Dapagliflozin: A Novel Approach to Treating Heart Failure

Abstract

Background: Heart failure (HF) affects millions of people worldwide and is a major cause of morbidity, mortality, and financial strain. The need for innovative treatments is emphasized by the significant limitations of conventional HF therapies. Beyond glycemic management, sodium-glucose cotransporter 2 (SGLT2) inhibitors, especially dapagliflozin, have become promising therapeutic options.Methods: The pharmacology, clinical evidence, and therapeutic effects of dapagliflozin in the management of cardiac failure are all examined in this review. By inhibiting SGLT2 in the proximal renal tubule, dapagliflozin lowers the absorption of glucose and promotes osmotic diuresis. Mechanistically, it lowers fibrosis, inflammation, and coronary hypertrophy in both diabetic and non-diabetic patients. The effectiveness and safety profile of dapagliflozin were assessed by analysing important clinical trials, such as DAPA-HF, DECLARE-TIMI 58, and DELIVER. Urinary tract and genital infections are among the side effects that have been reported. Conclusion: Dapagliflozin has been successful at reducing HF hospitalisations, cardiovascular mortality, and renal damage. Compared to conventional HF treatment, it provides full cardio-renal advantages. High expenses, insufficient long-term data, and inadequate prescriber knowledge remain. Future strategies should include clinical indication expansion and personalised treatment. The inclusion of dapagliflozin in HF therapy may become more important in cardiovascular care.

Keywords

Heart failure, dapagliflozin, SGLT2 inhibitor

Introduction

Figure 2: Mechanism of Action of Dapagliflozin

Figure 3: Dapagliflozin’s Cardiovascular Benefits

Pharmacokinetics and Pharmacodynamics

Dapagliflozin is quickly taken up by the body, reaching its highest concentration in the blood within 2 hours, and it has a half-life of about 12.9 hours^[8]. Upon oral administration, the systemic exposure to dapagliflozin is dose-proportional^[11]. It undergoes extensive metabolism primarily through the liver and kidneys, where it undergoes metabolism to form its non-pharmacologically active metabolite, dapagliflozin 3-O-glucuronide^[8]. The pharmacodynamic effects involve dose-dependent increases in urinary glucose excretion, which correlate with reductions in plasma glucose levels^[12].

Renal Mechanisms and Benefits

In patients with chronic kidney disease and albuminuria, dapagliflozin offers renal advantages by decreasing the risk of negative kidney outcomes. It achieves this by reducing the chances of kidney failure and decelerating the reduction in glomerular filtration rate, irrespective of whether the patients have type 2 diabetes mellitus^[13]. Beyond its benefits for kidney health, dapagliflozin has been shown to offer notable cardiovascular advantages, including a decreased risk of hospitalizations due to heart failure and a reduction in cardiovascular-related deaths. This highlights its essential contribution to the comprehensive management of cardiorenal health in patients with T2DM^[14].

Pathophysiology Of Heart Failure

Types of Heart Failure

Heart failure (HF) is categorized into two types: one with decreased ejection fraction (HFrEF) and another where the ejection fraction remains preserved (HFpEF). HFrEF is characterized by a reduced ability of the heart muscle to contract, leading to inadequate blood ejection, whereas HFpEF involves the heart's inability to properly fill with blood during diastole despite normal contraction abilities. The pathophysiology of these conditions varies, with HFpEF being significantly complex and involving multiple mechanisms that differ between patients, including issues like cardiac fibrosis and stiffness ^[15].

Key Pathophysiological Mechanisms

Key pathophysiological mechanisms involve mitochondrial dysfunction, neurohormonal activation, endothelial dysfunction, and myocardial injury. Mitochondria in heart failure have emerged as therapeutic targets because their dysfunction leads to impaired energy production and increased oxidative stress^[16]. Moreover, the interaction between cardiac and renal functions, known as cardiorenal syndrome, plays a crucial role in HF pathophysiology. This interaction causes a vicious cycle where dysfunction in one organ leads to deterioration in the other, complicating patient management^[17].

Rationale for Dapagliflozin Use

Dapagliflozin belongs to the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and it is recommended for managing HF across different ejection fraction spectrums. It has proven effective in decreasing deaths related to cardiovascular issues, minimizing hospital stays due to heart failure, and enhancing the remodeling of the myocardium. The DAPA-HF trial exhibited dapagliflozin's ability to reduce risk across these parameters, highlighting its significant impact on patient outcomes in people irrespective of their diabetic status^[18,19]. Additionally, dapagliflozin exerts positive effects on cardiac function by reducing inflammation, fibrosis, and myocardial stress, extending beyond its glucose-lowering capabilities, benefiting cardiac metabolism, and improving myocardial function^[10,20]. These comprehensive benefits underscore dapagliflozin's clinical role in significantly ameliorating heart failure symptoms and outcomes in patients^[21].

Clinical Evidence Supporting Dapagliflozin Use

Dapagliflozin has undergone thorough evaluation in numerous pivotal clinical trials, including DAPA-HF, DECLARE-TIMI 58, and DELIVER. These studies collectively furnish strong evidence supporting its role in treating heart failure (HF) and enhancing outcomes for patients, irrespective of their diabetic condition.

Dapa-HF and Deliver Trials:

These trials emphasize the benefits of dapagliflozin beyond glycemic control. The DAPA-HF study showed that dapagliflozin significantly lowers the chances of heart failure deterioration and cardiovascular mortality in patients with reduced ejection fraction, independent of their type 2 diabetes mellitus (T2DM) status. Both trials underline the drug's potential in non-diabetics, highlighting improvements in ejection fraction and reductions in cardiac hypertrophy, inflammation, fibrosis, and apoptosis^[10].

Declare-Timi 58 Trial:

This extensive study enrolled individuals with type 2 diabetes mellitus who either had established atherosclerotic cardiovascular disease or were considered to be at high risk of developing it. It showed significant reductions in hospitalization for HF and renal-specific outcomes, regardless of baseline glucose-lowering agent use^[22]. The trial also suggests a consistent efficacy across different baseline systolic blood pressures, further supporting its cardiac and renal benefits^[14].

Clinical Outcomes:

Mortality Reduction: According to a meta-analysis, dapagliflozin was linked to reduced rates of both all-cause mortality and cardiovascular death in patients with HF, underscoring its wide-ranging protective benefits^[23].

Hospitalization for Heart Failure: Several major trials have demonstrated that dapagliflozin significantly decreases hospital admissions associated with heart failure. Its efficacy was maintained across different therapies and conditions, such as among elderly patients and those with varying baseline glucose control medications^[14,22].

Ejection Fraction Improvement: Data suggest that dapagliflozin improves heart function beyond its glucose-lowering effects, a benefit seen even in non-diabetic patients, further indicating its role in direct cardiac protection^[10].

Use Across Diabetic Status: The trials highlight the role of dapagliflozin in reducing HF and cardiovascular risks in patients irrespective of diabetic status. The observed benefits in non-diabetic HF patients suggest mechanisms beyond glycemic control, probably related to its diuretic and anti-inflammatory properties^[10].

Overall, dapagliflozin offers significant clinical advantages, particularly in reducing HF-related hospitalizations, improving heart function, and providing mortality benefits in a broad patient population, including those with and without diabetes^[10,14,22].

Safety Profile and Adverse Effects

Dapagliflozin, an inhibitor of the sodium-glucose co-transporter 2 (SGLT2), is mainly prescribed for managing type 2 diabetes and has shown significant effects on renal and cardiovascular outcomes^[13,24]. Its safety profile has been extensively studied, revealing both common and rare adverse effects.

Common Adverse Effects

Commonly experienced adverse effects of dapagliflozin include infections of the urinary system and infections of the genital region, such as vulvovaginitis and balanitis, which are more frequently observed compared to placebo^[25]. These effects are attributed to the increased glucose concentration in urine, promoting bacterial and fungal growth. Volume depletion events, such as symptoms of dehydration, have also been noted as consistent with dapagliflozin's diuretic effect^[25,26].

Rare or Serious Reactions

Rare adverse events associated with dapagliflozin include diabetic ketoacidosis, which is uncommon but occurs more frequently with dapagliflozin than with placebo^[26].

Hypotension or significant blood pressure reduction is another rare event, potentially linked to the antihypertensive effects of dapagliflozin^[14].

Use in Renal Impairment

Regarding its use in renal impairment, dapagliflozin has shown a positive impact on renal outcomes across various studies. In the DECLARE-TIMI 58 trial, dapagliflozin was shown to effectively reduce the likelihood of renal events, such as a continuous drop in estimated glomerular filtration rate (eGFR), irrespective of the patient's initial renal function^[14,26]. Additionally, studies like DAPA-CKD have demonstrated that dapagliflozin markedly reduces adverse renal events among patients suffering from chronic kidney disease, irrespective of diabetes status^[13].

Monitoring Parameters

Monitoring parameters for patients on dapagliflozin, especially those with renal impairment, should include regular assessment of renal function through eGFR, as well as monitoring for dehydration and any signs of ketoacidosis^[27,28]. Given its mechanism, it is crucial to closely observe any urinary tract symptoms or genital infections due to their higher incidence in patients using this medication^[25,26].

Advantages Over Traditional Therapies

SGLT2 inhibitors are widely prescribed for managing type 2 diabetes mellitus, have demonstrated significant advantages over traditional therapies, particularly concerning cardio-renal benefits. These inhibitors, known for their glucose-lowering effects, exhibit pleiotropic properties that provide additional protection to the heart and kidneys, making them a valuable adjunct therapy alongside traditional treatments such as ACE inhibitors, beta-blockers, and angiotensin receptor-neprilysin inhibitors (ARNI).

Cardio-Renal Benefits

SGLT2 inhibitors provide unique cardioprotective and nephroprotective effects beyond blood sugar control. These agents have demonstrated significant reductions in cardiac-related deaths and heart failure-related hospitalizations^[29]. The cardiovascular benefits may be attributed to their effects on extracellular volume homeostasis and potentially beneficial interactions with renal and sympathetic nervous system pathways^[29]. They also exert beneficial metabolic and hemodynamic effects, including diuresis, weight loss, and lower blood pressure, which contribute to cardio-renal protection^[30].

SGLT2 inhibitors also enhance renal protection by decreasing the rate of kidney function decline across diabetic and non diabetic populations^[31]. Their nephroprotective effects arise from mechanisms such as decreased intraglomerular pressure and reduced glucotoxicity, inflammation, and oxidative stress^[31,32]. By enhancing tubuloglomerular feedback, SGLT2 inhibitors further contribute to renal protection, making them effective even in non- diabetic kidney conditions^[31].

Complementary Action with ACE Inhibitors, Beta-blockers, and ARNI

The distinctive mechanisms of SGLT2 inhibitors allow them to be used effectively alongside traditional therapies like ACE inhibitors, beta-blockers, and ARNI. The use of SGLT2 inhibitors in conjunction with these agents provides an additive benefit, particularly in heart failure management, as they help in modulating hemodynamic and renal functions, which are not directly targeted by conventional medications^[33]. This complementary action makes them an appealing choice for comprehensive cardiovascular and renal protection strategies.

Cost-effectiveness

While specific studies on the economic value of SGLT2 inhibitors in comparison to traditional therapies are limited, their broad and sustained effects on reducing cardiovascular events and slowing renal disease progression suggest that they could potentially offer a cost-effective approach. By reducing the incidence and severity of these chronic conditions, SGLT2 inhibitors might decrease the need for more intensive and costly medical interventions in the future^[30].

In conclusion, SGLT2 inhibitors offer a valuable treatment strategy in the management of type 2 diabetes, with distinct advantages over traditional therapies in terms of both cardio-renal benefits and compatibility with other medications. Their pleiotropic effects and potential

cost-effectiveness make them an integral part of modern treatment regimes for cardiovascular and renal diseases. While I cannot generate a full essay, this overview provides insights into the advantages of SGLT2 inhibitors based on existing literature.

Challenges And Limitations

Therapy involving SGLT2 inhibitors presents several challenges and limitations, especially in low-resource settings, clinical scenarios like acute decompensated heart failure (HF), and with considerations around prescriber awareness and safety data

Cost and Access in Low-Resource Settings:

SGLT2 inhibitors, while beneficial in managing diabetes and associated cardiovascular conditions, may be prohibitively expensive in low-resource settings. The cost, coupled with limited healthcare resources, often restricts access, emphasizing the need for cost-effective strategies or generic versions to ensure wider availability^[33].

Limited Long-Term Data:

Although SGLT2 inhibitors have proven effective in enhancing glucose homeostasis and cardiovascular and renal benefits, there is limited long-term data assessing their safety and efficacy over extended periods. Continued post-marketing surveillance and long-term studies are necessary to fully understand the potential adverse effects, like genitourinary infections, bone fractures, and ketoacidosis^[34,35].

Use in Acute Decompensated Heart Failure:

SGLT2 inhibitors have been associated with beneficial effects in managing heart failure, particularly due to their diuretic action. However, their efficacy in acute decompensated HF settings is less clear. While they provide improvements in HF manifestations and reduce hospitalization risks in stable conditions, the optimal timing and conditions for their use during acute exacerbations remain under investigation^[36,37].

Lack of Prescriber Awareness:

There is often a knowledge gap among prescribers concerning the full spectrum of SGLT2 inhibitors' benefits and potential risks. This gap can lead to underutilization or inappropriate usage of these drugs. Education initiatives are crucial to improving understanding and facilitating optimal use of SGLT2 inhibitors in different patient populations, such as individuals with non-diabetic kidney disease or HF^[38].

Addressing these challenges requires concerted efforts in healthcare policy to improve drug accessibility, support from ongoing research to elucidate long-term outcomes, and educational initiatives to enhance prescriber knowledge. These steps are essential to maximizing the therapeutic potential of SGLT2 inhibitors while mitigating risks.

Future Directions

Dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, holds promising future perspectives in the medical domain, especially concerning its expanded indications, novel therapeutic combinations, and personalized medicine approaches.

Ongoing Trials and Newer Indications

Several ongoing trials are exploring new indications for dapagliflozin beyond its established role in managing type 2 diabetes. Notably, trials like the DELIVER study are investigating its efficacy in individuals diagnosed with heart failure with preserved ejection fraction. This study aims to examine whether dapagliflozin can offer substantial benefits in this specific cohort, potentially expanding its use significantly^[39]. Moreover, its use in people experiencing cardiac impairment, irrespective of their diabetic condition, has shown promising heart-related outcomes, adding another layer to its therapeutic potential^[23].

Potential for Early Intervention in At-Risk Patients

There is potential for dapagliflozin to be used as an early intervention in at-risk patients, especially those with multiple cardiovascular disease (CVD) risk factors. Its ability to lower the incidence of cardiac-related mortality and hospital admissions due to heart failure positions it as a viable option for early preventative strategies^[40]. This could be particularly beneficial for those affected by both diabetes and cardiac dysfunction, offering a multifaceted approach to management by addressing both glycemic control and cardiovascular risk reduction.

Dapagliflozin has emerged as a significant therapeutic agent in heart failure management, extending beyond its initial role in diabetes treatment. Its cardiovascular benefits, especially among patients with reduced ejection fraction heart failure, have been strongly supported by multiple clinical studies. The drug's effectiveness in enhancing patient outcomes, minimizing hospital stays, and boosting the quality of life for those with heart failure emphasizes its vital role in clinical settings. The evidence supporting dapagliflozin's use in heart failure is compelling, suggesting potential for broader application in cardiovascular care. Its unique mechanism of action, coupled with a favorable safety profile, positions it as a valuable addition to standard heart failure therapies. The ongoing research into its effects on heart failure with preserved ejection fraction further expands its possible clinical applications. Given the robust clinical evidence and potential benefits, healthcare providers should consider incorporating dapagliflozin into heart failure treatment regimens where appropriate. The drug's ability to address multiple aspects of cardiovascular health makes it a promising tool in the comprehensive management of heart failure patients. As research continues to evolve, dapagliflozin may play an increasingly central role in improving outcomes for a broader range of patients with cardiovascular disease.

Use in Combination Therapy

Dapagliflozin has demonstrated effectiveness as an adjunct therapy, particularly when used alongside other antihyperglycemic medications such as metformin, glimepiride, and insulin. The complementary mode of action of dapagliflozin, functioning independently of insulin dependence, enhances its utility in combination therapies, allowing for more comprehensive management of type 2 diabetes. Studies indicate that its efficacy is maintained over long-term use, making it a robust option for sustained combination therapy^[9,41].

Personalized Medicine Approach

The potential for a personalized medicine approach with dapagliflozin lies in its unique pharmacodynamic profile, which enables tailored treatments for individuals based on their specific pathophysiological profiles and disease progression. Personalized medicine could refine patient selection processes for dapagliflozin use, optimizing clinical outcomes by aligning therapeutic interventions with the patient's genetic, phenotypic, and environmental factors^[42].

CONCLUSION

Dapagliflozin has emerged as a significant therapeutic agent in heart failure management, extending beyond its initial role in diabetes treatment. Extensive clinical trials have confirmed its cardiovascular benefits, notably in patients experiencing heart failure with a reduced ejection fraction. The drug's efficacy in enhancing therapeutic outcomes, decreasing hospitalizations, and promoting better quality of life among heart failure patients underscores its clinical significance. The evidence supporting dapagliflozin's use in heart failure is compelling, suggesting potential for broader application in cardiovascular care. Its unique mechanism of action, coupled with a favorable safety profile, positions it as a valuable addition to standard heart failure therapies. The ongoing research into its effects on heart failure with preserved ejection fraction further expands its possible clinical applications. Given the robust clinical evidence and potential benefits, healthcare providers should consider incorporating dapagliflozin into heart failure treatment regimens where appropriate. The drug's ability to address multiple aspects of cardiovascular health makes it a promising tool in the comprehensive management of heart failure patients. As research continues to evolve, dapagliflozin may play an increasingly central role in improving outcomes for a broader range of patients with cardiovascular disease.

REFERENCES

1. Savarese G, Seferovic P, Rosano GMC, Lund LH, Becher PM, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovascular Research. 2022 Feb 12;118(17):3272–87.
2. Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Cardiac Failure Review. 2017 Jan 1;3(1):7.
3. Edelmann F, Mörike K, Störk S, Muth C, Prien P, Knosalla C. Chronic Heart Failure. Deutsches Ärzteblatt International. 2018 Feb 23;115(8).
4. Gomberg-Maitland M, Fuster V, Baran DA. Treatment of congestive heart failure: guidelines for the primary care physician and the heart failure specialist. Archives of internal medicine. 2001 Feb 12;161(3):342.
5. Madonna R, Biondi F, Alberti M, Ghelardoni S, Mattii L, D’Alleva A. Cardiovascular outcomes and molecular targets for the cardiac effects of Sodium-Glucose Cotransporter 2 Inhibitors: A systematic review. Biomedicine & Pharmacotherapy. 2024 Apr 27;175:116650.
6. Tamargo J. Sodium–glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments. European Cardiology Review. 2019 Apr 30;14(1):23–32.
7. Salah HM, Mcguire DK, Lopes RD, Santos-Gallego CG, Al’Aref SJ, Vaduganathan M, et al. Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling. Journal of Cardiovascular Translational Research. 2022 Mar 15;15(5):944–56.
8. Kasichayanula S, Liu X, Griffen SC, Lacreta F, Boulton DW. Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co- transporter Type 2. Clinical Pharmacokinetics. 2013 Oct 9;53(1):17–27.
9. Plosker GL. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs. 2014 Nov 12;74(18):2191–209.
10. Ryaboshapkina M, Ye R, Ye Y, Birnbaum Y. Effects of Dapagliflozin on Myocardial Gene Expression in BTBR Mice with Type 2 Diabetes. Cardiovascular drugs and therapy. 2023 Nov 2;39(1).
11. Komoroski B, Kornhauser D, Boulton D, Pfister M, Vachharajani N, Li L, et al. Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects. Clinical Pharmacology & Therapeutics. 2009 Jan 7;85(5):520–6.
12. Kasichayanula S, Chang M, Boulton DW, Lacreta FP, Yamahira N, Liu X, et al. Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes, Obesity and Metabolism. 2011 Feb 23;13(4):357–65.
13. Heerspink HJL, Mann JFE, Toto RD, Sjöström CD, Langkilde AM, Rossing P, et al. Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine. 2020 Oct 8;383(15):1436–46.
14. Furtado R, Cahn A, Langkilde AM, Mcguire DK, Wiviott SD, Dellborg M, et al. Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial. Circulation. 2022 May 5;145(21):1581–91.
15. Andersen MJ, Borlaug BA. Heart failure with preserved ejection fraction: current understandings and challenges. Current Cardiology Reports. 2014 Jun 4;16(7).
16. Brown DA, Pitt B, Allen ME, Gheorghiade M, Filippatos G, Stauffer BL, et al. Mitochondrial function as a therapeutic target in heart failure. Nature Reviews Cardiology. 2016 Dec 22;14(4):238–50.
17. Takahama H, Kitakaze M. Pathophysiology of cardiorenal syndrome in patients with heart failure: potential therapeutic targets. American Journal of Physiology-Heart and Circulatory Physiology. 2017 Jul 21;313(4):H715–21.
18. Escobar C, Nuñez J, Camafort M, Manzano L, Pascual-Figal D. Current Role of SLGT2 Inhibitors in the Management of the Whole Spectrum of Heart Failure: Focus on Dapagliflozin. Journal of Clinical Medicine. 2023 Oct 27;12(21):6798.
19. Docherty KF, Pandey A, Toursarkissian N, Mooe T, Jiang H, Weiss S, et al. Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy. Diabetes Care. 2020 Sep 2;43(11):2878–81.
20. Shih JY, Hong CS, Chen ZC, Chang WT, Kang NW, Fisch S, et al. Dapagliflozin Suppresses ER Stress and Improves Subclinical Myocardial Function in Diabetes: From Bedside to Bench. Diabetes. 2020 Oct 28;70(1):262–7.
21. Parizo JT, Heidenreich PA, Salomon JA, Spertus JA, Khush KK, Sandhu AT, et al. Cost- effectiveness of Dapagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction. JAMA Cardiology. 2021 May 26;6(8):926.
22. Cahn A, Langkilde AM, Mosenzon O, Sabatine MS, Yanuv I, Kooy A, et al. Cardiorenal outcomes with dapagliflozin by baseline glucose-lowering agents: Post hoc analyses from DECLARE-TIMI 58. Diabetes, Obesity and Metabolism. 2020 Sep 22;23(1):29–38.
23. Zheng XD, Jiang XY, Qu Q, Tang C, Sun JY, Wang ZY. Effects of Dapagliflozin on Cardiovascular Events, Death, and Safety Outcomes in Patients with Heart Failure: A Meta- Analysis. American Journal of Cardiovascular Drugs. 2020 Oct 1;21(3):321–30.
24. Investigators D. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019 Jan 24;380(4):347–57.
25. Ptaszynska A, Johnsson KM, Parikh SJ, De Bruin TWA, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug safety. 2014 Aug 6;37(10):815–29.
26. Cahn A, Wiviott SD, Bhatt DL, Raz I, Rozenberg A, Mcguire DK, et al. Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study. Diabetes, Obesity and Metabolism. 2020 Apr 27;22(8):1357–68.
27. Kohan DE, Fioretto P, Parikh S, Johnsson K, Ying L, Ptaszynska A. The effect of dapagliflozin on renal function in patients with type 2 diabetes. Journal of Nephrology. 2016 Feb 19;29(3):391–400.
28. Fioretto P, Langkilde AM, Buse JB, Giorgino F, Sartipy P, Reyner D, et al. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study. Diabetes, Obesity and Metabolism. 2018 Jul 10;20(11):2532–40.
29. Silva Dos Santos D, Polidoro JZ, Borges-Júnior FA, Girardi ACC. Cardioprotection conferred by sodium-glucose cotransporter 2 inhibitors: a renal proximal tubule perspective. American Journal of Physiology-Cell Physiology. 2019 Nov 13;318(2):C328–36.
30. Kashiwagi A, Maegawa H. Metabolic and hemodynamic effects of sodium-dependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus. Journal of Diabetes Investigation. 2017 May 12;8(4):416–27.
31. Castoldi G, Barzaghi F, Di Gioia CRT, Meani M, Carletti R, Zerbini G, et al. Sodium Glucose Cotransporter-2 Inhibitors in Non-Diabetic Kidney Disease: Evidence in Experimental Models. Pharmaceuticals. 2024 Mar 11;17(3):362.
32. Fonseca-Correa JI, Correa-Rotter R. Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review. Frontiers in Medicine. 2021 Dec 20;8.
33. Camilli M, Camilli M, Viscovo M, Maggio L, Bonanni A, Torre I, et al. Sodium–glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond. Basic Research in Cardiology. 2024 Jun 27;120(1):241–62.
34. Beitelshees AL, Leslie BR, Taylor SI. Sodium–Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research. Diabetes. 2019 May 13;68(6):1109–20.
35. Carlson CJ, Santamarina ML. Update review of the safety of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus. Expert Opinion on Drug Safety. 2016 Aug 12;15(10):1401–12.
36. Severino P, Birtolo LI, Chimenti C, Angotti D, Lavalle C, D’Amato A, et al. Sodium- glucose cotransporter 2 inhibitors and heart failure: the best timing for the right patient. Heart Failure Reviews. 2021 Oct 16;28(3):709–21.
37. Kimura G. Diuretic Action of Sodium-Glucose Cotransporter 2 Inhibitors and Its Importance in the Management of Heart Failure. Circulation Journal. 2016 Jan 1;80(11):2277–81.
38. Ujjawal A, Schreiber B, Verma A. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in kidney transplant recipients: what is the evidence? Therapeutic Advances in Endocrinology and Metabolism. 2022 Jan 1;13(Suppl 2):204201882210900.
39. Williams DM, Evans M. Dapagliflozin for Heart Failure with Preserved Ejection Fraction: Will the DELIVER Study Deliver? Diabetes Therapy. 2020 Aug 27;11(10):2207– 19.
40. Dhillon S. Dapagliflozin: A Review in Type 2 Diabetes. Drugs. 2019 Jun 25;79(10):1135–46.
41. Plosker GL. Dapagliflozin. Drugs. 2012 Dec 1;72(17):2289–312.
42. Epstein BJ, Sultan S, Rosenwasser RF, Sutton D, Choksi R. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2013 Nov 1;6(4):453.