Long-term effects of intensive glycemic and blood pressure control and fenofibrate use on kidney outcomes

Background and objectives In people with type 2 diabetes, aggressive control of glycemia, BP, and lipids have resulted in conflicting short-term (<5 years) kidney outcomes. We aimed to determine the long-term kidney effects of these interventions. Design, setting, participants, & measurements The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a multifactorial intervention study in people with type 2 diabetes at high risk for cardiovascular disease (n=10,251), to examine the effects of intensive glycemic control (hemoglobin A1c <6.0% versus 7%-7.9%), BP control (systolic BP <120 mm Hg versus <140 mm Hg) or fenofibrate versus placebo added to simvastatin on cardiovascular events and death. The glycemia trial lasted 3.7 years and participants were followed for another 6.5 years in ACCORDION, the ACCORD Follow-On Study. The post hoc primary composite kidney outcome was defined as incident macroalbuminuria, creatinine doubling, need for dialysis, or death by any cause. Cox proportional hazards regression estimated the effect of each intervention on the composite outcome and individual components. In secondary outcome analyses, competing risk regression was used to account for the risk of death in incident kidney outcomes. Analyses were adjusted for sociodemographics, randomization groups, and clinical factors. Results There were 988 cases of incident macroalbuminuria, 954 with doubling of creatinine, 351 requiring dialysis, and 1905 deaths. Hazard ratios (HRs) for the composite outcome with intensive glycemic, BP control, and fenofibrate use compared with standard therapy were 0.92 (95% confidence interval [95% CI], 0.86 to 0.98), 1.16 (95% CI, 1.05 to 1.28), and 1.16 (95% CI, 1.06 to 1.27). Multivariable, secondary outcome analyses showed that in the glycemia trial, only macroalbuminuria was significantly decreased (HR, 0.68; 95% CI, 0.59 to 0.77). In the BP and lipid trials, only creatinine doubling was affected (HR, 1.64; 95% CI, 1.30 to 2.06 and HR, 2.00; 95% CI, 1.61 to 2.49, respectively). Conclusions In people with type 2 diabetes at high risk for cardiovascular disease, intensive glycemic control may result in a long-term reduction in macroalbuminuria; however, intensive BP control and fenofibrates may increase the risk for adverse kidney events

Modulation of GLP-1 levels by a genetic variant that regulates the cardiovascular effects of intensive glycemic control in ACCORD

OBJECTIVE A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants. RESEARCH DESIGN AND METHODS Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD- MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (D), among white subjects, with genotype data (n = 351) stratified by intervention arm. RESULTS A significant association was observed between GRS and DGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 3 1024). This effect was driven by rs57922 (P = 5 3 1024). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between DGLP-1 and GRS or rs57922 was observed in the standard treatment arm. CONCLUSIONS Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor

Rhythm of Pandanaceae

Essential oil is commonly used for emotional and physical wellness applications (aromatherapy). To date, approximately 3,000 varieties of essential oils have been identified. The quality of essential oil depends on the season, geographic location, method and duration of distillation, year the extract plant is grown, and the climate

Genetic tools for coronary risk assessment in type 2 diabetes: A cohort study from the ACCORD clinical trial

OBJECTIVE We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. RESEARCH DESIGN AND METHODS A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. RESULTS The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18–1.37, P = 4 3 10210, and HR per SD 1.35, 95% CI 1.16–1.58, P = 2 3 1024, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 3 1024). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. CONCLUSIONS When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci

PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes: Findings from accord-lipid

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-a), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction 5 3.7 3 1024). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N 5 585, P 5 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N 5 3059, P 5 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction 5 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia

Increasing age is a major risk factor for susceptibility to heat stress during physical activity

We evaluated the extent to which age, cardiorespiratory fitness, and body fat can independently determine wholebody heat loss (WBHL) in 87 otherwise healthy adults. We show that increasing age is a major predictor for decreasing WBHL in otherwise healthy adults (aged 20-70 years), accounting for 40% of the variation in the largest study to date. While greater body fat also had a minor detrimental impact on WBHL, there was no significant role for cardiorespiratory fitness. © 2017, Canadian Science Publishing. All rights reserved

Exercise Heat Stress in Patients with and Without Type 2 Diabetes

[No abstract available

Aging Impairs Whole-Body Heat Loss in Women under Both Dry and Humid Heat Stress

Purpose This study was designed to determine whether age-related impairments in whole-body heat loss, which are known to exist in dry heat, also occur in humid heat in women. Methods To evaluate this possibility, 10 young (25 ± 4 yr) and 10 older (51 ± 7 yr) women matched for body surface area (young, 1.69 ± 0.11; older, 1.76 ± 0.14 m2, P = 0.21) and peak oxygen consumption (VO2peak) (young, 38.6 ± 4.6; older, 34.8 ± 6.6 mL·kg-1·min-1, P = 0.15) performed four 15-min bouts of cycling at a fixed metabolic heat production rate (300 W; equivalent to 45% VO2peak), each separated by a 15-min recovery, in dry (35°C, 20% relative humidity) and humid heat (35°C, 60% relative humidity). Total heat loss (evaporative ± dry heat exchange) and metabolic heat production were measured using direct and indirect calorimetry, respectively. Body heat storage was measured as the temporal summation of heat production and loss. Results Total heat loss was lower in humid conditions compared with dry conditions during all exercise bouts in both groups (all P &lt; 0.05), resulting in 49% and 39% greater body heat storage in young and older women, respectively (both P &lt; 0.01). Total heat loss was also lower in older women compared with young women during exercise bouts 1, 2 and 3 in dry heat (all P &lt; 0.05) and bouts 1 and 2 in humid heat (both P &lt; 0.05). Consequently, body heat storage was 29% and 16% greater in older women compared with young women in dry and humid conditions, respectively (both P &lt; 0.05). Conclusions Increasing ambient humidity reduces heat loss capacity in young and older women. However, older women display impaired heat loss relative to young women in both dry and humid heat, and may therefore be at greater risk of heat-related injury during light-to-moderate activity. © 2017 by the American College of Sports Medicine

Exercise-heat tolerance in middle-aged-to-older men with type 2 diabetes

[No abstract available

The recommended threshold limit values for heat exposure fail to maintain body core temperature within safe limits in older working adults

Purpose: The American Conference of Governmental and Industrial Hygienists (ACGIH®) Threshold Limit Values (TLV® guidelines) for work in the heat consist of work-rest (WR) allocations designed to ensure a stable core temperature that does not exceed 38°C. However, the TLV® guidelines have not been validated in older workers. This is an important shortcoming given that adults as young as 40 years demonstrate impairments in their ability to dissipate heat. We therefore evaluated body temperature responses in older adults during work performed in accordance to the TLV® recommended guidelines. Methods: On three occasions, 9 healthy older (58 ± 5 years) males performed a 120-min work-simulated protocol in accordance with the TLV® guidelines for moderate-to-heavy intensity work (360 W fixed rate of heat production) in different wet-bulb globe temperatures (WBGT). The first was 120 min of continuous (CON) cycling at 28.0°C WBGT (CON[28°C]). The other two protocols were 15-min intermittent work bouts performed with different WR cycles and WBGT: (i) WR of 3:1 at 29.0°C (WR3:1[29°C]) and (ii) WR of 1:1 at 30.0°C (WR1:1[30°C]). Rectal temperature was measured continuously. The rate of change in mean body temperature was determined via thermometry (weighting coefficients: rectal, 0.9; mean skin temperature, 0.1) and direct calorimetry. Results: Rectal temperature exceeded 38°C in all participants in CON[28°C] and WR3:1[29°C] whereas a statistically similar proportion of workers exceeded 38°C in WR1:1[30°C] (χ2; P = 0.32). The average time for rectal temperature to reach 38°C was: CON[28°C], 53 ± 7; WR3:1[29°C], 79 ± 11; and WR1:1[30°C], 100 ± 29 min. Finally, while a stable mean body temperature was not achieved in any work condition as measured by thermometry (i.e., &gt;0°C·min−1; all P&lt;0.01), heat balance as determined by direct calorimetry was achieved in WR3:1[29°C] and WR1:1[30°C] (both P ≤ 0.08). Conclusion: Our findings indicate that the TLV® guidelines do not prevent body core temperature from exceeding 38°C in older workers. Furthermore, a stable core temperature was not achieved within safe limits (i.e., ≤38°C) indicating that the TLV® guidelines may not adequately protect all individuals during work in hot conditions. © 2017 JOEH, LLC