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 <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >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 m2), 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

Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions

: This article summarizes the current literature and documents new evidence concerning drug-drug interactions (DDI) stemming from pharmacogenomic and circadian rhythm determinants of therapies used to treat common cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Patients with CVD often have more than one pathophysiologic condition, namely metabolic syndromes, hypertension, hyperlipidemia, and hyperglycemia, among others, which necessitate polytherapeutic or polypharmaceutic management. Interactions between drugs, drugs and food/food supplements, or drugs and genetic/epigenetic factors may have adverse impacts on the cardiovascular and other systems of the body. The mechanisms underlying cardiovascular DDI may involve the formation of a complex pharmacointeractome, including the absorption, distribution, metabolism, and elimination of drugs, which affect their respective bioavailability, efficacy, and/or harmful metabolites. The pharmacointeractome of cardiovascular drugs is likely operated with endogenous rhythms controlled by circadian clock genes. Basic and clinical investigations have improved the knowledge and understanding of cardiovascular pharmacogenomics and pharmacointeractomes, and additionally they have presented new evidence that the staging of deterministic circadian rhythms, according to the dosing time of drugs, e.g., upon awakening vs. at bedtime, cannot only differentially impact their pharmacokinetics and pharmacodynamics but also mediate agonistic/synergetic or antagonistic DDI. To properly manage CVD patients and avoid DDI, it is important that clinicians have sufficient knowledge of their multiple risk factors, i.e., age, gender, and life style elements (like diet, smoking, psychological stress, and alcohol consumption), and comorbidities, such as diabetes, hypertension, dyslipidemia, and depression, and the potential interactions between genetic or epigenetic background of their prescribed therapeutics

Chronotherapy of blood pressure medications to improve management of hypertension and reduce vascular risk

Correlation between blood pressure (BP) and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than daytime in-clinic measurements. Additionally, consistent evidence of numerous studies substantiates the ABPM-determined asleep BP mean is an independent and stronger predictor of CVD risk than the awake or 24h means. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of six different classes and their combinations significantly impacts their beneficial and/or adverse effects. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime versus morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) better controls the asleep BP mean, with additional benefit, independent of medication terminal half-life, of converting the 24h BP profile into more normal dipper patterning. The MAPEC Study, first prospective randomized treatment-time investigation testing the worthiness of bedtime chronotherapy with ≥1 conventional hypertension medications to specifically target attenuation of asleep BP, demonstrated, relative to conventional morning therapy, significant reduction of CVD risk: adjusted hazard ratio (HR) of total CVD events (HR=0.39 95%CI [0.29-0.51]; P<0.001) and major CVD events, i.e., CVD deaths, myocardial infarctions, and ischemic and hemorrhagic strokes (HR=0.33 [0.19-0.55]; P<0.001). CVD risk reduction was strongest when bedtime treatment included an ARB. The MAPEC Study not only documents the asleep BP mean is the most significant prognostic marker of CVD and stroke morbidity and mortality, but it also substantiates attenuation of the asleep BP mean by a bedtime hypertension treatment strategy with the entire daily dose of ≥1 hypertension medications significantly reduces CVD risk, both in the general hypertension population and in patients of greater vulnerability and enhanced CVD risk, i.e., those diagnosed with chronic kidney disease, diabetes, and resistant hypertension

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention

Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ τ 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker – the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase “circadian disruption” (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson’s disease; Smith–Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain β-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it

Prognostic Effect of the Nocturnal Blood Pressure Fall in Hypertensive Patients

The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment ( P <0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels