Nephrologists meet the crossroads of diabetes, CVD and CKD with new treatment approaches
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Diabetic kidney disease is the leading cause of ESKD worldwide,1 but the only guideline-based therapy for renoprotection in the past 2 decades was the blockade of the renin-angiotensin-aldosterone-system.2
The evidence base for this guidance was provided by two landmark trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in Non-insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial, both published in 2001.3,4 These landmark trials showed that among patients with overt diabetic kidney disease (DKD) compared with placebo (in RENAAL) or active-treatment (a dihydropyridine calcium channel blocker or placebo in IDNT), treatment with an angiotensin II receptor blocker provoked a greater than 20% reduction in the composite outcome of doubling of serum creatinine, ESKD or death.3,4
This benefit in kidney outcomes was paralleled with a greater than 20% to 30% reduction in the risk of hospitalization for heart failure (HF).3,4 Thus, a therapy that protected the kidney also appeared to protect the heart. It has to be noted, however, that despite the optimal management of DKD with the available therapeutic approaches, including the use of renin-angiotensin-aldosterone-system (RAAS)-blockade and BP control, these patients continued to progress to ESKD. Thus, a substantial residual risk of kidney and cardiovascular morbidity and mortality remained. An unmet need to improve outcomes in these patients persisted.
SGLT-2 inhibitors: A new option
The sodium-glucose co-transporter type-2 (SGLT-2) inhibitors represent a novel class of drugs that were originally developed to improve glycemic control in patients with type 2 diabetes.5 As is required by the FDA, each of the drugs developed for glycemic controls have to demonstrate cardiovascular safety. Accordingly, three large randomized trials — the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients,6 the Canagliflozin Cardiovascular Assessment Study7 and the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 — were designed to test the cardiovascular safety of these compounds (see Table). Each of these trials unambiguously demonstrated SGLT-2 inhibitors are noninferior to placebo,8 but two of the trials unexpectedly showed canagliflozin and empagliflozin are superior to placebo in lowering the primary composite outcome of cardiovascular death, nonfatal myocardial infarction (MI) or nonfatal stroke.6,7 In fact, SGLT-2 inhibitors did not only improve the risk of atherosclerotic cardiovascular events, but provoked an impressive reduction in the risk of HF hospitalization.
Secondary or exploratory analyses of these trials showed SGLT-2 inhibition may be beneficial in retarding the progression of kidney injury to ESKD. In a meta-analysis incorporating data from 34,322 participants in these 3 trials, Zelniker and colleagues9 showed SGLT-2 inhibitors improve the composite outcome of cardiovascular death, nonfatal MI or nonfatal stroke in those with established atherosclerotic cardiovascular disease. By contrast, in the absence of established atherosclerotic cardiovascular disease at baseline, no cardiovascular protection was seen.9
CREDENCE trial offers evidence
As the above-described trials were only designed to test cardiovascular safety outcomes as the primary endpoint, more conclusive evidence on whether SGLT-2 inhibitors are effective in retarding the progression of DKD was provided by the CREDENCE trial, a study was performed to specifically demonstrate kidney protection in patients with DKD.10 This trial randomized 4,401 patients with type 2 diabetes with overt nephropathy [defined as urinary-albumin-to-creatinine-ratio greater than 300 mg/g to 5000 mg/g and estimated glomerular filtration rate (eGFR) ranging from 30 mL/min/1.73 m2 to 90 mL/min/1.73 m2] to receive canagliflozin (100 mg/dL) or placebo on top of “optimal” background treatment with a RAAS-blocker. CREDENCE was prematurely terminated at a median follow-up of 2.62 years because of a 30% reduction in the occurrence of the primary kidney outcome, which was doubling of serum creatinine and ESKD of death from cardiovascular or renal causes with canagliflozin.10 Compared with placebo, canagliflozin also lowered by 20% the risk of cardiovascular death, nonfatal MI or nonfatal stroke and improved by 39% the risk of hospitalization for HF.10 A therapy that was protective for the kidney was also protective for the heart.
In contrast with the aforementioned meta-analysis by Zelniker and colleagues,9 a post-hoc analysis of the CREDENCE trial showed the absence of interaction between the randomized arm and history of established cardiovascular disease at baseline for the composite outcome of cardiovascular death, nonfatal MI or nonfatal stroke (P value for the interaction: .25).11 The cardiorenal protection afforded by canagliflozin was similar in those with and in those without established cardiovascular disease at baseline,11 but this discrepancy with the earlier meta-analysis should be carefully interpreted. Compared to those with established cardiovascular disease, participants in the primary prevention stratum of CREDENCE were younger, were more commonly women and had a shorter clinical course of diabetes.11 However, the co-existence of diabetes with albuminuria and/or impaired kidney function magnifies their overall cardiovascular risk.12 Thus, the overall cardiovascular risk profile of participants stratified in the primary prevention subgroup of CREDENCE might not be substantially different from that of participants with established cardiovascular disease, providing a plausible explanation for the uniform cardiorenal protection with canagliflozin in the CREDENCE trial.
The mechanisms mediating these impressive benefits of SGLT-2 inhibitors on cardiovascular and kidney outcomes remain an area of uncertainty. For example, in CREDENCE,10 the average between-group difference in the reduction of glycated hemoglobin A1c during follow-up was only 0.25% [95% CI: 0.20% to 0.31%]. This implies that this modest hypoglycemic action is a less likely mechanistic explanation for the cardiorenal protection afforded by canagliflozin in this trial. Similarly, compared with placebo, canagliflozin provoked an average reduction of 3.3 mmHg (95% CI: 2.73-3.87) in systolic BP and an average reduction of 0.95 mmHg (95% CI: 0.61-1.28) in diastolic BP.10 This modest BP-lowering effect of canagliflozin in CREDENCE is in accordance with the results of a meta-analysis of seven randomized trials with 2,381 patients with diabetes who quantified the effect of SGLT-2 inhibitors on ambulatory BP.13 The average placebo-subtracted reduction was -3.62 mmHg (95% CI: -4.29, -2.94) for 24-hour ambulatory systolic BP and -1.70 mmHg (95% CI: -2.13, -1.26) for 24-hour diastolic BP.
In addition, this meta-analysis showed the ambulatory BP reduction provoked by SGLT-2 inhibitors was comparable with that of low-dose hydrochlorothiazide.13 If these two drug categories are equally effective in lowering ambulatory BP, then BP-lowering per se cannot be the prominent mechanism mediating the cardio- and renoprotective actions of SGLT-2 inhibitors that were demonstrated in CREDENCE10 and in earlier cardiovascular safety trials.6-8 Whether these benefits are mediated through improvement in intra-renal hemodynamics (ie, reduction in intra-glomerular pressure)14 or through other mechanisms remains to be elucidated in future studies.
SGLT-2 inhibitor adverse events
With respect to adverse events, SGLT-2 inhibitor use has been associated with higher risk of genital fungal infections. Euglycemic diabetic ketoacidosis is another rare adverse event but the exact pathogenic mechanism through which SGLT-2 inhibitors can produce elevation in circulating ketone levels is not yet fully clear.15 Safety concerns for higher risk of bone fractures and lower extremity amputations have been raised for canagliflozin. In CANVAS, the event-rate of amputations during the course of the trial was 1.97-fold higher in canagliflozin-treated than in placebo-treated participants.7
By contrast, the rates of fracture and lower limb amputation did not differ between the canagliflozin and placebo groups in CREDENCE.10 Whether this inconsistency is a matter of chance or is attributable to variant risk profiles of the populations studied in these two trials remains unknown.
In conclusion, for almost 2 decades, RAAS-blockade was the only guideline-based therapeutic approach to retard the progression of kidney injury in patients with DKD. RAAS-blockers had been originally developed as BP-lowering medications, but the results of the IDNT and RENAAL trials provided the scientific basis to use these agents for cardiorenal protection.
The story appears to be recapitulated with the SGLT-2 inhibitors. These agents were produced to improve glycemic control by provoking glycosuria, but with eGFR decline the hypoglycemic action of SGLT-2 inhibitors is progressively diminished. Based on the results of the CREDENCE trial, the 2019 American Diabetes Association guideline16 reappraised its recommendation for the use of these agents. SGLT-2 inhibitors are now recommended in patients with type 2 diabetes and with an eGFR greater than or equal to 30 mL/min/1.73m2, particularly in the presence of albuminuria greater than 300 mg/g, with an indication distinct from that of glucose-lowering. The indication for use is to halt the progression of DKD and reduce the risk of cardiovascular morbidity and mortality.16 Ongoing trials are evaluating the potential benefit of SGLT-2 inhibitors in patients with non-diabetic kidney disease and at least one trial — the DAPA-HF — shows cardiovascular benefits among patients with heart failure, regardless of diabetes.
Given the cardiovascular and kidney protection afforded by SGLT-2 inhibitors, these drugs will be used by internists, cardiologists and nephrologists. These drugs are no longer diabetes drugs alone and nephrologists must be familiar with this class to assure protection for the heart and the kidneys in those with DKD. The benefit to patients is clear – slowing the progression of renal failure.
- References:
- Liyanage T, et al. Lancet. 2015;doi:10.1016/S0140-6736(14)61601-9.
- Wheeler DC, et al. Kidney Int. 2013;doi:10.1038/ki.2012.425.
- Brenner BM, et al. N Engl J Med. 2001;doi:10.1056/NEJMoa011161.
- Lewis EJ, et al. N Engl J Med. 2001;doi:10.1056/NEJMoa011303.
- Perkovic V, et al. Kidney Int. 2016;doi:10.1016/j.kint.2016.09.010.
- Zinman B, et al. N Engl J Med.2015;doi:10.1056/NEJMoa1504720.
- Neal B, et al. N Engl J Med.2017;doi:10.1056/NEJMoa1611925.
- Wiviott SD, et al. N Engl J Med.2019;doi:10.1056/NEJMoa1812389.
- Zelniker TA, et al. Lancet. 2019;doi:10.1016/S0140-6736(18)32590-X.
- Perkovic V, et al. N Engl J Med.2019;doi:10.1056/NEJMoa1811744.
- Mahaffey KW, et al. Circulation.2019;doi:10.1161/CIRCULATIONAHA.119.042007.
- Debella YT, et al. Clin J Am Soc Nephrol.2011;6:1385-1392.
- Georgianos PI, et al. Diabetes Care.2019;doi:10.2337/dc18-2207.
- Cherney DZ, et al.Circulation.2014;doi:10.1161/CIRCULATIONAHA.113.005081.
- Alicic RZ, et al. Am J Kidney Dis. 2018;doi:10.1053/j.ajkd.2018.03.022.
- Microvascular complications and foot care: Standards of medical care in diabetes. Diabetes Care. 2019;42:S124-S138.
- For more information:
- Panagiotis I. Georgianos, MD, PhD, is with the Section of Nephrology and Hypertension, First Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
- Rajiv Agarwal, MD, MS, is with the Division of Nephrology, Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center in Indianapolis, Indiana.
Disclosures: Agarwal reports he is a member of the data safety monitoring committees for Astra Zeneca and Ironwood Pharmaceuticals; is a member of steering committees of randomized trials conducted by Akebia Therapeutics, Bayer, Janssen, GlaxoSmithKline, Relypsa, Sanofi and Genzyme US; is a member of adjudication committees for Bayer, Boehringer Ingelheim and Janssen; is a member of scientific advisory boards or a consultant for Celgene, Daiichi Sankyo Inc, Eli Lilly, Relypsa, Reata, Takeda Pharmaceuticals USA and ZS Pharma; and receives financial support from the NIH (5 R01 HL126903-04) and a grant from VA Merit Review (I01CX001753). Georgianos reports no relevant financial disclosures.
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