic metabolism, and has a half-life of 12–13 hours. Clinical evidence, particularly from the DAPA-CKD and DAPA-HF trials, shows that dapagliflozin slows the progression of chronic kidney disease (CKD), reduces albuminuria, delays eGFR decline, and lowers the risk of end-stage kidney disease in both diabetic and non-diabetic patients. It also significantly reduces hospitalization for heart failure and cardiovascular mortality. Although generally well tolerated, it may cause genital infections, dehydration, and rarely euglycemic ketoacidosis. Overall, dapagliflozin is an effective disease-modifying therapy across T2DM, CKD, and cardiovascular disease (CVD), offering strong glycemic, renal, and cardioprotective effects.

Keywords

Introduction

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was the first agent in this class to receive approval for the management of type 2 diabetes mellitus (T2DM). When used in combination with diet and exercise, it enhances glycaemic control by inhibiting glucose reabsorption in the proximal renal tubule, thereby promoting glycosuria. Clinical studies have evaluated dapagliflozin both as monotherapy and as an adjunct to insulin or other oral hypoglycaemic agents.

Initially approved by the U.S. FDA on January 8, 2014, for improving glycemic control in adults with T2DM, dapagliflozin later gained expanded indications. In April 2021, it was approved to reduce the risk of sustained kidney function decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease (CKD). Currently, it is indicated as adjunct therapy in patients aged ≥10 years with T2DM and as a treatment to mitigate the progression of CKD and associated cardiovascular complications.

Dapagliflozin exerts its therapeutic effect by lowering glycated hemoglobin (HbA1c) and fasting plasma glucose levels, while also contributing to reductions in body weight and blood pressure. Beyond glycemic control, it demonstrates significant cardiovascular and renal benefits, including a reduction in cardiovascular death and hospitalization for heart failure, without increasing the risk of major adverse cardiovascular events (MACE). Evidence also suggests a potential role in slowing CKD progression, particularly in patients with established atherosclerotic cardiovascular disease or multiple cardiovascular risk factors.

The safety profile of dapagliflozin is generally favorable, with a low risk of hypoglycemia. However, rare but notable adverse effects include diabetic ketoacidosis (DKA) and increased susceptibility to genital infections. Considering its antihyperglycemic, cardioprotective, and renoprotective properties, alongside good tolerability, dapagliflozin represents a valuable therapeutic option for a wide range of patients with T2DM and CKD, irrespective of cardiovascular disease history.

DAPAGLIFLOZIN

Dapagliflozin belongs to the class of Sodium–Glucose Co-Transporter 2 (SGLT2) Inhibitors, a group of oral antidiabetic agents that reduce plasma glucose by blocking renal glucose reabsorption.

Mechanism of Action:

Dapagliflozin is a selective SGLT2 inhibitor that blocks the SGLT2 transporters in the proximal convoluted tubule, thereby preventing the reabsorption of filtered glucose. This leads to increased urinary glucose excretion, decreased plasma glucose levels, and improvements in glucose toxicity, insulin resistance, and body weight. Additionally, SGLT2 inhibition reduces intraglomerular pressure by restoring tubule glomerular feedback, protecting nephrons from hyperfiltration injury—an essential mechanism in slowing the progression of chronic kidney disease (CKD).

Pharmacokinetics:

• Absorption: Well absorbed orally
• Distribution: Highly protein-bound
• Metabolism: Primarily metabolized in the liver via UGT1A9
• Excretion: Eliminated through renal and fecal routes
• Half-life: Approximately 12–13 hours

Therapeutic Uses:

Dapagliflozin is primarily used in the management of Type 2 Diabetes Mellitus, either as monotherapy or in combination with other antidiabetic agents, due to its ability to reduce blood glucose levels independently of insulin. Beyond glycemic control, dapagliflozin has significant renal protective effects, as demonstrated in the DAPA-CKD trial, where it slowed the progression of chronic kidney disease, reduced albuminuria, delayed eGFR decline, and lowered the risk of end-stage kidney disease. Importantly, these renal benefits extend to patients with or without diabetes. Additionally, dapagliflozin provides substantial cardiovascular protection, lowering hospitalization for heart failure, reducing cardiovascular mortality, and improving outcomes in patients with heart failure with reduced ejection fraction (HFrEF), irrespective of diabetic status. Because of these broad benefits, dapagliflozin is now recommended as an important part of therapy across diabetes, CKD, and heart failure management.

Adverse Effects:

Although dapagliflozin is generally well tolerated, several adverse effects have been reported. The most common are genital mycotic infections, especially in females, due to increased urinary glucose excretion. Patients may also experience polyuria, dehydration, and hypotension as a result of osmotic diuresis. Mild urinary tract infections and volume depletion may occur, particularly in elderly or dehydrated patients. Although rare, euglycemic diabetic ketoacidosis is a serious potential adverse effect, more likely in situations of prolonged fasting, acute illness, or reduced insulin doses. Dapagliflozin should be used cautiously in individuals with recurrent genital infections or volume depletion and is contraindicated in people with type 1 diabetes due to high ketoacidosis risk.

ROLE OF DAPAGLIFLOZIN IN CKD AND CVD PATIENTS

Dapagliflozin significantly reduces the risk of kidney disease progression, cardiovascular events, and death in CKD patients regardless of diabetes status, with an acceptable safety profile. It strengthens the role of SGLT2 inhibitors as essential therapy in CKD management beyond glycemic control.

Chronic kidney disease (CKD) is a major global health problem associated with substantial clinical, economic, and mortality burden. As CKD progresses toward kidney failure, the associated complications, healthcare utilization, and costs rise sharply. The DAPA-CKD trial previously demonstrated that dapagliflozin, an SGLT2 inhibitor, significantly slows the progression of CKD in patients both with and without type 2 diabetes. However, the long-term effect of dapagliflozin beyond the trial follow-up period remained uncertain.

Dapagliflozin slows the progression of chronic kidney disease (CKD) through multiple renal hemodynamic, tubular, and anti-inflammatory mechanisms. By inhibiting SGLT2 in the proximal tubule, it reduces sodium and glucose reabsorption, restoring tubulo-glomerular feedback and lowering intraglomerular pressure, which prevents hyperfiltration injury. This leads to a sustained reduction in albuminuria and a slower long-term decline in eGFR. Additionally, dapagliflozin reduces glucotoxicity, oxidative stress, and tubular oxygen demand, thereby decreasing renal inflammation and interstitial fibrosis. Its systemic effects—mild natriuresis, osmotic diuresis, reduced blood pressure, lower uric acid levels, and modest weight loss—further reduce renal workload and contribute to delaying kidney failure in patients with or without diabetes.

Dapagliflozin also provides strong cardiovascular protection through improvements in cardiac hemodynamics, myocardial metabolism, and endothelial function. By reducing plasma volume, preload, and afterload, it decreases cardiac strain and substantially reduces the risk of heart failure hospitalization. The drug increases ketone body availability, supplying the heart with a more efficient energy substrate and improving myocardial ATP production. It also reduces vascular inflammation, oxidative stress, arterial stiffness, and sympathetic activation, leading to improved vascular function and reduced risk of cardiovascular death. Through these combined renal and cardiovascular mechanisms, dapagliflozin acts as an effective disease-modifying therapy that slows CKD progression and improves major cardiovascular outcomes across a wide range of patients.

CONCLUSION

Dapagliflozin is now recognized as an important medicine not only for diabetes but also for protecting the kidneys and heart. It slows down kidney damage by reducing pressure in the kidneys, lowering albuminuria, and delaying the fall in eGFR. It also reduces the chances of developing end-stage kidney disease. In addition, it helps the heart by lowering hospital admissions for heart failure and reducing the risk of death due to heart problems. The drug is generally well tolerated, with most side effects being mild and manageable. Rarely, it may cause ketoacidosis or dehydration. Because of its proven benefits and safety, dapagliflozin is considered a valuable medicine for patients with diabetes, CKD, and cardiovascular disease, and it helps improve long-term health outcomes.

REFERENCES

1. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus Hiddo J.L. Heerspink, PharmD, PhD, Bruce A. Perkins, MD, MPH, David H. Fitchett, MD, Mansoor Husain, MD, and David Z. I. Cherney, MD, PhD
2. Wheeler, D.C., James, J., Patel, D. et al. SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes. Diabetes Ther 11, 2757–2774 (2020).
3. Dhillon S. Dapagliflozin: A Review in Type 2 Diabetes. Drugs. 2019 Jul;79(10):1135-1146. doi: 10.1007/s40265-019-01148-3.
4. Papakitsou I, Vougiouklakis G, Elisaf MS, Filippatos TD. Differential pharmacology and clinical utility of dapagliflozin in type 2 diabetes. Clin Pharmacol. 2019 Sep 19;11:133-143.
5. https://go.drugbank.com/drugs/DB06292
6. Phil McEwan, et al. The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis, Nephrology Dialysis Transplantation, Volume 39, Issue 12, December 2024, Pages 2040–2047, https://doi.org/10.1093/ndt/gfae106
7. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46.
8. Wheeler DC, Stefánsson BV, Jongs N, Chertow GM, Greene T, Hou FF, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22–31.
9. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.
10. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis. Lancet. 2019;393(10166):31–9.
11. Wheeler DC, James J, Serenyi D, et al. Long-term kidney outcomes with dapagliflozin treatment: extrapolation of real-world benefit from DAPA-CKD trial data. Kidney Int. 2023;103(4):750–62.