Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Duchenne muscular dystrophy: Current aspects and perspectives on treatment [Distrofia muscular de Duchenne: Actualidad y perspectivas de tratamiento]

Introduction and development. Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease of genetic origin that affects male children. It is characterized by progressive muscle deterioration which results in the patient becoming wheelchair-dependent until death from cardio-respiratory complications. A few years ago, DMD patients' life quality and expectancy were poor and treatment options limited; valuable recommendations that significantly delay the progress of the disease and improve the patient's life quality have been brought about recently. Numerous therapeutic approaches are now in development in order to correct the DMD genetic defect at molecular level. In the mean time, a comprehensive system to maintain patients in their best possible physical condition is needed. Conclusions. Accurate detection of complications enables caregivers to determine which patients are at higher risk and to provide treatment accordingly. Nevertheless, all of these efforts are dependent on early clinical and molecular diagnosis, careful record of clinical changes and long-term followup of DMD patients. Furthermore, the involvement of multidisciplinary groups and the patient's family is essential in said interventions. Zapotitlán 2009, Revista de Neurología

Duchenne muscular dystrophy in a developing country: Challenges in management and genetic counseling

Background and objective: Multidisciplinary management of Duchenne Muscular Dystrophy (DMD) has achieved outstanding results in developed nations. We aimed to describe the status of diagnosis and management of DMD in a developing country through the experience of non-profit organizations. Methods: A Multistate, multiple-source, population-based survey was performed from medical records of 432 patients. Data were retrospectively collected, reviewed and curated by health specialists; including clinical features, age at first symptoms, age at diagnosis, disease progression and management, family history, education, age and cause of death. Results: There is a delay in noticing first symptoms and it did not diminish over the past 20 years. Less than 30% of patients obtained definite diagnosis and most of them are in physiotherapy programs but not under steroid treatment. In our study, family history does not anticipate recognition of symptoms compared to sporadic cases (p=0.05). Approximately 93.33% of our patients attended to education programs. Mean age at death was 18.94 ± 6.73 years and the most frequent cause was pneumonia. Conclusion: Delayed diagnosis of DMD in Mexico is mainly caused by the late detection of first symptoms. There is no difference in early detection of symptoms between familiar and sporadic cases. Lifespan of patients in our cohort is reduced compared to developed countries. The late diagnosis and low percentage of definite cases may affect patient management and genetic counseling and could also preclude participation of patients into novel clinical trials

Duchenne muscular dystrophy in a developing country: Challenges in management and genetic counseling

Background and objective: Multidisciplinary management of Duchenne Muscular Dystrophy (DMD) has achieved outstanding results in developed nations. We aimed to describe the status of diagnosis and management of DMD in a developing country through the experience of non-profit organizations. Methods: A Multistate, multiple-source, population-based survey was performed from medical records of 432 patients. Data were retrospectively collected, reviewed and curated by health specialists; including clinical features, age at first symptoms, age at diagnosis, disease progression and management, family history, education, age and cause of death. Results: There is a delay in noticing first symptoms and it did not diminish over the past 20 years. Less than 30% of patients obtained definite diagnosis and most of them are in physiotherapy programs but not under steroid treatment. In our study, family history does not anticipate recognition of symptoms compared to sporadic cases (p=0.05). Approximately 93.33% of our patients attended to education programs. Mean age at death was 18.94 Zapotitlán 6.73 years and the most frequent cause was pneumonia. Conclusion: Delayed diagnosis of DMD in Mexico is mainly caused by the late detection of first symptoms. There is no difference in early detection of symptoms between familiar and sporadic cases. Lifespan of patients in our cohort is reduced compared to developed countries. The late diagnosis and low percentage of definite cases may affect patient management and genetic counseling and could also preclude participation of patients into novel clinical trials

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale &amp; Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study. Study Design: Secondary analysis of a randomized controlled trial. Setting &amp; Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (&lt;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 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite 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 [0.48-0.82], and 0.89 [0.61-1.29] for ages &lt;60, 60-69, and ≥70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] 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

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups Results From the Randomized CREDENCE Trial

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). METHODS: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791

The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics

Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of â\u88¼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate â\u89¥30 to 300 to â\u89¤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791