"A new day has dawned for diabetes". This quote, or one very similar, has reverberated extensively in journal articles and social media in recent times. This stems from the published results of a remarkable series of trials demonstrating a renoprotective (and cardioprotective) action of sodium-glucose co-transporter-2 (SGLT-2) inhibitors in subjects with type 2 diabetes with or without established chronic kidney disease (CKD).^1-3 The first hint of this effect came with the report of the EMPA-REG-OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study in 2016, using empagliflozin.¹ Dramatic confirmation of this effect with canagliflozin was provided by the CANVAS (CANagliflozin cardioVascular Assessment Study)² and CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy)³ randomized trials. Now we have additional evidence of a renoprotective action of dapagliflozin by the DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events)⁴ randomized trial, strongly suggesting that this is a class effect of the SGLT-2 inhibitors.

The DECLARE-TIMI 58 randomized trial involved 17,160 patients with type 2 diabetes with (41%) or without (59%) established atherosclerotic cardiovascular disease (ASCVD) allocated 1:1 to dapagliflozin (10mg daily) or a placebo. At randomization 83% of the subjects had an eGFR-creatinine of >60ml/min/1.73m², but 23.5% and 6.8 % had moderate to severe albuminuria, respectively. Hemoglobin A1c levels varied but were generally above 8%. Importantly, blood pressure was well controlled at baseline and about 85% of patients were receiving renin-angiotensin-aldosterone system inhibitor therapy at baseline. Pre-specified secondary composite and renal specific end points were examined. The renal specific outcome examined was a sustained 40% of more decline in eGFR-creatinine to a value less than 60ml/min/1.73m² or end-stage kidney disease (ESKD) (requirement for dialysis, kidney transplantation or an eGFR-creatinine of <15ml/min/1.73m²) or death from renal causes. The other end points of the study were cardiovascular in nature and have been reported separately.⁵ The median follow-up was 4.2 years.

The study identified a 46% reduction in the sustained decline of estimated glomerular filtration rate (eGFR) creatinine with dapagliflozin compared to placebo and a small, but significant, reduction in ESKD or renal death rates, from 0.3% to 0.1%. The beneficial effect of dapagliflozin on renal end points were consistently seen in various pre-specified subgroups, including those with established ASCVD. As reported separately, the composite cardiovascular disease (CVD) outcomes examined were also improved in the dapagliflozin treated subjects,⁵ although cardiovascular death rates were not different between the placebo and dapagliflozin groups. As has been seen in other trials of SGLT-2 inhibitors, an early exaggerated decline in eGFR-creatinine as observed in the dapagliflozin group, at least in those subjects with a baseline eGFR creatinine of >60ml/min/1.73m², but after 6-month the rate of decline in eGFR creatinine was significantly slower in the dapagliflozin group compared to placebo. Interaction analysis suggested that the effects of dapagliflozin on renal outcomes may have been greater in subjects not taking diuretics at baseline, but not with lower eGFR creatinine or higher albuminuria at baseline. Lack of renin-angiotensin system inhibitor use at baselines might have attenuated the beneficial effects of dapagliflozin, but this requires further study.

These trial results, although based on pre-specified secondary outcomes, are robust enough to be generally compatible with the emerging view that SGLT-2 inhibitors represent a new and effective way to delay progression of diabetic kidney disease in patients with type 2 diabetes, with or without established ASCVD or CKD. These beneficial effects were seen independent of baseline eGFR or albuminuria, but because so few subjects randomized had moderately severe reduction in eGFR creatinine at baseline (only 7.4% had an eGFR creatinine of <60ml/min/1.73m²) we cannot determine the lower eGFR limit of assured efficacy. The DECLARE-TIMI 58 trial did not examine the end point of a sustained decline in albuminuria, which has been proposed as a potential surrogate for "hard" eGFR/ESKD based outcome. Nevertheless, the DECLARE-TIMI 58 trial adds substantially to our knowledge of the effects of SGLT-2 inhibition when employed early in the course of type 2 diabetic kidney disease. The role of better glycemic and/or blood pressure control in the observed benefits of SGLT-2 inhibitors is not well understood, but based on the composite results of all trials, do not seem sufficient themselves to explain the substantial reno-protection observed. Various theories have been expounded to explain the effects upon modulation of afferent and efferent renal resistance such that intra-glomerular pressure is lowered by SGLT-2 inhibitors, by a tubuloglomerular feedback loop or other hemodynamic effects that modulate afferent glomerular resistance.⁶

Side effects of SGLT-2 inhibitors, such as non-hyperglycemic metabolic acidosis, serious perineal infections, amputations and acute kidney injury (AKI) remain of concern, but in the DECLARE-TIMI 58 trial the occurrence of AKI was actually reduced in the dapagliflozin arm. Other side effects or adverse events were not specifically analyzed in the DECLARE-TIMI 58 trial report analyzed here, but in general these adverse events are uncommon.⁷

The analysis results of the DECLARE-TIMI 58 trial provide support to the more widespread use of dapagliflozin and other SGLT-2 inhibitors in the management of type 2 diabetes, perhaps in conjunction with GLP-1 receptor antagonists.⁸ Since most of the trials of SGLT-2 inhibitors, including DECLARE-TIMI 58, used the SGLT-2 inhibitor as an add on to inhibitors of the renin-angiotensin-aldosterone system, we do not yet fully understand the benefits (and risks) of SGLT-2 monotherapy in type 2 diabetes. Since prior trials of type 2 diabetic kidney disease with overt proteinuria conducted almost 2 decades earlier, such as RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan),⁹ have clearly established the renal and cardiovascular benefits of renin-angiotensin inhibitors, it is likely that combined therapy will be the standard-of-care going forward. Trials of SGLT2 inhibitors in non-diabetic progressive kidney disease are in progress (DAPA- CKD, A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin).⁸ The evolution of the SGLT-2 class of agents from a primarily anti-hyperglycemia therapeutic to cardiorenal protective agents has been rapid with far-reaching consequences. The DECLARE-TIMI 58 trial has been an important part of this evolution.

References

1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-34
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57
3. Perkovic V, Jardine MJ, Neal B, et. al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
4. Mosenzon O, Wiviott SD, Cahn A, et. al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019;7:606-17
5. Wiviott SD, Raz I, Bonaca MP, et. al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57
6. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016;39 Suppl 2:S165-71.
7. Dhillon S. Dapagliflozin: a review in type 2 diabetes. Drugs 2019;79:1135-46.
8. Wanner C, Brenner S. CREDENCE and DELIGHT deliver on renal benefits. Nat Rev Nephrol 2019;15:459-460
9. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861-69.

Keywords: Diabetes Mellitus, Diabetes Mellitus, Type 2, Kidney Diseases, Diabetic Nephropathies, Hemoglobin A, Renin-Angiotensin System, Albuminuria, Creatinine, Losartan, Angiotensin II, Renin, Blood Pressure, Glomerular Filtration Rate, Kidney Transplantation, Diuretics, Follow-Up Studies, Standard of Care, Renal Dialysis, Glucosides, Benzhydryl Compounds, Blood Glucose, Kidney Failure, Chronic, Renal Insufficiency, Chronic, Acute Kidney Injury, Hyperglycemia, Cardiovascular Diseases, Protective Agents, Risk Assessment, Metabolic Syndrome

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