Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In an editorial published in the European Heart Journal last year, award-winning American cardiologist, Prof Eugene Braunwald, described SGLT2 inhibitors as one of the major pharmacological advances in cardiovascular (CV) medicine in the 21st century.¹ 

In South Africa, dapagliflozin is approved as monotherapy, or in combination with other glucose-lowering therapies (GLTs) together with diet and exercise for the treatment of type 2 diabetes (T2DM) in adult patients (≥18-years).² 

Dapagliflozin is also indicated for the treatment of patient with heart failure (HF) with a left ventricular ejection fracture (LVEF) of <40%, and to reduce the risk of CV mortality in patients living with T2DM, and established CV disease (CVD).² 

Fixed-dose dapagliflozin-metformin is approved for the treatment of adult patient living with T2DM in combination with diet and exercise to reduce the risk of new or progressive HF as well as the risk of CV death in patients with established CVD and multiple risk factors.³ 

Cardio- and renal benefits of SGLT2 inhibitors 

Over the past eight years, numerous studies have shown that treatment with SGLT2 inhibitors not only effectively lowers HbA1c, but also reduces the risk of CVD and end-stage renal disease (ESRD) in patients living with T2DM.¹ 

Metformin is a well-established drug and is recommended as first-line treatment in T2DM because of its efficacy in reducing HbA1c, less risk of hypoglycaemia, and its low cost compared to other oral anti-diabetic drugs (OADs).⁴ 

Efficacy and safety of dapagliflozin and dapagliflozin-metformin 

The efficacy and safety of dapagliflozin as monotherapy in T2DM, adjunctive therapy to several OADs, and in patients receiving concurrent insulin, have been shown in numerous trials.⁵ 

A recent comprehensive review of dapagliflozin-metformin (2022) showed that the combination reduced HbA1c by 20.7%-31.5% from baseline, compared to metformin alone. Furthermore, 40.6% of patients on combination therapy achieved the recommended HbA1c of <7%.⁴  

The Food and Drug Administration (FDA) approved dapagliflozin, and dapagliflozin-metformin for the treatment of T2DM in 2014.^5,6 Dapagliflozin was approved by the European Medicine Agency (EMA) for the treatment of T2DM, heart failure (HF) and chronic kidney disease (CKD) in 2012. Dapagliflozin-metformin was approved by the EMA in 2014.^5,7 

Effects of SGLT2i on Cardiovascular and renal outcomes 

Cardiovascular outcomes 

Speaking at the Cardio-Renal-Metabolic conference, Prof Antoni Ceriello, Chair of the Diabetes and CVD Study Group (European Association for the Study of Diabetes), said numerous studies have shown that all SGLT2 inhibitors significantly reduce the risk of HF and CVD in patients living with T2DM, and prolong their lifes.⁸ 

A 2022 meta-analysis by Tornyos et al on the class effect of SGLT2 inhibitors on CV outcomes, involving 88 419 patients, showed that these agents reduce the risk of HF-related hospitalisation (relative risk [RR]: 0.72), HF-related hospitalisation and CVD (RR: 0.78), as well as major adverse cardiac events.⁹   

Dapagliflozin in particular has been shown to reduce the risk of progression to CV death and ESRD independent of background GLTs, said Prof Ceriello. A study by Beernink et al (2023) included 4304 patients of which 43% were on metformin, 55% on insulin, 27% on sulfonylureas, 26% on dipeptidyl peptidase 4 inhibitors, and 4% on glucagon-like peptide 1 receptor agonists. They found that dapagliflozin reduced renal and CV events in patients living with T2DM and CKD across baseline GLT class or classes in combination.^8,10 

 Prof Gianluigi Savarese, a cardiologist based at the Karolinska Institutet and a consultant in HF at the Karolinska University Hospital (Sweden), said new studies show that treatment with dapagliflozin results in clinically meaningful changes in health status within a short period of time and across the ejection fracture spectrum.^8,11,12   

In the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure or DELIVER trial, involving 6263 patients, Vaduganathan et al (2022) found that dapagliflozin led to early and sustained reductions in clinical events in patients with HF with mildly reduced EF (HFmrEF) and HF with preserved EF (HFpEF) with statistically significant reductions observed within two weeks of treatment initiation.¹¹ 

Kosiborod et al (2023) evaluated the effects of dapagliflozin versus placebo on various domains. The study included 5795 participants with HFmrEF and HFpEF.  At the end of the study (16 weeks) the team found that significantly fewer participants in the dapagliflozin group experienced clinically meaningful deterioration, and more experienced clinically meaningful improvements in symptoms, physical limitations, and quality of life, regardless of ejection fracture. They concluded that the clinical benefits of dapagliflozin appear especially pronounced in those with greater baseline symptom impairment.¹² 

Renal outcomes 

Furthermore, said Prof Ceriello, over-expression of SGLT2 has been implicated in renal complications in patients living with T2DM. Dapagliflozin has been shown to inhibit over-expression and prevent high-glucose-induced cellular senescence in renal tubular epithelial cells as shown in the study by Eleftheriadis et al.^8,13 

Eleftheriadis et al (2022) evaluated the effects of dapagliflozin on cellular senescence in patients living with T2DM. Dapagliflozin decreased the entry of glucose into the cells, glucose consumption and SGLT2 expression under both normal and high-glucose conditions and prevented high-glucose-induced upregulation.¹³ 

In his presentation, Prof Christoph Wanner, Head of the Division of Nephrology in the Department of Medicine at the University Hospital of Würzburg (Germany), highlighted the findings of the Nuffield Department of Population Health Renal Studies Group published in The Lancet last year.¹⁴  

The group evaluated the efficacy and safety of SGLT2 inhibitors in reducing the risk of adverse renal and CV outcomes in patients with HF or CKD, and in those with T2DM and high risk of atherosclerotic CV disease.¹⁴ 

The main efficacy outcomes were CKD progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, ESRD, or death from renal failure), acute renal injury, and a composite of CV death or HF-hospitalisation. Other outcomes were death from CVD and non-CVD causes, and the main safety outcomes were ketoacidosis and lower limb amputation.¹⁴ 

The meta-analysis included 13 trials involving 90 409 patients of which 82.7% had diabetes (>99% with T2DM) and 17.3% without diabetes. Mean baseline eGFR ranged 37-85mL/min per 1.73 m2.¹⁴  

The group found compared to placebo, randomisation to a SGLT2 inhibitor reduced the risk of CKD progression by 37% with similar RRs in patients with and without diabetes.¹⁴  

In the four CKD trials included in the meta-analysis, RRs were similar, irrespective of primary renal diagnosis. SGLT2 inhibitors reduced the risk of acute renal injury by 23%, and the risk of CV death or HF-hospitalisation by 23%, again with similar effects in those with and without diabetes.¹⁴  

SGLT2 inhibitors also reduced the risk of CV-related death (0.86) but did not significantly reduce the risk of non-CV-related death. For these mortality outcomes, RRs were similar in patients with and without diabetes.¹⁴  

For all outcomes, results were broadly similar irrespective of mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation.¹⁴ 

In addition to the established CV benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of CKD progression and acute renal injury, not only in patients living with T2DM at high CV risk, but also in patients living with CKD or HF, irrespective of diabetes status, primary renal disease, or renal function.¹⁴ 

References  

1. Braunwald E. SGLT2 inhibitors: the statins of the 21st century. European Heart Journal, 2022. 
2. MobiMims. Forxiga. Available at https://www.mobimims.co.za/Product/Index?id=aa705ad7-e66d-4a74-b9f7-e79e51e639cb&classificationid=de72d60a-3c93-4792-9f1b-282a8846ad2d 
3. MobiMims. Xigduo. Available at https://www.mobimims.co.za/Product/Index?id=11662406-2f15-4d82-8fc9-7aab7e5abf27&classificationid=de72d60a-3c93-4792-9f1b-282a8846ad2d 
4. Alkhanferi SK, Alhuraiz KH, Alyami HS, et al. The Safety and Efficacy of Combination Therapy of Dapagliflozin and Metformin in Patient with Type 2 Diabetes Mellitus: A Review Study. Journal of Diabetes Mellitus, 2022. 
5. Anderson SL. Dapagliflozin efficacy and safety: a perspective review. Ther Adv Drug Saf, 2014. 
6. Mechcatie E. Dapagliflozin-metformin combination tablet approved by FDA [Internet]. Family Practice News, 2014. Available at: https://www.mdedge.com/familymedicine/article/88366/diabetes/dapagliflozin-metformin-combination-tablet-approved-fda 
7. European Medicines Agency. Forxiga (dapagliflozin) [Internet]. Available at: https://www.ema.europa.eu/en/documents/overview/forxiga-epar-medicine-overview_en.pdf 
8. E-Space 2023. Cardio-Renal-Metabolic virtual congress. Plenary session 2. SGLT2 updates [Internet]. Available at: https://www.radcliffecardiology.com/video-index/e-space-cardio-renal-metabolic-2023?ch=35131&ep=35137 
9. Tornyos D, Meuer M, Lukács R, et al. Cardiovascular outcomes in patients treated with sodium-glucose transport protein 2 inhibitors, a network meta-analysis of randomized trials. Front Cardiovasc Med, 2022. 
10. Beernink JM, Persson F, Jongs F, et al. Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study. Diabetes Care, 2023. 
11. Vaduganathan M, Claggett BL, Jhund P, et al. Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol, 2022. 
12. Kosiborod MN, Bhatt AS, Claggett BL, et al. Effect of Dapagliflozin on Health Status in Patients With Preserved or Mildly Reduced Ejection Fraction. J Am Coll Cardiol, 2023. 
13. Eleftheriadis T, Pissas G, Filippidis G, et al. Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells. Int J Mol Sci, 2022. 
14. Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet, 2022.