Division of Nephrology, University of British Columbia, Vancouver, BC, Canada
There is growing evidence for the cardiorenal protective benefits of sodium-glucose co-transport 2 (SGLT2) inhibitors for diabetic and non-diabetic-related chronic kidney disease (CKD) patients. As many clinical guidelines increasingly incorporate SGLT2 inhibitors, we sought to review: the rationale and background for their use in CKD, monitoring after initiation, how to handle concomitant diuretics and diabetic medication, therapeutic role and side effects, preventing adverse events, and the use of SGLT2 inhibitors with other novel agents for slowing the trajectory kidney function decline. We hope to overcome prescriber hesitancy and uncertainty through a case-based discussion and increase prescription rates in appropriate patients to benefit more from this therapy.
Il existe de plus en plus de données probantes à l’appui des avantages liés à la protection cardiorénale des inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2) chez les patients atteints d’insuffisance rénale chronique (IRC) liée ou non au diabète. Comme de nombreuses lignes directrices cliniques intègrent de plus en plus les inhibiteurs du SGLT2, nous avons cherché à faire le point sur : la justification et le contexte de leur utilisation en IRC, la surveillance après l’amorce du traitement, la façon de gérer la prise concomitante de diurétiques et de médicaments contre le diabète, le rôle thérapeutique et les effets secondaires, la prévention des évènements indésirables et l’utilisation des inhibiteurs du SGLT2 avec d’autres nouveaux agents pour ralentir la trajectoire du déclin de la fonction rénale. Par l’intermédiaire d’une analyse fondée sur des cas concrets, nous espérons surmonter les réticences et l’incertitude des prescripteurs et augmenter le taux de prescription pour les patients chez qui le traitement est approprié de sorte que davantage de patients puissent tirer profit de ce traitement.
Key words: SGLT2 inhibitor, chronic kidney disease, cardioprotective, euglycemic dka
Corresponding Author: Megan Borkum: email@example.com
Submitted: 19 June 2022; Accepted: 17 July 2022; Published: 17 October 2022
All articles published in DPG Open Access journals
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).
A 66-year-old gentleman was referred to a primary care medical clinic. He had a body mass index of 28 kg/m2 and a history of longstanding, poorly controlled diabetes, hypertension, hyperlipidemia, and a previous coronary stent. He was on a statin, and his low-density lipoprotein and triglycerides were not high. He was prescribed hydrochlorothiazide at 25 mg and on a maximally tolerated dose of candesartan with blood pressure (BP) treated to target. The patient was on a maximal dose of metformin, gliclazide, and the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin with a recent hemoglobin A1C (HbA1C) of 7.6%. His estimated glomerular filtration rate (eGFR) was 50 mL/min/1.73m2, stage IIIA chronic kidney disease (CKD), and he had urine albumin creatinine (ACR) of 1600 mg/g.
At each visit, it was recommended, ‘If you go to a hospital and need a scan ask the doctor to avoid contrast dye if possible and don’t take any over-the-counter drugs other than Tylenol. No Aleve, Motrin, or Advil.’ The patient asked: ‘but what more can I do for my kidneys?’. The internist remembered reading about the benefits of sodium-glucose co-transport 2 (SGLT2) inhibitors in CKD. He discussed the case with a nephrology colleague who advised adding dapagliflozin 10mg. The following questions arose in their discussions.
A relatively new class of agents with specific kidney- and cardioprotective effects are SGLT2 inhibitors or gliflozins. The sodium-glucose co-transporter 2 is located in the first segment of the proximal tubule and is the major transporter responsible for glucose reabsorption in the kidney.1 SGLT2 inhibitors are highly selective and reversible inhibitors of this transporter. Various SGLT2 inhibitors, such as dapagliflozin, empagliflozin, and canagliflozin are available for clinical use. These drugs cause direct and insulin-independent elimination of glucose by the kidneys, reducing blood glucose levels in type 2 diabetics.2 Therefore, SGLT2 inhibitors were developed initially as oral antihyperglycemic drugs, lowering HbA1C by 0.6–1% in people with type 2 diabetes with preserved kidney function or less advanced CKD.3,4
In recent years 2 dedicated kidney outcome trials demonstrated a clear benefit of SGLT2 inhibitors in kidney and cardiovascular outcomes and all-cause death in patients with CKD (Table 1). The first, CREDENCE, included adult patients with type 2 diabetes and CKD (eGFR 30–90 mL/min/1.73m2), canagliflozin reduced the risk of kidney and cardiovascular outcomes.5 The second, DAPA-CKD, showed similar outcomes with dapagliflozin use in patients with CKD (eGFR 25-75 mL/min/1.73 m2) with and without type 2 diabetes.6
Table 1. The effects of SGLT2 inhibitors on clinical outcomes
|Number of participants||4304||4401|
|Cause of kidney disease||Diabetic and non-diabetic||Diabetic|
|eGFR range at baseline||25–75 mL/min/1.73 m2||30–90 mL/min/1.73 m2|
|Kidney and cardiovascular outcomea||HR 0.61 (95% CI 0.51, 0.72)||HR 0.70 (95% CI 0.59, 0.82)|
|Kidney outcomeb||HR 0.56 (95% CI 0.45, 0.68)||HR 0.66 (95% CI 0.53, 0.81)|
|Kidney failure||HR 0.64 (95% CI 0.50, 0.82)||HR 0.68 (95% CI 0.54, 0.86)|
|All-cause death||HR 0.69 (95% CI 0.53, 0.88)||HR 0.83 (95% CI 0.68, 1.02)|
|Cardiovascular death or hospitalisation for heart failure||HR 0.71 (95% CI 0.55, 0.92)||HR 0.69 (95% CI 0.57, 0.83)|
|Hospitalisation for heart failure||HR 0.51 (95% CI 0.34, 0.76)||HR 0.61 (95% CI 0.47, 0.80)|
a≥50% eGFR decline/doubling of serum creatinine, kidney failure, or renal or cardiovascular death.
b≥50% eGFR decline/doubling of serum creatinine, kidney failure, or renal death.
The proposed mechanisms of kidney protection (Figure 1) include (but are not limited to):
In many conditions, proximal sodium and glucose reabsorption is enhanced leading to decreased distal delivery to the macular densa. These specialized epithelial cells (in the distal convoluted tubule) interpret the low sodium as reduced flow and therefore activate the autoregulatory tubular glomerular feedback system, resulting in afferent arteriolar vasodilation to promote renal artery perfusion.1 Long-term, this causes renal hyper-perfusion and hyperfiltration which scars the glomerulus. By blocking proximal reabsorption, SGLT2 inhibitors increase the sodium chloride delivery to the distal tubule causing adenosine release (from the production of adenosine triphosphate) and vasoconstriction of the afferent arteriole reducing intraglomerular pressure and albuminuria, which protects the kidney in the long term. This hemodynamic mechanism is thought to cause the initial reversible decline in kidney function seen upon SGLT2 inhibitor initiation.1,7–9
SGLT2 inhibitors reduce systolic BP by approximately 3–6 mmHg and diastolic BP by 1-2 mmHg.10–13 The mechanisms involved include diuretic and natriuretic action, weight loss (estimated at 1–3kg) and possibly the reduction in blood vessel stiffness.1,10,14–16
Figure 1. Kidney protective effects of SGLT2 inhibitors.
Based on the CREDENCE and DAPA-CKD trials, canagliflozin and dapagliflozin have been approved to treat CKD (canagliflozin in patients with type 2 diabetes) by regulatory agencies. The recent international KDIGO clinical guidelines recommend using SGLT2 inhibitors for treating CKD due to type 2 diabetes in patients with eGFR ≥30 mL/min/1.73m2.18 This population also has an alarmingly high burden of cardiovascular disease. SGLT2 inhibitor cardiovascular outcome trials have shown benefits for heart failure with preserved and reduced ejection fraction and significant reductions in major cardiac events and hospitalizations.14,19–22 Clinical indications for SGLT2 inhibitors (Table 2) are increasing over time.10,15,23
Table 2. Clinical Indications for SGLT2 Inhibitors
|Type 2 diabetes and albuminuric CKD plus eGFR ≥25ml/min/1.73 m2|
|Non-diabetic albuminuric CKD (including IgA nephropathy), eGFR ≥25 mL/min/1.73m2|
|Type 2 diabetes with atherosclerotic cardiovascular disease|
|Heart failure with preserved and reduced ejection fraction|
|Type 2 diabetes and hyperglycemia (in addition to metformin or as 1st line therapy)|
Numerous SGLT2 inhibitors have been studied. Dapagliflozin, empagliflozin, and ertugliflozin, exclusively inhibit the SGLT2 transporter. Canagliflozin and -sotagliflozin are dual SGLT2 and SGLT1 transporter inhibitors.15 SGLT1 is responsible for glucose absorption in the small intestine and is also expressed in the distal proximal tubule contributing to glucose reabsorption, especially after SGLT2 inhibition when tubular glucose concentrations are increased. As a result of SGLT-1 inhibition, a reduction in intestinal glucose absorption is associated with a sustained increase in circulating glucagon-like peptide-1(GLP1) and peptide YY, hormones that reduce appetite. Therefore, added SGLT1 inhibition is hypothesized to be beneficial, particularly in people with diabetes.24 However, cardiovascular outcome benefits seem consistent across the various agents.25,26 Until further head-to-head studies are available, the pragmatic approach is to prescribe according to local availability and cost-effectiveness. It is advised to initiate the SGLT2 inhibitor at the lowest recommended daily dose (10 mg empagliflozin, 100 mg canagliflozin, 10 mg dapagliflozin, or 5 mg ertugliflozin). Titration to a higher dose is not necessary for maximal cardiorenal benefits; however, could be used to improve glycemic control.20
SGLT2 inhibitors have a diuretic effect through their primary action on the proximal convoluted tubule. In a study attempting to quantify this effect, when used with a loop diuretic, the mean increase in 24 hours urine volume was found to be >500 mL.27 Accordingly, if patients are not volume overloaded on examination or at risk of hypovolaemia, decreasing thiazide or loop dosage could be considered with careful clinical monitoring after drug initiation.28 This should also be noted when prescribing any other medication with a diuretic effect such as mineralocorticoid receptor -antagonists.10 Patients should be advised to hold the drug if they experience symptoms such as diarrhea and vomiting which may place them at risk of volume depletion until symptoms resolve.
In people with normal kidney function, or eGFR ≥45 mL/min, if blood glucose is well-controlled at SGLT2 inhibitor initiation or the patient has a known history of frequent hypoglycemic events, it is advised to wean or stop the sulfonylurea/ meglitinides and consider reducing the total daily insulin dose by 10–20%. Patients should be advised to closely monitor their blood glucose at home for the first 4 weeks of therapy (especially if on insulin, sulfonylurea, and/or glinides).28,29 There is no increased risk of hypoglycemia in patients only taking metformin, DPP4 inhibitors, GLP-1 receptor agonists, and thiazolidinediones; these agents do not require dose adjustment at the time of SGLT2 inhibitor initiation.28 For those with lower GFR values, the hypoglycemic effect is attenuated.
A completely reversible decline in the eGFR may occur with SGLT2 inhibitor commencement, with or without intercurrent RAAS inhibitors, which is not an indication to discontinue therapy (or for repeat labs) but rather a positive hemodynamic effect of the medication. Indeed, a larger dip in eGFR correlates with greater long-term benefits.7,30,31 As well as slowing the trajectory of eGFR decline, SGLT2 inhibitors are associated with a lower risk of acute kidney injury, potentially resulting from improved kidney oxygenation and kidney perfusion.32–34 In EMPA-REG and CREDENCE, RAAS inhibitor use enhanced the effect of the SGLT2 inhibitor to reduce albuminuria and CKD progression with no additional safety findings.31,35 We do not recommend checking serum creatinine or eGFR after commencement, and would continue to monitor as per usual practice and frequency in that individual.
Few absolute contraindications to SGLT2 inhibitors exist, including a history of previous hypersensitivity reactions to the drug, pregnancy and breastfeeding.29They are not licensed for type 1 diabetics or kidney transplant recipients but are currently being investigated for use in these conditions under certain circumstances.36,37 The DAPA-CKD trial demonstrated that dapagliflozin is safe in diabetic and non-diabetic patients, with no increased risks of hypoglycemia or diabetic ketoacidosis (DKA), limb amputation, Fournier’s gangrene, and renal-related adverse events (including urinary tract infection and acute kidney injury).6
The predominant current concerns with the use of SGLT2 inhibitors remain the risk of euglycemic DKA: which tends to occur in those with an intercurrent event or infection and a history of reduction in dose or cessation of insulin.38 The other risk is mycotic genital infections (treatable with topical antifungal agents or a single oral dose of fluconazole): urinary glucose loss is central to the proposed mechanism behind these adverse effects.38,39 Euglycemic DKA is an infrequent but well-described complication seen in people with diabetes with SGLT2 inhibitors (Figure 2). This diagnosis should be considered in a patient on an SGLT2 inhibitor with normal glucose levels or mild hypoglycemia, ketonemia and a raised anion gap metabolic acidosis. SGLT2 inhibitors are consequently withheld during prolonged fasting, ideally 3 days before surgery or with critical medical illness (greater risk for ketosis).
Figure 2. Mechanism of euglycemic DKA.
On follow-up after 3 months, the patient’s urine protein was quantified as 1 g on 24-hour urine collection, his HbA1C was now 6.8%, and his BP was well controlled <120/70 mmHg on average. He knows that protein in the urine harms the kidneys and asks if anything else could be added to his medical therapy to further lower the protein levels in the urine. He also read on the internet that SGLT2 inhibitors should not be given to people with more severe kidney diseases. He wants to know at what level of kidney function he should stop his SGLT2 inhibitor?
Despite the nephroprotective effects of new therapies, high rates of albuminuria and kidney failure persist. In this case, the DPP4 inhibitor could be changed to a GLP-1 receptor agonist for weight and cardiovascular benefits.40 The FLOW trial investigates the GLP-1 agonist semaglutide versus placebo on the progression of renal impairment in subjects with type 2 diabetes and CKD (NCT03819153). Another option is the non-selective mineralocorticoid receptor antagonist (MRA) fineronone, which has been shown to lower risks of CKD progression and cardiovascular events in type 2 diabetics.41 In a small trial looking at albuminuria reduction the combination of dapagliflozin-eplerenone had, as a whole, a dramatic effect, possibly due to their complementary action.42 In addition, the known kaliuretic effect of SGLT2 inhibitors could help mitigate the hyperkalemia associated with MRA usage when the two are prescribed in combination. The efficacy and safety of the combination of finerenone and empagliflozin are further being studied in type 2 diabetics with CKD in the Confidence trial (NCT05254002).
In dedicated renal studies (CREDENCE, DAPA and EMPA CKD, the latter of which is soon to report), the SGLT2 inhibitors were continued until patients received a transplant or went on to dialysis. Interestingly, a subgroup analysis of DAPA-CKD showed no significant interaction of treatment effects (including efficacy and safety outcomes) by CKD stage 4 status (eGFR 25–29 vs. 30–75 mL/min/1.73m2).43 Since the glycosuric effect of this drug dissipates beyond stage 3 CKD, the risk of euglycemic DKA, genitourinary infections, and even hypoglycemia should not be of concern in more advanced CKD.1 Further, since the cardiovascular and renal benefits from SGLT2 inhibitors are only to a small extent attributable to the improvement of blood glucose control and associated BP reduction, it has been hypothesized that even patients with more advanced CKD can benefit from these agents.10 Emerging data show that SGLT2 inhibitors exert direct and indirect kidney and cardiac effects independent of their action in the proximal tubules (e.g., left ventricular mass reduction, coronary vasodilation, improving cardiac function).44–46 Therefore, although not started in advanced CKD, once initiated it is reasonable to continue to prescribe the medication when patients cross the threshold of eGFR <30 mL/min/1.73m2 (even into dialysis).
SGLT2 inhibitors offer cardiorenal protection for patients with and without T2DM and CKD. Initiation requires review and possible modification of anti-hypertensive, diuretic, and anti-glycemic agents to avoid overtreatment. Discussing sick day rules can mitigate potential adverse effects. There is growing evidence for these agents’ safe use and pleiotropic benefits and their ability to enhance the effect of other nephroprotective medications (both established and novel) when added in combination.
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