Authors: Kathryn M. Holt, PharmD, BCPS, University of Missouri-Kansas City School of Pharmacy, Clinical Assistant Professor Meritas Health North Kansas City
Amanda M. Stahnke, PharmD, BCACP, University of Missouri-Kansas City School of Pharmacy, Clinical Associate Professor Kansas City VA Honor Annex
Diabetes mellitus remains one of the leading causes of chronic kidney disease (CKD) and occurs in 20-40% of people with diabetes.1 With the continued increase in prevalence of CKD in diabetes, limited pharmacologic therapies exist to assist in decreasing the development and progression outside of renin-angiotensin-aldosterone system (RAAS) agents.1-2 Recent clinical trials with sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) have demonstrated their potential role in this much needed area. SGLT2-Is currently available on the market include canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin. Despite the potentially blunted glucose lowering effect in patients with CKD, several proposed mechanisms regarding renal benefit exist: reduced intraglomerular pressure, renal tubular reabsorption and oxidative renal stress; and improved tubuloglomerular feedback.1-5
Primary Outcome Data:
To date only canagliflozin has published primary literature regarding renal outcomes. CREDENCE enrolled 4401 patients and was published in June 2019. The trial included patients 30 years of age or older with type 2 diabetes (T2DM), a hemoglobin A1c (A1c) of 6.5-12%, and CKD (eGFR [estimated glomerular filtration rate] 30-90ml/min/1.73m²) with albuminuria (albumin-to-creatinine ratio [UACR] >300-5000mg/g). Patients were randomized in a 1:1 fashion to receive canagliflozin 100mg PO daily or matching placebo and had to be taking a RAAS agent (angiotensin converting enzyme inhibitor or angiotensin receptor blocker) for at least four weeks prior to entry in to the study. The majority of patients enrolled in the trial were Caucasian (66.6%), had baseline hypertension (HTN) (96.8%), and were male (66.1%). Average age and A1c at baseline were 63 and ~8.3%. An interim analysis resulted in sufficient number of primary outcome events, leading to the early termination of the trial at ~2.6 years. The primary composite outcome of end stage kidney disease (ESRD), including need for dialysis or eGFR <15ml/min/1.73m² for at least 30 days, kidney transplant; doubling of serum creatinine (SrCr) from baseline, and death from cardiovascular (CV) or renal disease occurred in 43.2 and 61.2 events per 1000 patient years in the canagliflozin and placebo groups respectively (HR 0.70, CI 0.59-0.82, P=0.00001, NNT 22). Doubling of SrCr from baseline and development of ESRD were also significantly different between groups (20.7 versus 33.8 events per 1000 patient years, HR 0.60, CI 0.48-0.76, P<0.001 and 20.4 versus 29.4 events per 1000 patient years, HR 0.68, CI 0.54-0.86, P=0.002). There were no statistically significant differences between subgroups in the trial though a trend favoring canagliflozin was seen in patients with lower eGFRs (30-<60ml/min/1.73m2) and higher baseline UACR (>1000mg/g). The results of CREDENCE support that SGLT2-Is may provide renal benefit, specifically in patients at high risk for CKD due to T2DM.6
Secondary Outcome Data:
Primary outcome data has yet to be published for the other SGLT2-Is; however, many of the cardiovascular outcomes trials (CVOTs) have included renal endpoints as secondary analyses. The CANVAS Program evaluated the effect of canagliflozin on the secondary outcome of progression of albuminuria (30% increase or change from normo- to micro- or micro- to macroalbuminuria) and included an exploratory composite outcome of need for dialysis or transplant, death from renal disease, and sustained 40% reduction in eGFR. Both the secondary and exploratory outcomes occurred less often in patients receiving canagliflozin versus placebo (HR 0.73, CI 0.67-0.79 for progression of albuminuria and HR 0.6, CI 0.47-0.77 for composite renal outcome), but due to sequential hypothesis testing and failure of the first secondary endpoint to meet statistical significance, statistical analysis was not completed on the renal secondary outcome.7
EMPA-REG OUTCOME assessed the impact of empagliflozin versus placebo on composite microvascular outcomes, which included incident or worsening nephropathy (progression to macroalbuminuria, doubling of SrCr with an eGFR ≤45ml/min/1.73m², initiation of renal replacement therapy or death from renal cause). The occurrence of nephropathy was lower in the empagliflozin group versus placebo (12.7 versus 18.8%, HR 0.61, CI 0.53-0.7, P<0.001). Additionally, all individual composite renal outcomes were found to be statistically significant favoring empagliflozin.5
DECLARE-TIMI 58, dapagliflozin CVOT, included analysis of new onset ESRD, death from renal or CV causes, and 40% sustained reduction in eGFR as a secondary composite endpoint. A lower incidence of the renal composite endpoint was seen in the dapagliflozin group versus placebo (4.3 versus 5.6%, HR 0.76, CI 0.67-0.87).8
Secondary outcomes in VERTIS-CV regarding renal effects of ertugliflozin include first event of renal death, dialysis or transplant, along with doubling of SrCr. The trial was expected to end late 2019 and results are pending.9
Based on CVOT and renal outcomes, The American Diabetes Association (ADA) now recommends SGLT2-Is (preferring agents with supporting data) as second line agents in many patients, including those with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), CKD, risk for hypoglycemia or those in which weight gain is a concern.2 Though some are rare, adverse drug reactions (ADRs) seen with the use of SGLT2-Is include genital mycotic infections, hypovolemia, hypotension, diabetic ketoacidosis (DKA), Fournier’s gangrene, lower limb amputation and hyperkalemia (canagliflozin).10-13 Acute kidney injury resulting from hypovolemia may be a concern in specific patient populations, such as those taking concomitant diuretics, but recent data did not support this association.6 Consideration to patient specific factors such as past medical history, baseline renal function, risk factors, and patient preference should be taken in to account when deciding to initiate an SGLT2-I.
SGLT2-Is are an exciting development in the treatment of T2DM and with growing evidence will likely become a mainstay in therapy to assist with decreasing the development and progression of CKD in this patient population. We anxiously await the publication of additional trials discussing the potential renal benefits of SGLT2-Is, including DAPA-CKD, EMPA-KIDNEY, and VERTIS-CV to solidify this important drug class’s place in therapy.