Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

In the citing paper

“However, during the CREDENCE trial recruitment, an amendment was introduced, excluding those at risk for amputation.”

In the citing paper

“SGLT2 inhibitors and finerenone, a nonsteroidal mineralocorticoid receptor antagonist, also reduce albuminuria in clinical trials of advanced diabetic kidney disease (471-473).”

In the citing paper

“canagli fl ozin reduced the risk of the secondary cardiovascular outcomes of hospitalization for heart failure and MACE by 39% (HR: 0.61; 95% CI: 0.47 -0.80)”

In the citing paper

“SGLT2i conferred less annual eGFR decline and a reduction in albuminuria or decreased progression to severely increased albuminuria.”

In the citing paper

“Of note, in the CREDENCE and DAPA-CKD trials, kidney outcomes were the primary outcome evaluated.”

In the citing paper

“Even for the secondary outcome of dialysis, kidney transplant, or death from kidney causes, there was evidence for signi fi cant bene fi t (HR: 0.72; 95% CI: 0.54 -0.97).”

In the citing paper

“Thus, the evidence is particularly strong for the population corresponding to the CREDENCE and DAPACKD studies (ACR > 200 -300 mg/g [ > 20 -30 mg/mmol] and eGFR > 25 -30 and < 75 -90 ml/min per 1.73 m 2 .”

In the citing paper

“In CREDENCE, a drop in eGFR $ 30% was uncommon (4% of participants assigned to canagli fl ozin) but was associated with modestly increased risks of kidney adverse events.”

In the citing paper

“Protocols of multiple RCTs, including CREDENCE and DAPA-CKD, speci fi ed continuation of study drug (active or placebo) even when observed eGFR dropped below the eligibility threshold speci fi ed for initiation.”

In the citing paper

“However, a sustained ≥57% decrease in eGFR (equivalent to doubling of serum creatinine) was selected in FIDELITY because it is a classic outcome in diabetic nephropathy studies2 , 12–14 and is a more robust kidney failure surrogate outcome than a ≥40% decrease in eGFR, particularly when initial changes in eGFR occur.14 , 15”

In the citing paper

“Previous studies assessing SGLT-2 inhibitors in patients with CKD and type 2 diabetes, such as CREDENCE or DAPA-CKD, included patient populations representing a substantially smaller part of the CKD spectrum than the FIDELITY analysis.”

In the citing paper

“while the glucose-lowering effects of SGLT2 inhibitors are blunted with eGFR <45 mL/min/1.73m 2 , the kidney and cardiovascular benefits were still seen at eGFR levels as low as 20 mL/min/ 1.73 m 2 even with no significant change in glucose (4,29,31,107,123,127,129,130).”

In the citing paper

“First, the patient populations differed in the two trials”

In the citing paper

“the mechanisms of action differ between drug classes, including different effects on metabolic, hemodynamic, and diuretic factors and on inflammation and fibrosis.4,13,18,19”

In the citing paper

“SGLT2 inhibitors reduce the incidence of heart failure and improve heart failurerelated outcomes, including hospitalization for heart failure and heart failure-related symptoms, in people with diabetes with preserved or reduced ejection fraction (250,(255)(256)(257)(298)(299)(300)(301)(302)(303)(304)(305)(306).”

In the citing paper

“While there was an increased risk of lower-limb amputation with canagliflozin in one trial (247), no significant increase in lower-limb amputations, fractures, AKI, or hyperkalemia was seen in other trials of canagliflozin (248).”

In the citing paper

“Results of large cardiovascular outcome trials of empagliflozin (10 mg or 25 mg daily) and canagliflozin (100 or 300 mg daily) showed that treatment with either drug reduced rates of MI, stroke, or cardiovascular death.”

In the citing paper

“The SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin reduce the incidence of heart failure and improve heart failure–related outcomes, including hospitalization for heart failure and heart failure–related symptoms, in people with diabetes with preserved or reduced ejection fraction (242,247,248,281,286–294).”

In the citing paper

“To date, two clinical trials with primary kidney disease outcomes using canagliflozin and dapagliflozin (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation [CREDENCE] and Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease [DAPA-CKD]) demonstrated significant benefit for composite outcomes including end points of substantial eGFR decl”

In the citing paper

“However, their ability to lower glucose levels declines when the eGFR falls below 45 mL/min/1.73m 2 (142-144).”

In the citing paper

“The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial showed that long-term administration of canagliflozin conferred renal and cardiovascular protection in patients with type 2 diabetes with chronic kidney disease.10”

In the citing paper

“The kidney-protective effects of SGLT2 inhibitors have previously been shown in patients with type 2 diabetes and chronic kidney disease in the CREDENCE trial.10”

In the citing paper

“Clinical trials of other SGLT2 inhibitors have shown similar results.8,10,19”

In the citing paper

“As in other trials of SGLT2 inhibitors, there was an initial dip in the estimated GFR, followed by a stabilization of kidney-function decline.7,8,10”

In the citing paper

“In patients with diabetic kidney disease with increased levels of albuminuria, large placebo-controlled trials have shown that renin-angiotensin system (RAS) inhibitors,3–5 sodium-glucose cotransporter 2 (SGLT2) inhibitors,6,7 and the non-steroidal mineralocorticoid receptor antagonist finerenone8,9 all reduced the risk of progression to kidney failure.”

In the citing paper

“The effect of SGLT2 inhibition on kidney disease progression or cardiovascular death seen in the present trial is quantitatively similar to that seen in two other large placebo-controlled trials in CKD populations.6,7”

In the citing paper

“The CREDENCE trial of canagliflozin required all participants to have type 2 diabetes and a urinary ACR of at least 300 mg/g, and excluded patients with an eGFR of less than 30 ml per minute per 1.73 m2.6”

In the citing paper

“It was stopped early due to positive efficacy and showed a 32% risk reduction for development of ESKD over control (29).”

In the citing paper

“Additionally, the development of the primary end point, which included dialysis for $30 days, kidney transplantation or eGFR <15 mL/min/1.73m 2 sustained for $30 days by central laboratory assessment, doubling from the baseline serum creatinine average sustained for $30 days by central laboratory assessment, or renal death or cardiovascular death, was reduced by 30%.”

In the citing paper

“Moreover, in this advanced CKD group, there were clear benefits on cardiovascular outcomes demonstrating a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (29,110,113).”

In the citing paper

“This benefit was on background ACE inhibitor or ARB therapy in >99% of the participants (29).”

In the citing paper

“In 2019, the results of the CREDENCE trial 17 -the first study designed to specifically assess the effect of an SGLT2 inhibitor (canagliflozin) on a primary kidney outcome in people with established diabetic kidney disease-were reported.”

In the citing paper

“and 20% (HR: 0.80; 95% CI: 0.67 -0.95), respectively.”

In the citing paper

“which was the fi rst RCT of an SGLT2i speci fi cally powered for primary kidney outcomes among patients with exclusively albuminuric CKD.”

In the citing paper

“The increased risk of lower-limb amputations seen with canagli fl ozin in the CANVAS trial 87 was not reproduced in the CREDENCE trial, 93 even though this trial did implement special attention to foot care for prevention.”

In the citing paper

“The primary outcome occurred in 43.2 and 61.2 per 1000 patient-years in the canagli fl ozin and placebo arms respectively, which translated to a 30% relative reduction in the primary kidney outcome by canagli fl ozin (HR: 0.70; 95% CI: 0.59 -0.82).”

In the citing paper

“in the CREDENCE trial, which evaluated 100 mg/d of canagli fl ozin, there was no excess fracture rate.”

In the citing paper

“There was no evidence of heterogeneity of treatment bene fi t of subgroups de fi ned by eGFR or ACR ( P -interactions were nonsigni fi cant).”

In the citing paper

“In the CREDENCE trial, this was 2.2 versus 0.2 per 1000 patient-years for canagli fl ozin versus placebo.”

In the citing paper

“Participants with T2D and an eGFR as low as 30 ml/min per 1.73 m 2 were included in the EMPA-REG, CANVAS, and CREDENCE trials, 87,90,93 and ef fi cacy and safety in these studies were consistent across both eGFR and albuminuria down to this threshold.”

In the citing paper

“Patients with chronic kidney disease (CKD) and type 2 diabetes have high residual cardiorenal morbidity and mortality, despite current therapies,1–5”

In the citing paper

“there were clear benefits on cardiovascular outcomes demonstrating a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (29,125,126).”

In the citing paper

“Additionally, the development of the primary end point, which included dialysis for ≥30 days, kidney transplantation or eGFR <15 mL/min/ 1.73 m 2 sustained for ≥30 days by central laboratory assessment, doubling from the baseline serum creatinine average sustained for ≥30 days by central laboratory assessment, or kidney death or cardiovascular death, was reduced by 30%.”

In the citing paper

“It was stopped early due to positive efficacy and showed a 32% risk reduction for development of kidney failure over placebo (29).”

In the citing paper

“This benefit was on background ACE inhibitor or ARB therapy in >99% of the participants (29).”

In the citing paper

“The magnitude of the between-group difference in the risk of a primary outcome event was smaller than that shown for the SGLT2 inhibitor canagliflozin in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial.4”

In the citing paper

“the CREDENCE trial excluded patients treated with mineralocorticoid receptor antagonists”

In the citing paper

“Additional data from the CREDENCE trial with canagliflozin showed a 39% reduction in hospitalization for heart failure and a 31% reduction in the composite of cardiovascular death or hospitalization for heart failure, in a population with CKD and albuminuria (UACR >300-5,000 mg/g) (257).”

In the citing paper

“Additional data from the CREDENCE trial with canagliflozin showed a 39% reduction in hospitalization for heart failure and a 31% reduction in the composite of cardiovascular death or hospitalization for heart failure, in a population with CKD and albuminuria (UACR >300-5,000 mg/g) (257).”

In the citing paper

“There was concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors may promote AKI through volume depletion, particularly when combined with diuretics or other medications that reduce glomerular filtration; however, this has not been found to be true in randomized controlled trials of advanced kidney disease (29) or high CVD risk with normal kidney function (30)(31)(32).”

In the citing paper

“In the CREDENCE trial, which was conducted in a population of patients with exclusively T2D and CKD, this occurred in 2.27% of those in the canagli fl ozin arm versus 0.59% of those receiving placebo.”

In the citing paper

“Additionally, the ERT identi fi ed 25 relevant RCTs in an updated Cochrane systematic review.”

In the citing paper

“There was concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors may promote AKI through volume depletion, particularly when combined with diuretics or other medications that reduce glomerular filtration; however, this has not been found to be true in randomized controlled trials of advanced kidney disease (29) or high CVD risk with normal kidney function (30)(31)(32).”

In the citing paper

“In the three kidney outcomes trials examining SGLT2i, the use of GLP-1 RAs was rare, below 5%12–14.”

In the citing paper

“Little is known about the effect of SGLT2 inhibitors on the broad spectrum of both inpatient and outpatient worsening heart failure events, because these were not documented in trials with these drugs in type 2 diabetes.1–5”

In the citing paper

“Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalizations for heart failure in 8 large-scale trials, including those that focused on type 2 diabetes, heart failure with a reduced ejection fraction, and chronic kidney disease.1–8”

In the citing paper

“Despite the fact that clinical trials have demonstrated the efficacy of these lifestyle and pharmacological interventions (3–10), residual cardiovascular (CV) and kidney risk remains present even with guideline-recommended treatment (8,10).”

In the citing paper

“Even with current therapies available [6–10], patients with T2DM and chronic kidney disease (CKD) still experience a significant cardiovascular and renal morbidity and mortality.”

In the citing paper

“Furthermore, SGLT2i have been studied specifically among patients with CKD with or without T2D in 3 completed primary kidney outcome trials (CREDENCE[15], DAPA-CKD[16], and EMPA-KIDNEY[17]), which showed benefit for both a significant reduction in the primary kidney outcomes and cardiovascular outcomes [18,19].”

In the citing paper

“This is in contrast to SGLT2i where there have been 3 dedicated kidney outcome trials that specifically enrolled a CKD population.”

In the citing paper

“In these patients at high risk of HF, a consistent risk reduction of CV death or HF hospitalization was observed ranging from 23% to 31%.150,153,542,543”

In the citing paper

“SGLT2 inhibitors, compared with placebo, were associated with more new-onset AF cases in EMPA-REG OUTCOME (empagliflozin vs. placebo), but fewer incident AF cases in CANVAS (canagliflozin vs. placebo) and DECLARE-TIMI 58 (dapagliflozin vs. placebo).71,151,153,603”

In the citing paper

“Combining RAS and SGLT2 inhibitors does not appear to cause hyperkalaemia, and a hypothesis has been raised that SGLT2 inhibitors reduce the risk of severe hyperkalaemia among MRA users with HF. 153,542,710,723,724,727,728”

In the citing paper

“In contrast, combining an SGLT2 inhibitor with an ACE-I or ARB has clear beneficial effects on risk of kidney failure and hospitalization for HF in patients with CKD and T2DM.153,542”

In the citing paper

“Information on the safety and efficacy of combining MRAs with SGLT2 inhibitors in CKD is limited as only ∼4% of FIDELIO-DKD, ∼8% of FIGARO-DKD, ∼5% of DAPA-CKD, and no CREDENCE participants were prescribed such a combination.153,718,719,721”

In the citing paper

“The CREDENCE, DAPA-CKD, and EMPA-KIDNEY placebo-controlled trials were all stopped early for efficacy while testing canagliflozin, dapagliflozin, and empagliflozin, respectively.153,543,711”

In the citing paper

“Combining RAS and SGLT2 inhibitors does not appear to cause hyperkalaemia, and a hypothesis has been raised that SGLT2 inhibitors reduce the risk of severe hyperkalaemia among MRA users with HF. 153,542,710,723,724,727,728”

In the citing paper

“All three trials found the RR reductions for kidney disease progression were unmodified by baseline eGFR, with EMPA-KIDNEY reporting clear benefits in patients with eGFR 20-30 mL/min/1.73m 2 .153,542,543,712,713”

In the citing paper

“Large trials have also shown that SGLT2 inhibitors reduce the risk of kidney disease progression in patients with type 2 diabetes and proteinuric chronic kidney disease,1, 6, 7, 8”

In the citing paper

“CREDENCE and SCORED exclusively studied patients with chronic kidney disease and type 2 diabetes,7, 9”

In the citing paper

“Individual trials have shown that kidney benefits translate into important reductions in the need for dialysis or kidney transplantation”

In the citing paper

“A total of 489 kidney disease progression outcomes accrued in those with an eGFR less than 30 mL/min per 1·73 m2 in those two trials.”

In the citing paper

“efficacy and safety data from EMPA-KIDNEY and DAPA-CKD combined include information on nearly 3000 patients with an eGFR of 20–30 mL/min per 1·73 m2.”

In the citing paper

“Regardless of the underlying mechanisms, relatively modest reductions in BP with SGLT2 inhibition are unlikely to fully explain the substantial risk reductions in kidney failure and cardiovascular outcomes with these agents, 9,[35][36][37] a conclusion supported by the finding that less than 10% of treatment effects on kidney and cardiovascular outcomes were explained by change in systolic BP.”

In the citing paper

“Analyses of change in systolic BP were based on-treatment analyses using complete data, as pre-specified in the statistical analysis plan and to be consistent with the primary trial report.9”

In the citing paper

“In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Trial, canagliflozin reduced the risk of kidney failure and of hospitalization for heart failure in patients with T2DM and CKD by 30 and 40% respectively.9”

In the citing paper

“The kidney benefits of SGLT2 inhibitors appear to be largely independent of glycemic control based on a growing series of observations.”

In the citing paper

“These collective findings were subsequently proven by the CREDENCE trial, the first to show superiority of an SGLT2 inhibitor added to the standard of care for CKD in T2DM for a primary outcome of kidney disease end points (14).”

In the citing paper

“Nevertheless, kidney protection is consistent and substantial in this population (14).”

In the citing paper

“Their glucose-lowering effects are modest, especially in people with baseline estimated GFR (eGFR) <45 mL/min/1.73 m2.”

In the citing paper

“In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2.”

In the citing paper

“Results from these CVOTs and CREDENCE revealed more robust and consistent benefits on HF than on MACE with SGLT2 inhibitors (14).”

In the citing paper

“Diuresis is an important mechanism for reducing blood pressure and risk for HF events (11–16,35).”

In the citing paper

“The CVOTs designed to test safety and a CKD trial (CREDENCE) were comparable in key aspects: participants with T2DM, placebo controls, SGLT2 inhibitor dose not based on glycemia, all participants treated by standard of care, and similarly defined and adjudicated outcomes.”

In the citing paper

“CREDENCE was the first clinical trial to be stopped early for overwhelming efficacy proving the kidney protective effects of SGLT2 inhibition for DKD.”

In the citing paper

“Starting at a mean baseline eGFR of 56 mL/min/1.73 m2, risk for the primary outcome (serum creatinine doubling, kidney failure treated by KRT, or death from kidney disease or CVD) was substantially reduced (HR, 0.70; 95% CI, 0.59–0.82).”

In the citing paper

“In the CVOTs and CREDENCE, kidney-protective effects are consistent overall (Fig. 6) (69) and in participants with different levels of glycemic control (HbA1c <7% or >9%) or eGFR strata (>90, 60–90, or 30–60 mL/min/1.73 m2) (11,12,14,70).”

In the citing paper

“These kidney-protective effects were accomplished with nominal between-group differences in HbA1c levels or blood pressure.”

In the citing paper

“The number needed to treat with canagliflozin to prevent a primary outcome event was 22 during a mean of 2.6 years.”

In the citing paper

“In CREDENCE, urinary albumin-creatinine ratio was reduced by 31% (14).”

In the citing paper

“After 3 weeks of treatment, the mean rate of eGFR decline was significantly slower in patients receiving canagliflozin compared with placebo (−1.85 vs. −4.59 mL/min/1.73 m2 per year) (Figs. 4 and 5).”

In the citing paper

“The effects on kidney disease outcomes are also similar irrespective of background use of renin-angiotensin system blockade (14).”

In the citing paper

“The effects of SGLT2 inhibitors on kidney disease end points do not differ in patients with established ASCVD or those with multiple CVD risk factors (12,14,70).”

In the citing paper

“Higher risks for amputation and fracture were not observed in CVOTs of other SGLT2 inhibitors or with canagliflozin in the CREDENCE trial (14,69,95).”

In the citing paper

“In CREDENCE, 29.8% (1,313/4,401) of participants had a baseline eGFR of 30 to 45 mL/min/1.73 m2, and kidney benefits did not differ from those in patients with higher eGFR (14,69).”

In the citing paper

“DECLARE enrolled more patients without preexisting cardiovascular disease (59%) than either CANVAS (34%) or EMPA-REG OUTCOME (0%), meaning that at least some of the benefits of SGLT2 inhibition extend to those without overt cardiovascular disease.”

In the citing paper

“adverse effects that have not been reported to date with other SGLT2 inhibitors and were not observed in a subsequent trial of canagliflozin”

In the citing paper

“Sodium glucose co-transporter (SGLT) 2 inhibitors reduce the risk of kidney failure in patients with and without type 2 diabetes (T2D).”

In the citing paper

“and of the composite of cardiovascular death or hospitalization for heart failure (HR 0.69 [95% CI 0.57 -0.83])”

In the citing paper

“as well as lower risk of hospitalizations for heart failure (HR 0.61 [95% CI 0.47 -0.80])”

In the citing paper

“Canagli fl ozin was additionally found to have a lower risk of the composite of cardiovascular death, MI, or stroke (HR 0.80 [95% CI 0.67 -0.95])”

In the citing paper

“The risk of the primary composite outcome was 30% lower with canagli fl ozin treatment when compared with placebo (HR 0.70 [95% CI 0.59 -0.82]).”

In the citing paper

“In terms of safety, no signi fi cant increase in lower-limb amputations, fractures, acute kidney injury, or hyperkalemia was noted for canaglifl ozin relative to placebo in CREDENCE.”

In the citing paper

“An increased risk for diabetic ketoacidosis was noted, however, with 2.2 and 0.2 events per 1,000 patient-years noted in the canagli fl ozin and placebo groups, respectively (HR 10.80 [95% CI 1.39 -83.65]) (194).”

In the citing paper

“Moreover, it reduced the prespeci fi ed end point of end-stage kidney disease alone by 32% (HR 0.68 [95% CI 0.54 -0.86]).”

In the citing paper

“The trial was stopped early due to conclusive evidence of ef fi cacy identi fi ed during a prespeci fi ed interim analysis with no unexpected safety signals.”

In the citing paper

“Reduced incidence of heart failure has been observed with the use of SGLT2 inhibitors (8,194,196).”

In the citing paper

“In summary, there are now numerous large randomized controlled trials reporting statistically signi fi cant reductions in cardiovascular events for three of the FDA-approved SGLT2 inhibitors (empagli fl ozin, canagli fl ozin, dapagli fl ozin, with lesser bene fi ts seen with ertugli fl ozin)”

In the citing paper

“Additional data from the CREDENCE trial with canagli fl ozin showed a 39% reduction in hospitalization for heart failure, and 31% reduction in the composite of cardiovascular death or hospitalization for heart failure, in a diabetic kidney disease population with albuminuria (UACR &gt; 300 to 5,000 mg/g) (194).”

In the citing paper

“In addition, they slow the rate of decline in kidney function in these patients and reduce renal morbidity and mortality in patients with type 2 diabetes and kidney dysfunction.”

In the citing paper

“Despite improvements in kidney outcomes with available pharmacotherapies, the risk of kidney failure in people with CKD and T2D remains high [14,15].”

In the citing paper

“Despite the availability of established and newer pharmacotherapies to delay CKD progression in people with T2D, the risk of progression and the associated morbidity and mortality remains substantial [14,15].”

In the citing paper

“However, increased amputation risk has not been seen with other SGLT2 inhibitors, nor with canagliflozin in the subsequent CREDENCE (Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation) trial, in which such adverse events were systematically collected.40”