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The Interaction of a Diabetes Gene Risk Score With 3 Different Antihypertensive Medications for Incident Glucose-level Elevation.

ABSTRACT: BACKGROUND:Elevations of fasting glucose (FG) levels are frequently encountered in people treated with thiazide diuretics. The risk is lower in people treated with ACE inhibitors (ACEi). To determine if genetic factors play a role in FG elevation, we examined the interaction of a diabetes gene risk score (GRS) with the use of 3 different antihypertensive medications. METHODS:We examined 376 nondiabetic hypertensive individuals with baseline FG <100 mg/dl who were genotyped for 24 genes associated with risk of elevated glucose levels. All participants had ?1 follow-up FG level over 6 years of follow-up. Participants were randomized to treatment with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (CCB; amlodipine), or an ACEi (lisinopril). Outcomes were an FG increase of ?13 or ?27 mg/dl, the upper 75% and 90% FG increase in the parent cohort from which the present cohort was obtained. Odds ratios were adjusted for factors that increase FG levels. RESULTS:For every 1 allele increase in GRS, the adjusted odds ratios (ORs) were 1.06 (95% confidence interval (CI): 0.99, 1.14; P = 0.06) and 1.09 (95% CI: 0.99, 1.20; P = 0.08). When results were examined by randomized medications, participants randomized to amlodipine had statistically significant odds for either outcome (OR: 1.23; 95% CI: 1.03, 1.48; P = 0.01 and OR: 1.31; 95% CI: 1.06, 1.62; P = 0.01). No such risk increase was found in participants randomized to the other 2 medications. CONCLUSIONS:A diabetes GRS predicts FG elevation in people treated with a CCB, but not with an ACEi or diuretic. These findings require confirmation. CLINICAL TRIALS REGISTRATION:Trial number NCT00000542.

SUBMITTER: Barzilay JI

PROVIDER: S-EPMC6420683 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The Interaction of a Diabetes Gene Risk Score With 3 Different Antihypertensive Medications for Incident Glucose-level Elevation.

Barzilay Joshua I JI Lai Dejian D Davis Barry R BR Pressel Sara S Previn Hannah E HE Arnett Donna K DK

American journal of hypertension 20190301 4

<h4>Background</h4>Elevations of fasting glucose (FG) levels are frequently encountered in people treated with thiazide diuretics. The risk is lower in people treated with ACE inhibitors (ACEi). To determine if genetic factors play a role in FG elevation, we examined the interaction of a diabetes gene risk score (GRS) with the use of 3 different antihypertensive medications.<h4>Methods</h4>We examined 376 nondiabetic hypertensive individuals with baseline FG <100 mg/dl who were genotyped for 24 ...[more]

PMID: 30590387

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Project description:Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ? 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

Project description:Background and objectivesIn individuals with diabetes, the comparative effectiveness of add-on antihypertensive medications added to an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on the risk of significant kidney events is unknown.Design, setting participants, & measurementsWe used an observational, multicenter cohort of 21,897 individuals with diabetes to compare individuals who added β-blockers, dihydropyridine calcium channel blockers, loop diuretics, or thiazide diuretics to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. We examined the hazard of significant kidney events, cardiovascular events, and death using Cox proportional hazard models with propensity score weighting. The composite significant kidney event end point was defined as the first occurrence of a ≥30% decline in eGFR to an eGFR<60 ml/min per 1.73 m2, initiation of dialysis, or kidney transplant. The composite cardiovascular event end point was defined as the first occurrence of hospitalization for acute myocardial infarction, acute coronary syndrome, stroke, or congestive heart failure; coronary artery bypass grafting; or percutaneous coronary intervention, and it was only examined in those free of cardiovascular disease at baseline.ResultsOver a maximum of 5 years, there were 4707 significant kidney events, 1498 deaths, and 818 cardiovascular events. Compared with thiazide diuretics, hazard ratios for significant kidney events for β-blockers, calcium channel blockers, and loop diuretics were 0.81 (95% confidence interval, 0.74 to 0.89), 0.67 (95% confidence interval, 0.58 to 0.78), and 1.19 (95% confidence interval, 1.00 to 1.41), respectively. Compared with thiazide diuretics, hazard ratios of mortality for β-blockers, calcium channel blockers, and loop diuretics were 1.19 (95% confidence interval, 0.97 to 1.44), 0.73 (95% confidence interval, 0.52 to 1.03), and 1.67 (95% confidence interval, 1.31 to 2.13), respectively. Compared with thiazide diuretics, hazard ratios of cardiovascular events for β-blockers, calcium channel blockers, and loop diuretics compared with thiazide diuretics were 1.65 (95% confidence interval, 1.39 to 1.96), 1.05 (95% confidence interval, 0.80 to 1.39), and 1.55 (95% confidence interval, 1.05 to 2.27), respectively.ConclusionsCompared with thiazide diuretics, calcium channel blockers were associated with a lower risk of significant kidney events and a similar risk of cardiovascular events.

Project description:BackgroundStrong evidence supports that dietary modifications may decrease incident type 2 diabetes mellitus (T2DM). Numerous diabetes risk models/scores have been developed, but most do not rely specifically on dietary variables or do not fully capture the overall dietary pattern. We prospectively assessed the association of a dietary-based diabetes-risk score (DDS), which integrates optimal food patterns, with the risk of developing T2DM in the SUN ("Seguimiento Universidad de Navarra") longitudinal study.MethodsWe assessed 17,292 participants initially free of diabetes, followed-up for a mean of 9.2 years. A validated 136-item FFQ was administered at baseline. Taking into account previous literature, the DDS positively weighted vegetables, fruit, whole cereals, nuts, coffee, low-fat dairy, fiber, PUFA, and alcohol in moderate amounts; while it negatively weighted red meat, processed meats and sugar-sweetened beverages. Energy-adjusted quintiles of each item (with exception of moderate alcohol consumption that received either 0 or 5 points) were used to build the DDS (maximum: 60 points). Incident T2DM was confirmed through additional detailed questionnaires and review of medical records of participants. We used Cox proportional hazards models adjusted for socio-demographic and anthropometric parameters, health-related habits, and clinical variables to estimate hazard ratios (HR) of T2DM.ResultsWe observed 143 T2DM confirmed cases during follow-up. Better baseline conformity with the DDS was associated with lower incidence of T2DM (multivariable-adjusted HR for intermediate (25-39 points) vs. low (11-24) category 0.43 [95% confidence interval (CI) 0.21, 0.89]; and for high (40-60) vs. low category 0.32 [95% CI: 0.14, 0.69]; p for linear trend: 0.019).ConclusionsThe DDS, a simple score exclusively based on dietary components, showed a strong inverse association with incident T2DM. This score may be applicable in clinical practice to improve dietary habits of subjects at high risk of T2DM and also as an educational tool for laypeople to help them in self-assessing their future risk for developing diabetes.

Project description:ImportanceAntidepressants are one of the most commonly prescribed classes of psychotropic medications among US youths. For adults, there is emerging evidence on the increased risk of type 2 diabetes in association with antidepressant use. However, little is known about the antidepressant treatment-emergent risk of type 2 diabetes among youths.ObjectiveTo assess the association between antidepressant use and the risk of incident type 2 diabetes in youths by antidepressant subclass and according to duration of use, cumulative dose, and average daily dose.Design, setting, and participantsA retrospective cohort study was conducted using Medicaid claims data from 4 geographically diverse, large states of youths 5 to 20 years of age who initiated antidepressant treatment from January 1, 2005, to December 31, 2009.ExposuresAntidepressant use (selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic or other cyclic antidepressants, and other antidepressants) was assessed using the following 4 time-varying measures: current or former use, duration of use, cumulative dose, and average daily dose.Main outcomes and measuresIncident type 2 diabetes was assessed using discrete-time failure models, adjusting for disease risk score estimated using more than 125 baseline and time-dependent covariates.ResultsIn this cohort of 119 608 youths aged 5 to 20 years who initiated antidepressant treatment (59 087 female youths and 60 521 male youths; 54.7% between 5 and 14 years of age) with a mean follow-up of 22.8 months, 79 285 [66.3%] had SSRI or SNRI exposure. The risk of type 2 diabetes was significantly greater during current use than former use of SSRIs or SNRIs (absolute risk, 1.29 per 10 000 person-months vs 0.64 per 10 000 person-months; adjusted relative risk [RR], 1.88; 95% CI, 1.34-2.64) and tricyclic or other cyclic antidepressants (absolute risk, 0.89 per 10 000 person-months vs 0.48 per 10 000 person-months; RR, 2.15; 95% CI, 1.06-4.36), but not of other antidepressants (absolute risk, 1.15 per 10 000 person-months vs 1.12 per 10 000 person-months; RR, 0.99; 95% CI, 0.66-1.50). Furthermore, for youths currently using SSRIs or SNRIs, the risk of type 2 diabetes increased with the duration of use (RR, 2.66; 95% CI, 1.45-4.88 for >210 days and RR, 2.56; 95% CI, 1.29-5.08 for 151-210 days compared with 1-90 days) and with the cumulative dose (RR, 2.44; 95% CI, 1.35-4.43 for >4500 mg and RR, 2.17; 95% CI, 1.07-4.40 for 3001-4500 mg compared with 1-1500 mg in fluoxetine hydrochloride dose equivalents). By contrast, neither the duration nor the cumulative dose of other antidepressants was associated with an increased risk of type 2 diabetes. The risk of type 2 diabetes increased significantly with the average daily dose among youths with more than 150 days of SSRI or SNRI use (RR, 2.39; 95% CI, 1.04-5.52 for >15.0 vs ≤15.0 mg/d) but not among youths with 1 to 150 days of SSRI or SNRI use.Conclusions and relevanceIn a large cohort of youths insured by Medicaid, the use of SSRIs or SNRIs-the most commonly used antidepressant subclass-was associated with an increased risk of type 2 diabetes that intensified with increasing duration of use, cumulative dose, and average daily dose.

Project description:BackgroundDementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia.MethodsWe did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses.ResultsSix prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease.InterpretationOver a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia.FundingThe Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.

Project description:BackgroundTo further inform benefits and risks of medications on physical function in aging populations, we have evaluated the associations of antihypertensive (antiHTN) class and number used with skeletal muscle function, mobility, sedentary time, and symptoms in older persons.MethodsUsing baseline data from the Lifestyle Interventions and Independence in Elder (LIFE) study (N = 1567, mean age 78.9 years) and multivariable models, we evaluated cross-sectional associations of antiHTN class and number used with physical measures and symptom questionnaires. AntiHTN class included diuretics, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and beta blockers (BB). Physical measures included respiratory muscle weakness (maximal inspiratory pressure), grip weakness (dynamometer), impaired lower extremity proximal muscle strength (chair stands), impaired balance (three-stage test), slow gait (400 m walk), mobility impairment (Short Physical Performance Battery), and high sedentary time (accelerometry). Symptoms included dyspnea and fatigue. Covariates included clinical characteristics and non-antiHTNs.ResultsUse of any antiHTN was highly prevalent (n = 1248 [79.6%]). In the antiHTN subgroup, each antiHTN class was well represented (ranging 36.6%-62.7%) and included use of three or more antiHTNs (32.0%). In adjusted models, the only statistically significant associations were use of BB and three or more antiHTNs with high sedentary time: odds ratios (95% confidence intervals) 1.44 (1.12, 1.85) and 1.52 (1.04, 2.23), respectively.ConclusionUse of BB and three or more antiHTNs yielded 44% and 52% increased odds of accelerometry-defined high sedentary time, respectively. Notably, high sedentary time is a risk factor for adverse health outcomes. Thus, future work should evaluate whether high sedentary time mitigates benefits or increases risks, regarding antiHTN use in aging populations.

Dataset Information

The Interaction of a Diabetes Gene Risk Score With 3 Different Antihypertensive Medications for Incident Glucose-level Elevation.

Publications

The Interaction of a Diabetes Gene Risk Score With 3 Different Antihypertensive Medications for Incident Glucose-level Elevation.

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