SGLT2 Inhibitors and CKD in 2021

AUTHOR:
James Matera, DO
Practicing Nephrologist, Senior Vice President for Medical Affairs, and Chief Medical Officer
CentraState Medical Center, Freehold, New Jersey

CITATION:
Matera J. SGLT2 inhibitors and CKD in 2021. Consultant360. Published online May 25, 2021.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been the recent focus in a multitude of clinical situations, including not only type 2 diabetes but also congestive heart failure and chronic kidney disease (CKD). The positive studies that have been published, starting with the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study, have elevated these agents to the forefront of many clinicians’ treatment protocols. Not since the advent of renin-angiotension-aldosterone system (RAAS) agents has there been so much excitement about the benefit of a class of agents used to treat CKD.

Type 2 diabetes and CKD often occur together and because of this, lead to a high risk for morbidity and mortality. In the United States, 34.2 million adults (10.5% of the population) are estimated to have diabetes, but more than 7 million may not even be aware they have this diagnosis.¹ Type 2 diabetes accounts for the vast majority of cases that we see in the United States and carries significant morbidity as well. There have been multiple trials with SGLT2 inhibitors including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.

The first landmark trial that highlights the power of these agents was the CREDENCE trial.² It was a double-blind, randomized trial where patients were assigned to a placebo arm vs oral canagliflozin, 100 mg, twice daily. Patients with advanced CKD (estimated glomerular filtration rate [eGFR], < 30 ml/min) were excluded, but all patients had proteinuria (> 300 mg/g) and were receiving RAAS blockage. The primary outcome was progression to end-stage kidney disease (dialysis, transplantation, or eGFR of < 15 ml/min), doubling of the creatinine level from baseline, or death from renal or cardiovascular causes. The mean follow-up lasted up to 2.5 years.²

The CREDENCE trial was stopped early because of noted marked positive results. The risk of the primary outcomes were 30% lower in the canagliflozin group compared with the placebo group, which was exciting news. In regard to the renal-specific outcomes studied, they were lowered by 34%. The canagliflozin group also had a lower risk of cardiovascular death and hospitalization rates for heart failure, leading to a subset of investigations on the effects on cardiovascular disease and heart failure.²

This was game-changing news, but the mechanism of action was not well-known at the time. The renal benefits of SGLT2 inhibitors are independent of glycemic control, as the glucose-lowering effects are only modest, when eGFR is less than 45 ml/min.³ In the CREDENCE trial, however, the renal results were significant and notable. The renal protection mechanisms are not well-known, and various targets for research have been proposed, including:

• Positive effects on renal hemodynamics
• Tubular workload and hypoxemia
• Potential diuresis effects
• Reduction of inflammation and fibrosis⁴
   

And there was more good news! Since CREDENCE, a series of large clinical trials evaluating the effects on CKD and cardiovascular outcomes have been published. In addition to the CREDENCE trial, several others have looked at SGLT2 agents such as Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD), Empagliflozin Outcome Trial in Patients With Chronic Heart Failure (EMPEROR-Reduced), and Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS CV) Trials.⁵ A recent meta-analysis of these trials reached the following conclusions:

• SGLT2 inhibitors vs placebo significantly reduced the risk of acute kidney injury and showed the reduced trend in the risk of severe hypoglycemia, regardless of type of chronic diseases and type of SGLT2 inhibitor, thus deeming more of a “class” effect.
• SGLT2 inhibitors vs placebo significantly increased the risks of diabetic ketoacidosis and genital infection, as well as a tendency toward dehydration, which were all known adverse effects of the class.⁵
   

I think the DAPA-CKD trial is also worth mentioning here. In this trial, more than 4000 patients with an eGFR between 25 and 75 ml/min and greater than 200 mg/g of albuminuria were assigned to the placebo arm or oral dapagliflozin, 10 mg, twice daily. The primary renal outcome was a decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.⁶ This trial was also stopped early because of significant efficacy noted in the dapagliflozin arm. During a mean follow-up of 2.4 years,  9.2% of patients in the dapagliflozin group and 14.5% of patients in the placebo group had a primary outcome event.⁶  Adverse events rates were similar in both groups. Fournier gangrene had occurred in one patient in the placebo group, and none in the treatment arm. 

In addition to the renal benefits, congestive heart failure or heart failure with reduced ejection fraction (HFrEF) benefits have been postulated. This centers around a potential diuresis effect seen with SGLT2 agents, making them attractive in patients where fluid retention is a major comorbid condition.⁷ In the EMPEROR-reduced trial, Packer and colleagues⁸ found that diuresis was not a primary factor leading to clinical benefits of SGLT2 inhibitors in these patients.⁸ In the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF) study, empagliflozin did improve secondary outcomes of deteriorations in heart failure while hospitalized, readmission for heart failure, or death within 60 days.⁹

With all of this promising evidence, are we using SGLT2 inhibitors appropriately? And if not, why not?  As we have discussed, multiple studies have shown significant reductions in death from cardiovascular causes, lower rates of hospitalization for heart failure, and reduced progression of CKD.¹⁰ Assessing the benefits of SGLT2 inhibitors, has led the American Diabetes Association and the American College of Cardiology to recommend their use for patients with diabetes who have or are at high risk for cardiovascular disease, CKD, or heart failure despite overall glycemic control and HbA1c levels.¹¹ 

Racial disparities in health care have become more evident—partly brought on by the COVID-19 pandemic where it is estimated that excess all-cause mortality during the early pandemic was 6.8 per 10,000 for Black patients, 4.3 for Hispanic patients, 2.7 for Asian patients, and 1.5 for White patients.¹² A recent article published in JAMA highlighted disparity as a potential cause for the lack of capture among practitioners when choosing agents like SGLT2 inhibitors. Black patients with type 2 diabetes have more problems with cardiovascular and advanced kidney disease. Mortality rates from cardiovascular disease are highest among Black patients in the United States.¹³

When it comes to choosing new therapies among Black patients, women, and those with low socioeconomic status, there are often discrepancies with adopting therapies in these subgroups.¹⁴ A recent article published in JAMA pointed out these differences related to the use of SGLT2 inhibitors based on social determinants of health. As far as use of SGLT2 inhibitors, of more than 900,000 patients, 81,000 received an SGLT2 inhibitor during the study period. Between 2015 and 2019, the percentage of patients with type 2 diabetes receiving an SGLT2 inhibitor increased from 3.8% to 11.9%, which may be related to the positive studies discussed earlier, like CREDENCE and DAPA-CKD. Interestingly, higher-risk subgroups like Black race, Asian race, and women sex had lower rates of SGLT2 inhibitor use. This finding occurred among patients with other comorbidities including HFrEF, atherosclerotic cardiovascular disease, and CKD.¹⁵ The need to bridge the gap of social, economic, and racial inequalities in delivering medical care is a paramount task for us medical professionals as we climb out from under the COVID-19 crisis.

When we look at all of the trials surrounding the use of these agents, some salient points rise to the top. SGLT2 inhibitors can lower all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, and renal related outcomes. SGLT2 inhibitors can also reduce mortality and admission to the hospital for heart failure, as well as readmission for HFrEF. Adverse effects include genital infection and dehydration. The absolute benefit of using these agents varies; however, SGLT2 inhibitors can reduce cardiovascular and renal outcomes, with notable differences in benefits and harms.¹⁶

SGLT2 Inhibitors are an important weapon in our arsenal against not only type 2 diabetes, but also the conditions that we encounter that go hand-in-hand, including CKD and cardiovascular disease. We must continue to follow these studies as we discern improvements in renal disease, heart failure, and overall cardiovascular mortality and be proactive in closing the gaps in racial and ethnic roadblocks as we find them.

References:

1. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention. Updated August 28, 2020. Accessed May 24, 2021. https://www.cdc.gov/diabetes/data/statistics-report/index.html

2. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE trial investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New Eng J Med. 2019;380(24):2295-2306. https://doi.org/10.1056/nejmoa1811744

3. Cannon CP, Perkovic V, Agarwal R, et al. Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbvA1c <7%: results from the CREDENCE trial. Circulation. 2020;141(5):407-410. https://doi.org/10.1161/circulationaha.119.044359

4. Tuttle KR, Brosius FC 3rd, Cavender MA, et al. SGLT2 inhibition for chronic kidney disease and cardiovascular disease in type 2 diabetes: report of scientific workshop sponsored by the National Kidney Foundation. Am J Kidney Dis. 2021;77(1):94-109. https://doi.org/10.1053/j.ajkd.2020.08.003

5. Qiu Mei, Ding LL, Zhang M, Zhou HR. Safety of four SGLT2 inhibitors in three chronic diseases: a meta-analysis of large randomized controlled trials of SGLT2 inhibitors. Diab Vasc Dis Res. 2021;18(2): 14791641211011016. https://doi.org/10.1177/14791641211011016

6. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. New Engl J Med. 2020;383(15):1436-1446. https://doi.org/10.1056/nejmoa2024816

7. Ohara K, Masuda T, Morinari M, et al. The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease. Diabetol Metab Syndr. 2020;12:37. https://doi.org/10.1186/s13098-020-00545-z

8. Packer M, Anker SD, Butler J, et al; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in patients with heart failure, reduced ejection fraction, and volume overload: EMPEROR-Reduced Trial. J Am Coll Cardiol. 2021;77(11):1381-1392. https://doi.org/10.1016/j.jacc.2021.01.033

9. Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020;22(4):713-722. https://doi.org/10.1002/ejhf.1713

10. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New Engl J Med. 2017;377(7)644-657. https://doi.org/10.1056/nejmoa1611925

11. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(9):1117-1145. https://doi.org/10.1016/j.jacc.2020.05.037

12. Polyakova M, Udalova V, Kocks G, Genadek K, Finlay K, Finkelstein AN. Racial disparities in excess all-cause mortality during the early COVID-19 pandemic varied substantially across states. Health Aff (Millwood). 2021;40(2):307-316. https://doi.org/10.1377/hlthaff.2020.02142

13. Nadruz W Jr, Claggett B, Henglin M, et al. Widening racial differences in risks for coronary heart disease. Circulation. 2018;137(11)1195-1197. https://doi.org/10.1161/circulationaha.117.030564

14. Nathan AS, Geng Z, Dayoub EJ, et al. Racial, ethnic, and socioeconomic inequities in the prescription of direct oral anticoagulants in patients with venous thromboembolism in the United States. Circ Cardiovasc Qual Outcomes. 2019;12(4):e005600. https://doi.org/10.1161/circoutcomes.119.005600

15. Eberly LA, Yang L, Eneanya ND, et al. Association of race/ethnicity, gender, and socioeconomic status with sodium-glucose cotransporter 2 inhibitor use among patients with diabetes in the US. JAMA Netw Open. 2021;4(4):e216139. https://doi.org/10.1001/jamanetworkopen.2021.6139

16. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2021;372:m4573. https://doi.org/10.1136/bmj.m4573