Browsing by Author "Mahaffey, Kenneth W."
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Item Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial(American Heart Association, 2021) Ye, Nan; Jardine, Meg J.; Oshima, Megumi; Hockham, Carinna; Heerspink, Hiddo J. L.; Agarwal, Rajiv; Bakris, George; Schutte, Aletta E.; Arnott, Clare; Chang, Tara I.; Górriz, Jose L.; Cannon, Christopher P.; Charytan, David M.; de Zeeuw, Dick; Levin, Adeera; Mahaffey, Kenneth W.; Neal, Bruce; Pollock, Carol; Wheeler, David C.; Di Tanna, Gian Luca; Cheng, Hong; Perkovic, Vlado; Neuen, Brendon L.; Medicine, School of MedicineBackground: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. Methods: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. Conclusions: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier:Item Canagliflozin, Blood Pressure Variability, and Risk of Cardiovascular, Kidney, and Mortality Outcomes: Pooled Individual Participant Data From the CANVAS and CREDENCE Trials(American Heart Association, 2023) Fletcher, Robert A.; Arnott, Clare; Rockenschaub, Patrick; Schutte, Aletta E.; Carpenter, Lewis; Vaduganathan, Muthiah; Agarwal, Rajiv; Bakris, George; Chang, Tara I.; Heerspink, Hiddo J. L.; Jardine, Meg J.; Mahaffey, Kenneth W.; Neal, Bruce; Pollock, Carol; Jun, Min; Rodgers, Anthony; Perkovic, Vlado; Neuen, Brendon L.; Medicine, School of MedicineBackground: Sodium glucose cotransporter‐2 inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty regarding the prognostic value of SBP variability for different clinical outcomes. Methods and Results: Using individual participant data from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, we assessed the effect of canagliflozin on SBP variability in people with type 2 diabetes across 4 study visits over 1.5 years as measured by standard deviation, coefficient of variation, and variability independent of the mean. We used multivariable Cox regression models to estimate associations of SBP variability with cardiovascular, kidney, and mortality outcomes. In 11 551 trial participants, canagliflozin modestly lowered the standard deviation of SBP variability (−0.25 mm Hg [95% CI, –0.44 to −0.06]), but there was no effect on coefficient of variation (0.02% [95% CI, –0.12 to 0.16]) or variability independent of the mean (0.08 U [95% CI, –0.11 to 0.26]) when adjusting for correlation with mean SBP. Each 1 standard deviation increase in standard deviation of SBP variability was independently associated with higher risk of hospitalization for heart failure (hazard ratio [HR], 1.19 [95% CI, 1.02–1.38]) and all‐cause mortality (HR, 1.12 [95% CI, 1.01–1.25]), with consistent results observed for coefficient of variation and variability independent of the mean. Increases in SBP variability were not associated with kidney outcomes. Conclusions: In people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease, higher visit‐to‐visit SBP variability is independently associated with risks of hospitalization for heart failure and all‐cause mortality. Canagliflozin has little to no effect on SBP variability, independent of its established SBP‐lowering effect.Item Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial(Wiley, 2016-07) Pun, Patrick H.; Abdalla, Safa; Block, Geoffrey A.; Chertow, Glenn M.; Correa-Rotter, Ricardo; Dehmel, Bastian; Drüeke, Tilman B.; Floege, Jürgen; Goodman, William G.; Herzog, Charles A.; London, Gerard M.; Mahaffey, Kenneth W.; Moe, Sharon M.; Parfrey, Patrick S.; Wheeler, David C.; Middleton, John P.; Medicine, School of MedicineAmong patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.Item Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial(American Heart Association, 2022) Li, Jing-Wei; Arnott, Clare; Heerspink, Hiddo J.L.; Li, Qiang; Cannon, Christopher P.; Wheeler, David C.; Charytan, David M.; Barraclough, Jennifer; Figtree, Gemma A.; Agarwal, Rajiv; Bakris, George; de Zeeuw, Dick; Greene, Tom; Levin, Adeera; Pollock, Carol; Zhang, Hong; Zinman, Bernard; Mahaffey, Kenneth W.; Perkovic, Vlado; Neal, Bruce; Jardine, Meg J.; Medicine, School of MedicineBackground: The sodium‐glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. Methods and Results: The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m2, over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63–0.86]; P<0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59–0.86]; P<0.001). The absolute risk difference per 1000 patients treated over 2.5 years was −44 (95% CI, −67 to −21) first cardiovascular events and −73 (95% CI, −114 to −33) total events. Conclusions: Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events.Item Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2: Subgroup Analysis of the Randomized CREDENCE Trial(Wolters Kluwer, 2020-12-07) Bakris, George; Oshima, Megumi; Mahaffey, Kenneth W.; Agarwal, Rajiv; Cannon, Christopher P.; Capuano, George; Charytan, David M.; de Zeeuw, Dick; Edwards, Robert; Greene, Tom; Heerspink, Hiddo J.L.; Levin, Adeera; Neal, Bruce; Oh, Richard; Pollock, Carol; Rosenthal, Norman; Wheeler, David C.; Zhang, Hong; Zinman, Bernard; Jardine, Meg J.; Perkovic, Vlado; Medicine, School of MedicineBackground and objectives: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization. Design, setting, participants, & measurements: Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2). Results: From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12). Conclusions: This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.Item Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial(Elsevier, 2021) Sarraju, Ashish; Li, JingWei; Cannon, Christopher P.; Chang, Tara I.; Agarwal, Rajiv; Bakris, George; Charytan, David M.; de Zeeuw, Dick; Greene, Tom; Heerspink, Hiddo J. L.; Levin, Adeera; Neal, Bruce; Pollock, Carol; Wheeler, David C.; Yavin, Yshai; Zhang, Hong; Zinman, Bernard; Perkovic, Vlado; Jardine, Meg; Mahaffey, Kenneth W.; Medicine, School of MedicineWe aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.Item The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial(American Society of Nephrology, 2015-05-07) Parfrey, Patrick S.; Drüeke, Tilman B.; Block, Geoffrey A.; Correa-Rotter, Ricardo; Floege, Jürgen; Herzog, Charles A.; London, Gerard M.; Mahaffey, Kenneth W.; Moe, Sharon M.; Wheeler, David C.; Kubo, Yumi; Dehmel, Bastian; Goodman, William G.; Chertow, Glenn M.; Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Investigators; Department of Medicine, IU School of MedicineBACKGROUND AND OBJECTIVES: The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. RESULTS: Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. CONCLUSIONS: In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.Item Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial(Ovid Technologies Wolters Kluwer -American Heart Association, 2014-12) Wheeler, David C.; London, Gerard M.; Parfrey, Patrick S.; Block, Geoffrey A.; Correa‐Rotter, Ricardo; Dehmel, Bastian; Drüeke, Tilman B.; Floege, Jürgen; Kubo, Yumi; Mahaffey, Kenneth W.; Goodman, William G.; Moe, Sharon M.; Trotman, Marie-Louise; Abdalla, Safa; Chertow, Glenn M.; Herzog, Charles A.; Department of Medicine, IU School of MedicineBACKGROUND: Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial. METHODS AND RESULTS: EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance. CONCLUSIONS: Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes. CLINICAL TRIALS REGISTRATION: Unique identifier: NCT00345839. URL: ClinicalTrials.gov.Item Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial(American Society of Nephrology (ASN), 2015-06) Moe, Sharon M.; Abdalla, Safa; Chertow, Glenn M.; Parfrey, Patrick S.; Block, Geoffrey A.; Correa-Rotter, Ricardo; Floege, Jürgen; Herzog, Charles A.; London, Gerard M.; Mahaffey, Kenneth W.; Wheeler, David C.; Dehmel, Bastian; Goodman, William G.; Drüeke, Tilman B.; Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Investigators; Department of Medicine, IU School of MedicineFractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.Item Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice(Elsevier, 2021) Oshima, Megumi; Jardine, Meg J.; Agarwal, Rajiv; Bakris, George; Cannon, Christopher P.; Charytan, David M.; de Zeeuw, Dick; Edwards, Robert; Greene, Tom; Levin, Adeera; Lim, Soo Kun; Mahaffey, Kenneth W.; Neal, Bruce; Pollock, Carol; Rosenthal, Norman; Wheeler, David C.; Zhang, Hong; Zinman, Bernard; Perkovic, Vlado; Heerspink, Hiddo J. L.; Medicine, School of MedicineCanagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.