Effects of the sodium–glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b–4 chronic kidney disease

BACKGROUND: The sodium–glucose co-transporter 2 inhibitor dapagliflozin decreases haemoglobin A1c (HbA1c), body weight, blood pressure (BP) and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes. The efficacy and safety of this drug have not been properly defined in patients with type 2 diabetes and Stages 3b–4 chronic kidney disease (CKD). METHODS: In a pooled analysis of 11 phase 3 randomized controlled clinical trials, we determined least square mean changes in HbA1c, body weight, BP, estimated glomerular filtration rate (eGFR) and UACR over 102 weeks in patients with type 2 diabetes and an eGFR between 12 to less than 45 mL/min/1.73 m2 receiving placebo (n = 69) or dapagliflozin 5 or 10 mg (n = 151). Effects on UACR were determined in a subgroup of patients with baseline UACR ≥30 mg/g (n = 136). RESULTS: Placebo-corrected changes in HbA1c with dapagliflozin 5 and 10 mg were 0.03% [95% confidence interval (CI) −0.3–0.3] and 0.03% (95% CI −0.2–0.3) during the overall 102-week period. Dapagliflozin 5 and 10 mg compared with placebo reduced UACR by − 47.1% (95% CI −64.8 to − 20.6) and −38.4% (95% CI −57.6 to − 10.3), respectively. Additionally, dapagliflozin 5 and 10 mg compared with placebo reduced BP and body weight. eGFR increased with placebo during the first 4 weeks but did not change with dapagliflozin. There were no between-group differences in eGFR at the end of follow-up. Adverse events associated with renal function occurred more frequently in the dapagliflozin 10-mg group. These events were mainly asymptomatic increases in serum creatinine. CONCLUSIONS: Dapagliflozin did not decrease HbA1c in patients with type 2 diabetes and Stages 3b–4 CKD, but decreased UACR, BP and body weight to a clinically meaningful extent. These results support a large outcome trial in this population to confirm long-term safety and efficacy in reducing adverse clinical endpoints

The potential roles of osmotic and non-osmotic sodium handling in mediating effects of SGLT2 inhibitors on heart failure

Concomitant type 2 diabetes and chronic kidney disease (CKD) increases the risk of heart failure (HF). Recent STUDIES: demonstrate beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on CKD progression and HF hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2i reduce proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2i's natriuretic and osmotic diuretic effects mediate their cardio-protective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2i could also modulate non-osmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional two-compartment model of sodium balance to provide support for a three-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on non-osmotic sodium storage, as well as direct cardiac effects of SGLT2i, provides possibilities for other ways in which SGLT2i might mitigate HF risk. Overall, we review the effects of SGLT2i on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and non-osmotic sodium storage

Mechanisms of action of the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial

Aims: To test the hypothesis that the reduction in urinary kidney injury molecule-1 (KIM-1) observed with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein-1 (MCP-1) by assessing the proportion of the effect of canagliflozin on KIM-1 that is mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. Material and methods: We measured KIM-1 and MCP-1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation. Results: In total, 763 patients with micro- or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr and KIM-1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95% CI 9.4, 24.5). Conclusion: Canagliflozin reduces urinary KIM-1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings

Data from a pooled post hoc analysis of 14 placebo-controlled, dapagliflozin treatment studies in patients with type 2 diabetes with and without anemia at baseline

Dapagliflozin is a highly selective sodium-glucose cotransporter 2 inhibitor associated with stabilization of estimated glomerular filtration rate (eGFR); reductions in glycated hemoglobin (HbA1c), systolic blood pressure, body weight, and albuminuria; and a small and consistent increase in hematocrit [1], [2], [3], [4]. This data set is based on the associated article [5] analyzing data from 5325 patients with type 2 diabetes from 14 placebo-controlled, phase 3 (one phase 2/3), double-blind dapagliflozin treatment studies of 24-104 weeks' duration. Data on dapagliflozin's effects (vs. placebo) on hemoglobin (Hb), hematocrit, serum albumin, serum total protein concentrations, urine albumin/creatinine ratio, eGFR, heart rate, blood pressure, body weight, and safety in patients with type 2 diabetes with and without anemia were pooled and analyzed. Patients were divided into two groups according to baseline Hb levels: anemia (Hb 16.5 g/dL in men and >16.0 g/dL in women). Because anemia commonly occurs in patients with diabetes and chronic kidney disease [6], the data can be of value to further analyze trends in relevant physiological and pathophysiological parameters

Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers

BACKGROUND: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function. METHODS: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes. RESULTS: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively. CONCLUSIONS: The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints

Association between circulating GDF-15 and cardio-renal outcomes and effect of canagliflozin: results from the CANVAS trial

Background Studies have suggested that sodium glucose co-transporter 2 inhibitors exert anti-inflammatory effects. We examined the association of baseline growth differentiation factor-15 (GDF-15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on circulating GDF-15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF-15 and cardiovascular (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end-stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow-up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF-15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF-15 did not modify canagliflozin's effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF-15 compared with placebo; however, GDF-15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF-15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF-15, but GDF-15 reduction did not mediate the protective effect of canagliflozin

Interleukin-6 and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: New Insights From CANVAS

OBJECTIVE The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multi-variable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model. RESULTS The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively. CONCLUSIONS In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6–lowering therapy on CV, kidney, and safety outcomes remains to be tested

Different eGFR decline thresholds and renal effects of cnagliflozin: data from the CANVAS program

BACKGROUND: Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes. METHODS: To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect. RESULTS: Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect. CONCLUSIONS: Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754

Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial

Background: Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause. Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25–75 mL/min per 1·73m2 were randomly assigned (1:1) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. Secondary efficacy outcomes were a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality. In this study, we conducted a prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by aetiology of chronic kidney disease. DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150. Findings: The study took place between Feb 2, 2017, and June 12, 2020. 4304 participants were randomly assigned (2152 to dapagliflozin and 2152 to placebo) and were followed up for a median of 2·4 years (IQR 2·0–2·7). Overall, 2906 (68%) participants had a diagnosis of type 2 diabetes, of whom 396 (14%) had chronic kidney disease ascribed to causes other than diabetic nephropathy. The relative risk reduction for the primary composite outcome with dapagliflozin was consistent in participants with type 2 diabetes (hazard ratio [HR] 0·64, 95% CI 0·52–0·79) and those without diabetes (0·50, 0·35–0·72; pinteraction=0·24). Similar findings were seen for the secondary outcomes: kidney-specific composite outcome (0·57 [0·45–0·73] vs 0·51 [0·34–0·75]; Pinteraction=0·57), cardiovascular death or hospital admission for heart failure (0·70 [0·53–0·92] vs 0·79 [0·40–1·55]; Pinteraction=0·78), and all-cause mortality (0·74 [0·56–0·98] vs 0·52 [0·29–0·93]; Pinteraction=0·25). The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51–0·78), glomerulonephritides (n=695; 0·43, 0·26–0·71), ischaemic or hypertensive chronic kidney disease (n=687; 0·75, 0·44–1·26), and chronic kidney disease of other or unknown cause (n=412; 0·58, 0·29–1·19; Pinteraction=0·53), with similar consistency seen across the secondary outcomes. The proportions of participants in the dapagliflozin and placebo groups who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes. Interpretation: Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease