Jeffrey A. Henderson

Effect of Statins Alone Versus Statins Plus Ezetimibe on Carotid Atherosclerosis in Type 2 Diabetes The SANDS (Stop Atherosclerosis in Native Diabetics Study) Trial

OBJECTIVES This secondary analysis from the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial examines the effects of lowering low-density lipoprotein cholesterol (LDL-C) with statins alone versus statins plus ezetimibe on common carotid artery intima-media thickness (CIMT) in patients with type 2 diabetes and no prior cardiovascular event. BACKGROUND It is unknown whether the addition of ezetimibe to statin therapy affects subclinical atherosclerosis. METHODS Within an aggressive group (target LDL-C <or=70 mg/dl; non-high-density lipoprotein cholesterol <or=100 mg/dl; systolic blood pressure <or=115 mm Hg), change in CIMT over 36 months was compared in diabetic individuals >40 years of age receiving statins plus ezetimibe versus statins alone. The CIMT changes in both aggressive subgroups were compared with changes in the standard subgroups (target LDL-C <or=100 mg/dl; non-high-density lipoprotein cholesterol <or=130 mg/dl; systolic blood pressure <or=130 mm Hg). RESULTS Mean (95% confidence intervals) LDL-C was reduced by 31 (23 to 37) mg/dl and 32 (27 to 38) mg/dl in the aggressive group receiving statins plus ezetimibe and statins alone, respectively, compared with changes of 1 (-3 to 6) mg/dl in the standard group (p < 0.0001) versus both aggressive subgroups. Within the aggressive group, mean CIMT at 36 months regressed from baseline similarly in the ezetimibe (-0.025 [-0.05 to 0.003] mm) and nonezetimibe subgroups (-0.012 [-0.03 to 0.008] mm) but progressed in the standard treatment arm (0.039 [0.02 to 0.06] mm), intergroup p < 0.0001. CONCLUSIONS Reducing LDL-C to aggressive targets resulted in similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus ezetimibe. Common carotid artery IMT increased in those achieving standard targets. (Stop Atherosclerosis in Native Diabetics Study [SANDS]; NCT00047424).

Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial

CONTEXT Individuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested. OBJECTIVE To compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower. DESIGN, SETTING, AND PARTICIPANTS A randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events. INTERVENTIONS Participants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both. MAIN OUTCOME MEASURES Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events. RESULTS Mean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (-0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (-0.02 mm(2) vs 1.05 mm(2); P < .001); and there was greater decrease in left ventricular mass index (-2.4 g/m(2.7) vs -1.2 g/m(2.7); P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87) did not differ significantly between groups. CONCLUSIONS Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047424.

Effect of Statins Alone Versus Statins Plus Ezetimibe on Carotid Atherosclerosis in Type 2 Diabetes

OBJECTIVES This secondary analysis from the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial examines the effects of lowering low-density lipoprotein cholesterol (LDL-C) with statins alone versus statins plus ezetimibe on common carotid artery intima-media thickness (CIMT) in patients with type 2 diabetes and no prior cardiovascular event. BACKGROUND It is unknown whether the addition of ezetimibe to statin therapy affects subclinical atherosclerosis. METHODS Within an aggressive group (target LDL-C <or=70 mg/dl; non-high-density lipoprotein cholesterol <or=100 mg/dl; systolic blood pressure <or=115 mm Hg), change in CIMT over 36 months was compared in diabetic individuals >40 years of age receiving statins plus ezetimibe versus statins alone. The CIMT changes in both aggressive subgroups were compared with changes in the standard subgroups (target LDL-C <or=100 mg/dl; non-high-density lipoprotein cholesterol <or=130 mg/dl; systolic blood pressure <or=130 mm Hg). RESULTS Mean (95% confidence intervals) LDL-C was reduced by 31 (23 to 37) mg/dl and 32 (27 to 38) mg/dl in the aggressive group receiving statins plus ezetimibe and statins alone, respectively, compared with changes of 1 (-3 to 6) mg/dl in the standard group (p < 0.0001) versus both aggressive subgroups. Within the aggressive group, mean CIMT at 36 months regressed from baseline similarly in the ezetimibe (-0.025 [-0.05 to 0.003] mm) and nonezetimibe subgroups (-0.012 [-0.03 to 0.008] mm) but progressed in the standard treatment arm (0.039 [0.02 to 0.06] mm), intergroup p < 0.0001. CONCLUSIONS Reducing LDL-C to aggressive targets resulted in similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus ezetimibe. Common carotid artery IMT increased in those achieving standard targets. (Stop Atherosclerosis in Native Diabetics Study [SANDS]; NCT00047424).

Changes in Cardiovascular Disease Risk Factors among American Indians: The Strong Heart Study

PURPOSE This study describes changes in cardiovascular disease (CVD) risk factors in older American Indians over a 4-year period. METHODS The Strong Heart Study, a longitudinal population-based study of CVD and CVD risk factors among American Indians aged 45-74 years, measured CVD risk factors among 3638 members of 13 tribes in three geographic areas during examinations in 1989 to 1991 and 1993 to 1995. RESULTS Changes in mean low-density lipoprotein (LDL) cholesterol and the prevalence of elevated LDL cholesterol were inconsistent. Mean high- density lipoprotein (HDL) cholesterol decreased, and the prevalence of low HDL cholesterol increased throughout. Mean systolic blood pressure and hypertension rates increased in nearly all center-sex groups, and hypertension awareness and treatment improved. Smoking rates decreased but remained higher than national rates except among Arizona women. Mean weight and percentage body fat decreased in nearly all center-sex groups but the prevalence of obesity did not change significantly in any group. Diabetes and albuminuria prevalence rates increased throughout the study population. The prevalence of alcohol use decreased, but binge drinking remained common in those who continued to drink. CONCLUSIONS Improvements in management and prevention of hypertension, diabetes, renal disease, and obesity, and programs to further reduce smoking and alcohol abuse, are urgently needed.

Evaluating Strategies For Reducing Health Disparities By Addressing The Social Determinants Of Health

The opportunities for healthy choices in homes, neighborhoods, schools, and workplaces can have decisive impacts on health. We review scientific evidence from promising interventions focused on the social determinants of health and discuss how such interventions can improve population health and reduce health disparities. We found sufficient evidence of successful outcomes to support disparity-reducing policy interventions targeted at education and early childhood; urban planning and community development; housing; income enhancements and supplements; and employment. Cost-effectiveness evaluations show that these interventions lead to long-term societal savings, but the interventions require more routine attention to cost considerations. We discuss challenges to implementation, including the need for long-term financing to scale up effective interventions for implementation at the local, state, and national levels.

Culture: The missing link in health research

Culture is essential for humans to exist. Yet surprisingly little attention has been paid to identifying how culture works or developing standards to guide the application of this concept in health research. This paper describes a multidisciplinary effort to find consensus on essential elements of a definition of culture to guide researchers in studying how cultural processes influence health and health behaviors. We first highlight the lack of progress made in the health sciences to explain differences between population groups, and then identify 10 key barriers in research impeding progress in more effectively and rapidly realizing equity in health outcomes. Second, we highlight the primarily mono-cultural lens through which health behavior is currently conceptualized, third, we present a consensus definition of culture as an integrating framework, and last, we provide guidelines to more effectively operationalize the concept of culture for health research. We hope this effort will be useful to researchers, reviewers, and funders alike.

Trends and Disparities in Heart Disease Mortality Among American Indians/Alaska Natives, 1990–2009

OBJECTIVES We evaluated heart disease death rates among American Indians and Alaska Natives (AI/ANs) and Whites after improving identification of AI/AN populations. METHODS Indian Health Service (IHS) registration data were linked to the National Death Index for 1990 to 2009 to identify deaths among AI/AN persons aged 35 years and older with heart disease listed as the underlying cause of death (UCOD) or 1 of multiple causes of death (MCOD). We restricted analyses to IHS Contract Health Service Delivery Areas and to non-Hispanic populations. RESULTS Heart disease death rates were higher among AI/AN persons than Whites from 1999 to 2009 (1.21 times for UCOD, 1.30 times for MCOD). Disparities were highest in younger age groups and in the Northern Plains, but lowest in the East and Southwest. In AI/AN persons, MCOD rates were 84% higher than UCOD rates. From 1990 to 2009, UCOD rates declined among Whites, but only declined significantly among AI/AN persons after 2003. CONCLUSIONS Analysis with improved race identification indicated that AI/AN populations experienced higher heart disease death rates than Whites. Better prevention and more effective care of heart disease is needed for AI/AN populations.

Patterns of Cigarette Smoking Initiation in Two Culturally Distinct American Indian Tribes

OBJECTIVES To better understand patterns of initiation among American Indians we examined age-related patterns of smoking initiation during adolescence and young adulthood in 2 American Indian tribes. METHODS We used log-rank comparison and a Cox proportional hazard regression model to analyze data from a population-based study of Southwest and Northern Plains American Indians aged 18 to 95 years who initiated smoking by age 18 years or younger. RESULTS The cumulative incidence of smoking initiation was much higher among the Northern Plains Indians (47%) than among the Southwest Indians (28%; P < .01). In the Southwest, men were more likely than women to initiate smoking at a younger age (P < .01); there was no such difference in the Northern Plains sample. Northern Plains men and women in more recent birth cohorts initiated smoking at an earlier age than did those born in older birth cohorts. Southwest men and women differed in the pattern of smoking initiation across birth cohorts as evidenced by the significant test for interaction (P = .01). CONCLUSION Our findings underscore the need to implement tobacco prevention and control measures within American Indian communities.

A Gene-Family Analysis of 61 Genetic Variants in the Nicotinic Acetylcholine Receptor Genes for Insulin Resistance and Type 2 Diabetes in American Indians

Cigarette smoking is a risk factor for type 2 diabetes. Genetic variants in the nicotinic acetylcholine receptor (nAChR) genes have been associated with smoking phenotypes and are likely to influence diabetes. Although each single variant may have only a minor effect, the joint contribution of multiple single nucleotide polymorphisms (SNPs) to the occurrence of disease may be larger. In this study, we conducted a gene-family analysis to investigate the joint impact of 61 tag SNPs in 7 nAChRs genes on insulin resistance and type 2 diabetes in 3,665 American Indians recruited by the Strong Heart Family Study. Results show that although multiple SNPs showed marginal individual association with insulin resistance and type 2 diabetes, only a few can pass adjustment for multiple testing. However, a gene-family analysis considering the joint impact of all 61 SNPs reveals significant association of the nAChR gene family with both insulin resistance and type 2 diabetes (both P < 0.0001), suggesting that genetic variants in the nAChR genes jointly contribute to insulin resistance and type 2 diabetes among American Indians. The effects of these genetic variants on insulin resistance and diabetes are independent of cigarette smoking per se.

Calling for a bold new vision of health disparities intervention research

The author discusses the need for new health disparities intervention research based upon the experience of the Centers for Population Health and Health Disparities (CPHHD) Program. Topics include the effectiveness of interventions addressing social determinants of health to reduce health disparities, the potential use of genomic strategies to determine population health disparities, and the enhancement of communication and cultural competency in health professionals to improve healthcare equity.