Dapagliflozin is a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor that was recently approved in the USA and the EU for the treatment of adults with chronic kidney disease (CKD) with or without diabetes mellitus (DM). The DAPA-CKD trial showed a 39% decline in the risk of worsening kidney function, onset of end-stage kidney disease, or kidney failure-related death. Patients with lower levels of eGFR and higher levels of albuminuria are among those who stand to gain the greatest absolute benefits. These benefits were similar in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related nephrotoxicity. Suggested mechanisms for renal protection include hemodynamic effects; BP reduction and improving salt sensitivities and metabolic effects; and glucose, uric acid and triglycerides (TG)-lowering effects. There he been already many excellent reviews on dapagliflozin and CKD management. Most of them cover both efficacy and safety. This review will focus on clinical perspectives and patient selection for the practicing clinician.
Keywords: dapagliflozin, SGLT 2inhibitors, CKD, proteinuria
Introduction Chronic Kidney Disease Management and the Evolution of SGLT-s InhibitorsThe Kidney Disease: Improving Global Outcomes (KDIGO) working group defines Chronic Kidney Disease (CKD) as abnormalities of kidney structure or function present for >3 months, with implications for health. The KDIGO CKD risk score is classified based on estimated glomerular filtration rate (eGFR) and albuminuria (Figure 1).1 Diabetes and hypertension remain the leading causes of CKD in the United States and worldwide.1
Figure 1.
KDIGO CKD staging by GFR and albuminuria categories.
Notes: Reprinted from Kidney Int Suppl, 3(1), Levin A, Stevens PE, Bilous RW, et al. Kidney Disease: Improving Global Outcomes CKD Working Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease, 1–150, Copyright (2013), with permission from Elsevier.1
CKD affects 12% of the global population and is a major cause of morbidity and mortality consuming a significant proportion of the health-care resources.2,3 According to the United States Center for Disease Control and Prevention (CDC), 1 in 7 (15%) US adults or a total of 37 million people are estimated to he CKD. Globally, the prevalence of CKD is estimated at 9.1% (697.5 million cases)4 CKD increases the risk for all-cause mortality, cardiovascular mortality, kidney failure, and other adverse outcomes. In 2018, treating Medicare beneficiaries with CKD cost over $81.8 billion, and treating people with end-stage kidney disease (ESKD) cost and additional $36.6 billion.3
Often times, CKD is referred to as the “silent killer” considering that as many as 9 in 10 adults with CKD do not know they he CKD. Global estimates indicate that 1.2 million deaths were attributable to chronic kidney disease in 2017. Additionally, about 2 in 5 adults with severe CKD do not know they he the disease, leading to delayed diagnosis and delivery of care.3,5
There is no cure for CKD and for decades, management has been focused on delaying its progression and preventing cardiovascular complications. Treatment options he been limited to blood pressure control, reduction of albuminuria and optimization of glycemic control. Clinicians he a few tools to achieve these treatment targets. Guidelines recommend reducing blood pressure to a target of 130/80 mm Hg in most CKD patients. Screening for proteinuria is recommended at the time of diagnosis and at least once a year thereafter. Random measurement of urinary albumin and urinary creatinine is the method of choice.1
For almost 20 years, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were the cornerstone of CKD progression retardation strategies. However, neither class reduced the risk of all-cause mortality in patients with CKD and evidence for their use in patients with CKD without T2D is relatively limited. Results from two landmark clinical trials: Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT), he shown a reduction in CKD progression in diabetic patients by 16–20% compared to placebo and calcium channel blockers.6,7 Although renin angiotensin aldosterone blocking drugs reduce the risk of adverse renal outcomes in patients with diabetes, the risk remains high and there is a large need for new treatments that lower the risk of kidney failure and improve cardiovascular risks independent of BP control.8 Furthermore, despite the above evidence of the benefits of renin aldosterone angiotensin system (RAAS) blockade, a large proportion of patients who meet the criteria for this treatment do not initiate it within 1 year of CKD diagnosis, highlighting a need for new therapies that can slow the progression of CKD.9
The Advent of SGLT-2 InhibitorsMany years of research dedicated to understanding the role the kidneys play in handling glucose he led to the discovery of sodium-glucose co-transporters (SGLT). Currently, six different isoforms of SGLT cotransporters he been identified. However, SGLT-1 and 2 he been studied the most due to their role in glucose and sodium transport across the brush border of intestines and kidney cells.10 SGLT2 is a transport protein responsible for the reabsorption of approximately 90% of filtered glucose, with the remainder being absorbed by another transporter protein, sodium-glucose co-transporter 1 (SGLT1). The development of inhibitors targeting SGLT began with experiments around the compound phlorizin, first isolated over 150 years ago by French chemists from the root bark and the apple tree.11 In 1975, DeFronzo et al showed that phlorizin infusion in dogs increased fractional excretion of glucose by 60%, improving blood glucose levels without affecting the glomerular filtration rate and renal plasma flow. Despite these encouraging results, the use of phlorizins in the treatment of diabetes mellitus was not pursued due to their poor bioailability and their interference with glucose transport in other parts of the body.12 It was not until 1995, when researchers found that phlorizin inhibited both SGLT1 and SGLT2 that revealed the phlorizin’s side effects as SGLT1 is found in many tissues and plays a key role in absorbing glucose in the intestine. Subsequent research focused on phlorizins more selective to SGLT2 led to their approval for the treatment of diabetes mellitus type 2 by the European Medicines Agency in 2012. In the US, the first SGLT2 inhibitor to be FDA-approved was canagliflozin (marketed as Invokana®) in March 2013, followed by the approval of dapagliflozin (marketed as Farxiga®) in January 2014 and empagliflozin (marketed as Jardiance®) in August 2014. Ertugliflozin (Steglatro®) was approved in 2017. A fifth SGLT2i, sotagliflozin (Zynquista) is being developed.13
SGLT2 inhibitors he a unique mechanism of action independent of insulin or insulin sensitivity resulting from inhibition of SGLT2 in the proximal tubule of the kidney and allowing for their use in combination with other hypoglycemic agents including insulin. Inhibition of SGLT2 results in decreased renal glucose reabsorption by approximately 50% and therefore modestly lower elevated blood glucose levels and glycated hemoglobin (HbA1c) levels in patients with type 2 diabetes. Along, they do not usually cause hypoglycemia. SGLT2 inhibitors also he a modest natriuretic effect that may lower blood pressure; however, this effect is typically transient due to other compensatory mechanisms. The blood pressure-lowering effect of SGLT2 inhibitors is likely influenced by several other effects of SGLT2 inhibition, including weight loss and diuresis.14
In 2008, the FDA antidiabetic drug guidance required cardiovascular outcome trials (CVOTs) for novel anti-diabetic medications to ensure that they do not increase the risk of myocardial infarction, stroke or cardiac death. Three SGLT2is (canagliflozin, empagliflozin, dapagliflozin) he been studied in cardiovascular outcomes trials; canagliflozin has also been studied in an additional randomized clinical trial involving patients with diabetic kidney disease. These studies revealed improved cardiovascular and renal outcomes which sparked interest in studying the cardio-renal protective effects of these agents.15
Table 1 summarizes the safety studies for the approved SGLT2 inhibitors ailable in the US.
Table 1.Summary of Trials on SGLT2 Inhibitors with Kidney Outcomes
Trial CREDENCE (n = 4401) CANVAS Program (n = 10,142) EMPA-REG OUTCOME (n = 7020) DECLARE-TIMI 58 (n = 17,160) DAPA-CKD (n = 4304) Inclusion criteria eGFR 30 to 300–5000 mg/g eGFR ≥30 mL/min/1.73 m2 eGFR ≥ 30 mL/min/1.73 m2 CLcr ≥60 mL/min eGFR 25–75 mL/min/1.73 m2; UACR 200–5000 mg/g Drug Canagliflozin Canagliflozin Empagliflozin Dapagliflozin Dapagliflozin Median follow-up 2.6 yr 2.4 yr 3.1 yr 4.2 yr 2.4 yr Outcomes: RR or HR Comparing SGLT2i with Placebo Dialysis, Txp, or death from kidney disease 0.72 (0.54–0.97) 0.56 (0.23–1.32) 0.90 (0.30–2.67) 0.42 (0.20–0.87) NA Dialysis, Txp, or sustained eGFR