Anemia is common in type 2 diabetes (T2D), particularly in patients with kidney impairment, and often goes unrecognized. Dapagliflozin treatment increases hemoglobin and serum erythropoietin levels. ...We investigated the effect of dapagliflozin 10-mg/day on hemoglobin in T2D patients with and without anemia.
Data from 5325 patients from 14 placebo-controlled, dapagliflozin-treatment studies of at least 24-weeks duration were pooled. Dapagliflozin's effects (vs. placebo) on hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), systolic blood pressure, body weight, and safety in patients with and without anemia were evaluated.
At baseline, 13% of all T2D patients and 28% of those with chronic kidney disease (eGFR <60 mL/min/1.73 m2) had anemia. Hemoglobin increased continuously to at least week 8 and was sustained throughout 24-weeks follow-up in dapagliflozin-treated patients. Serum albumin increased in dapagliflozin-treated patients at week 4 and remained stable thereafter. Dapagliflozin was well tolerated and corrected anemia in 52% of patients with anemia at baseline (placebo: 26%). Incidences of new-onset anemia were lower in dapagliflozin-treated (2.3%) versus placebo-treated (6.5%) patients.
Treatment with dapagliflozin can correct and prevent anemia in T2D patients. A gradual increase in hemoglobin beyond week 4 may indicate an erythropoiesis-stimulating effect of sodium-glucose cotransporter 2 inhibition.
•14 placebo-controlled, dapagliflozin (DAPA)-treatment studies (N = 5325) were pooled.•Hemoglobin increase was sustained through 24-weeks follow-up in DAPA-treated patients.•DAPA corrected anemia in 52% of patients with anemia at baseline (placebo: 26%).•Incidences of new-onset anemia were lower in DAPA (2.3%) vs placebo (6.5%).•Treatment with DAPA can correct and prevent anemia in patients with type 2 diabetes.
Chronic kidney disease (CKD) is highly prevalent but identification of patients at high risk for fast CKD progression before reaching end-stage renal disease in the short-term has been challenging. ...Whether factors associated with fast progression vary by diabetes status is also not well understood. We examined a large community-based cohort of adults with CKD to identify predictors of fast progression during the first 2 years of follow-up in the presence or absence of diabetes mellitus.
Within a large integrated healthcare delivery system in northern California, we identified adults with estimated glomerular filtration rate (eGFR) 30-59 ml/min/1.73 m
by CKD-EPI equation between 2008 and 2010 who had no previous dialysis or renal transplant, who had outpatient serum creatinine values spaced 10-14 months apart and who did not initiate renal replacement therapy, die or disenroll during the first 2 years of follow-up. Through 2012, we calculated the annual rate of change in eGFR and classified patients as fast progressors if they lost > 4 ml/min/1.73 m
per year. We used multivariable logistic regression to identify patient characteristics that were independently associated with fast CKD progression stratified by diabetes status.
We identified 36,195 eligible adults with eGFR 30-59 ml/min/1.73 m
and mean age 73 years, 55% women, 11% black, 12% Asian/Pacific Islander and 36% with diabetes mellitus. During 24-month follow-up, fast progression of CKD occurred in 23.0% of patients with diabetes vs. 15.3% of patients without diabetes. Multivariable predictors of fast CKD progression that were similar by diabetes status included proteinuria, age ≥ 80 years, heart failure, anemia and higher systolic blood pressure. Age 70-79 years, prior ischemic stroke, current or former smoking and lower HDL cholesterol level were also predictive in patients without diabetes, while age 18-49 years was additionally predictive in those with diabetes.
In a large, contemporary population of adults with eGFR 30-59 ml/min/1.73 m
, accelerated progression of kidney dysfunction within 2 years affected ~ 1 in 4 patients with diabetes and ~ 1 in 7 without diabetes. Regardless of diabetes status, the strongest independent predictors of fast CKD progression included proteinuria, elevated systolic blood pressure, heart failure and anemia.
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.
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.
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.
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.
Aims/hypothesis
In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart ...failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories.
Methods
DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25–75 ml min
−1
1.73 m
−2
and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200–5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories.
Results
Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all
p
for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (
p
for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories.
Conclusion/interpretations
The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity.
Trial registration
ClinicalTrials.gov
NCT03036150.
Funding
The study was funded by AstraZeneca.
Graphical abstract
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).
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).
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.
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.
Greater interdialytic weight gain (IDWG) is associated with risk of all-cause mortality and hospitalization. Dialysis patients are also at greater risk of cardiovascular (CV) events than patients ...without kidney disease. This retrospective study examined the potential association between IDWG and specific types of CV events.
Data were obtained from United States Renal Data System claims and the electronic health records of Medicare patients who initiated hemodialysis between 01 January 2007 and 31 December 2008 at a large dialysis organization. Absolute IDWG was defined as predialysis weight minus postdialysis weight from the prior treatment, and relative IDWG was calculated as percentage of postdialysis weight with mean values for each, calculated over dialysis days 91 to 180. Patient outcomes were considered beginning on day 181, continuing until death, discontinuation of care, censoring, or study end (31 December 2009). Outcomes included all-cause mortality, CV mortality, hospitalization for nonfatal heart failure/volume overload, hospitalization for nonfatal myocardial infarction, MACE (a composite measure of nonfatal myocardial infarction, nonfatal ischemic stroke, or CV death), and MACE+ (events comprising MACE as well as arrhythmia, nonfatal hemorrhagic stroke, or hospitalization for heart failure). Associations between IDWG and outcomes over the exposure period were estimated using proportional hazards regression and adjusted for baseline characteristics.
39,256 patients qualified for analysis. In general, associations of relative IDWG with outcomes were more potent, consistent, and monotonic than those for absolute IDWG. Relative IDWG > 3.5 % body weight was independently associated with all outcomes studied: point estimates ranged from 1.18 (myocardial infarction) to 1.26 (CV mortality) and were consistent among patients with and without diabetes, and with and without baseline heart failure. Absolute IDWG > 3 kg was associated with outcomes other than myocardial infarction: point estimates ranged from 1.11 (MACE) to 1.20 (heart failure).
Greater IDWG is associated with an increased risk of CV morbid events. Strategies that mitigate IDWG may improve CV health and survival among hemodialysis patients.
Dapagliflozin reduces kidney failure risk in patients with CKD but can result in a reversible acute reduction in eGFR upon treatment initiation. Determinants of this eGFR reduction and its ...associations with efficacy and safety outcomes are unknown.
The DAPA-CKD trial randomized 4304 adults with CKD and albuminuria to once-daily dapagliflozin 10 mg or placebo, added to standard care. We prespecified an analysis comparing the effects of dapagliflozin among patients who experienced relative reductions in eGFR (>10% or >0%-10%) or an increase in eGFR from baseline to 2 weeks and assessed long-term efficacy and safety thereafter.
A total of 4157 (96.6%) patients had eGFR data available at baseline and at 2 weeks. In the dapagliflozin and placebo groups, 1026 (49.4%) and 494 (23.7%), respectively, experienced an acute reduction in eGFR >10%. Among patients receiving dapagliflozin, those with an acute reduction in eGFR >10% experienced a long-term eGFR decline of -1.58 ml/min per 1.73 m
per year compared with -2.44 and -2.48 ml/min per 1.73 m
per year among those experiencing a less pronounced reduction or increase in eGFR, respectively (
-interaction=0.05). In the placebo group, long-term eGFR decline was -3.27, -3.84, and -3.77 ml/min per 1.73 m
per year for acute eGFR reduction subgroups of >10%, >0%-10%, or increase in eGFR (
-interaction=0.48). Rates of serious adverse events and adverse events of special interest in patients randomized to dapagliflozin were unrelated to the acute eGFR change.
Among patients with CKD and albuminuria treated with dapagliflozin, an acute reduction in eGFR (from baseline to 2 weeks) is not associated with higher rates of CKD progression.
A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) NCT03036150.
Hypomagnesemia (serum magnesium Mg <0.74 mmol/L <1.8 mg/dL) is commonly observed in patients with type 2 diabetes (T2D). This study investigated the effect of treatment with dapagliflozin 10 mg on Mg ...concentrations in patients with T2D.
In this post hoc analysis, we used pooled data from 10 placebo-controlled studies of dapagliflozin over 24 weeks of treatment in patients with T2D. We evaluated the change in Mg in patients receiving dapagliflozin vs. placebo overall, and in subgroups with baseline hypomagnesemia and normal/hypermagnesemia (≥0.74 mmol/L ≥1.8 mg/dL). We determined the proportion of patients with baseline hypomagnesemia who achieved Mg ≥0.74 mmol/L (≥1.8 mg/dL).
A total of 4398 patients with T2D were included. The mean change from baseline to week 24 in Mg was significantly larger with dapagliflozin vs. placebo; difference, 0.06 mmol/L (95% confidence interval CI: 0.05, 0.06). The proportion of patients with Mg within the population reference range after 24 weeks of treatment was significantly higher with dapagliflozin vs. placebo; difference, 47.8% (95% CI: 41.4, 53.9). The proportion of patients displaying hypermagnesemia did not increase with dapagliflozin treatment.
Treatment with dapagliflozin 10 mg resulted in correction of Mg concentrations in patients with T2D and hypomagnesemia.
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