Dapagliflozin effects on chronic kidney disease in type 2 diabetes analysis of the declare-timi 58 randomized trial – american bacterial yeast infection college of cardiology

"A new day has dawned for diabetes". This quote, or one very similar, has reverberated extensively in journal articles and social media in bacterial yeast infection recent times. This stems from the published results of a remarkable series bacterial yeast infection 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 bacterial yeast infection established chronic kidney disease (CKD). 1-3 the first hint of this effect came with the bacterial yeast infection report of the EMPA-REG-OUTCOME (empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus bacterial yeast infection patients) study in 2016, using empagliflozin. 1 dramatic confirmation of this effect with canagliflozin was provided bacterial yeast infection by the CANVAS (canagliflozin cardiovascular assessment study) 2 and CREDENCE (evaluation of the effects of canagliflozin on renal and cardiovascular bacterial yeast infection outcomes in participants with diabetic nephropathy) 3 randomized trials. Now we have additional evidence of a renoprotective action of bacterial yeast infection dapagliflozin by the DECLARE-TIMI 58 (multicenter trial to evaluate the effect of dapagliflozin on the bacterial yeast infection incidence of cardiovascular events) 4 randomized trial, strongly suggesting that this is a class effect of the bacterial yeast infection 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/1.73m 2, 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/1.73m 2 or end-stage kidney disease (ESKD) (requirement for dialysis, kidney transplantation or an egfr-creatinine of 60ml/min/1.73m 2, but after 6-month the rate of decline in egfr creatinine was significantly bacterial yeast infection slower in the dapagliflozin group compared to placebo. Interaction analysis suggested that the effects of dapagliflozin on renal bacterial yeast infection outcomes may have been greater in subjects not taking diuretics bacterial yeast infection at baseline, but not with lower egfr creatinine or higher albuminuria at bacterial yeast infection baseline. Lack of renin-angiotensin system inhibitor use at baselines might have attenuated the bacterial yeast infection 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 bacterial yeast infection view that SGLT-2 inhibitors represent a new and effective way to delay bacterial yeast infection progression of diabetic kidney disease in patients with type 2 bacterial yeast infection diabetes, with or without established ASCVD or CKD. These beneficial effects were seen independent of baseline egfr or bacterial yeast infection albuminuria, but because so few subjects randomized had moderately severe reduction bacterial yeast infection in egfr creatinine at baseline (only 7.4% had an egfr creatinine of <60ml/min/1.73m 2) we cannot determine the lower egfr limit of assured efficacy. The DECLARE-TIMI 58 trial did not examine the end point of bacterial yeast infection 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 bacterial yeast infection effects of SGLT-2 inhibition when employed early in the course of type bacterial yeast infection 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 bacterial yeast infection 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 bacterial yeast infection 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 bacterial yeast infection in the dapagliflozin arm. Other side effects or adverse events were not specifically analyzed bacterial yeast infection 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 bacterial yeast infection 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 bacterial yeast infection 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 bacterial yeast infection overt proteinuria conducted almost 2 decades earlier, such as RENAAL (reduction of endpoints in NIDDM with the angiotensin II antagonist bacterial yeast infection losartan), 9 have clearly established the renal and cardiovascular benefits of bacterial yeast infection 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 bacterial yeast infection 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 bacterial yeast infection far-reaching consequences. The DECLARE-TIMI 58 trial has been an important part of this bacterial yeast infection evolution.

• mosenzon O, wiviott SD, cahn A, et. Al. Effects of dapagliflozin on development and progression of kidney disease bacterial yeast infection in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet diabetes endocrinol 2019;7:606-17

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