Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed... Show moreRationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (<60, 60-69, and >_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 & PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and >_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791. Show less
The debate whether statins, 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are safe to use has been raging since their introduction in 1987. Statins are generally well tolerated... Show moreThe debate whether statins, 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are safe to use has been raging since their introduction in 1987. Statins are generally well tolerated and are believed to have minimal adverse effects. However, individual, specific rare adverse events have been reported, such as elevations of liver enzymes, muscle aches, and very rarely, rhabdomyolysis. Discontinuation and/or reduction in the dose of the statin usually leads to resolution of these side effects. Recently, however, debate has focused on the possible negative long-term effects of statin treatment on cognitive decline, the incidence of cancer, and the development of diabetes mellitus. Recently, the U.S. Food and Drug Administration has expanded the warning for statins with a statement that statin use may lead to cognitive impairment. In this review, we discuss all levels of evidence, from case reports to large randomized controlled clinical trials, for the possible adverse effects of statins on cognitive decline, cancer, and diabetes. After careful consideration of all discussed scientific evidence, we conclude that there is no increased risk of cognitive decline or cancer with statin use. However, statin use is related to a small increased risk of type 2 diabetes mellitus. In view of the overwhelming benefit of statins in the reduction of cardiovascular events, we believe the small absolute risk for development of diabetes is outweighed by the cardiovascular benefits in patients for whom statin therapy is recommended. We, therefore, suggest that clinical practice for statin therapy should not be changed on the basis of the most recent Food and Drug Administration informational warnings. Show less
