Angela Silverman

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).

Postmenopausal Hormone Therapy Is Associated With Atherosclerosis Progression in Women With Abnormal Glucose Tolerance

Background—Abnormal glucose tolerance (AGT; diabetes or impaired glucose tolerance) is associated with increased risk of cardiovascular disease, especially in women. Cardiovascular disease rates in women increase after menopause. The Women’s Health Initiative found that postmenopausal hormone therapy (PHT) increased the risk of cardiovascular disease and that effects in diabetic women did not differ from those in women without diabetes. In this study, we hypothesized that PHT would have a worse effect on disease among women with AGT. Methods and Results—We randomly assigned 423 postmenopausal women with angiographically defined atherosclerosis (321 women had exit angiograms) with (n=140) or without (n=181) AGT to receive estrogen, estrogen plus progestin, or a placebo for 2.8±0.9 years. LDL was lower and HDL and triglycerides were higher after PHT in non-AGT and AGT women, but more adverse changes occurred in C-reactive protein and fibrinogen in women with AGT (P =0.11 and P =0.02 for interactions). PHT had no effect on fasting glucose or insulin concentrations in women without AGT, but in women with AGT, fasting glucose levels, insulin concentration, and insulin resistance as assessed by the HOMA (homeostasis model) calculation decreased slightly (P =0.28, P =0.25, P =0.14 for interaction, respectively). Athero-sclerotic progression was greater in women with AGT. Atherosclerotic progression in previously nondiseased segments was enhanced by PHT to a greater extent in women with AGT (P =0.11 for interaction). Conclusions—PHT is associated with a worsening of coronary atherosclerosis and exacerbation of the profile of inflammatory markers in women with AGT. Therefore, PHT is not warranted for use in diabetic women. Further study is needed to explore the improvement in insulin resistance and glycemia that appears to occur with PHT in women with AGT.

Cardiovascular disease prevalence and its relation to risk factors in Alaska Eskimos

BACKGROUND AND AIMS Although Eskimos were thought to be protected from cardiovascular disease (CVD), state health data show a large proportion of deaths from CVD, despite traditional lifestyles and high omega-3 fatty acid intake. This article explores CVD prevalence and its relation to risk factors in Alaska Eskimos. METHODS AND RESULTS A population-based cohort of 499 Alaska Eskimos > age 45 from the Norton Sound region was examined in 2000-2004 for CVD and associated risk factors as part of the Genetics of Coronary Artery Disease in Alaska Natives study. CVD and atherosclerosis were evaluated and adjudicated using standardized methods. Average age was 58 years; diabetes prevalence was low and high-density lipoprotein cholesterol (HDL-C) concentrations were high, but a large proportion smoked and had high pathogen burden. CVD was higher in men (12.6%) than in women (5.3%) (prevalence ratio 2.4, CI 1.3-4.4). Rates of stroke (6.1% in men, 1.8% in women) were similar to those for coronary heart disease (CHD) (6.1% men, 2.5% women). MI prevalence was low in both genders (1.9% and 0.7%). CVD was higher in men and in those >60 years. Hypertension, diabetes, high LDL-C, high apoB, and low HDL-C were all strong correlates (<.002) and albuminuria and CRP were also correlated with CVD (p<.05) after adjustment for age and gender. Carotid atherosclerosis was correlated with CVD (p=.0079) independent of other risk factors. CONCLUSION These data show high CHD and stroke prevalence in Alaska Eskimos, despite low average LDL-C and high HDL-C. Hypertension and high LDL-C were independent correlates; identifying these risk factors early and treating to target is recommended.

C-reactive protein, insulin resistance, and metabolic syndrome in a population with a high burden of subclinical infection: Insights from the genetics of coronary artery disease in Alaska natives (GOCADAN) study

OBJECTIVE—To explore relationships between C-reactive protein (CRP), subclinical infection, insulin resistance, and metabolic syndrome. RESEARCH DESIGN AND METHODS—Data from 1,174 Eskimos, aged ≥18 years, from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study were analyzed; 40 participants with diabetes were eliminated. Baseline assessment included interviews, physical exam, and blood and urine sampling. Metabolic syndrome was assessed using Adult Treatment Panel III criteria. CRP and antibodies to common pathogens were measured. RESULTS—Although CRP was related in univariate analyses to insulin resistance and metabolic syndrome, relations were attenuated or eliminated after adjustment for relevant covariates. CRP was not higher among those with impaired fasting glucose (IFG), and pathogen burden was not related to insulin resistance, metabolic syndrome, or IFG. CONCLUSIONS—Pathogen burden and inflammation do not seem to be related to insulin resistance, metabolic syndrome, or IFG in this population. The inflammatory process may reflect insulin resistance or its correlates but most likely is not causative.

C-Reactive Protein, Insulin Resistance, and Metabolic Syndrome in a Population with a High Burden of Subclinical Infection: Insights from the GOCADAN Study

OBJECTIVE—To explore relationships between C-reactive protein (CRP), subclinical infection, insulin resistance, and metabolic syndrome. RESEARCH DESIGN AND METHODS—Data from 1,174 Eskimos, aged ≥18 years, from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study were analyzed; 40 participants with diabetes were eliminated. Baseline assessment included interviews, physical exam, and blood and urine sampling. Metabolic syndrome was assessed using Adult Treatment Panel III criteria. CRP and antibodies to common pathogens were measured. RESULTS—Although CRP was related in univariate analyses to insulin resistance and metabolic syndrome, relations were attenuated or eliminated after adjustment for relevant covariates. CRP was not higher among those with impaired fasting glucose (IFG), and pathogen burden was not related to insulin resistance, metabolic syndrome, or IFG. CONCLUSIONS—Pathogen burden and inflammation do not seem to be related to insulin resistance, metabolic syndrome, or IFG in this population. The inflammatory process may reflect insulin resistance or its correlates but most likely is not causative.

Safety and feasibility of achieving lower systolic blood pressure goals in persons with type 2 diabetes: the SANDS trial.

The Stop Atherosclerosis in Native Diabetics Study (SANDS) was a randomized open‐label clinical trial in type 2 diabetics designed to examine the effects of intensive reduction of blood pressure, aggressive vs standard goals (≤115/75 mm Hg vs ≤130/80 mm Hg), and low‐density lipoprotein (LDL) cholesterol on the composite outcome of change in carotid intimal‐medial thickness and cardiovascular events. The study demonstrated that in conjunction with a lower LDL cholesterol target of 70 mg/dL, aggressive systolic blood pressure–lowering resulted in a reduction in carotid intimal‐medial thickness and left ventricular mass without measurable differences in cardiovascular events. The blood pressure treatment algorithm included renin‐angiotensin system blockade, with other agents added if necessary. The authors conclude that both standard and more aggressive systolic blood pressure reduction can be achieved with excellent safety and good tolerability in patients with type 2 diabetes mellitus.

Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes

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.

Achieving lipid targets in adults with type 2 diabetes: The Stop Atherosclerosis in Native Diabetics Study

BACKGROUND Although lipid management in diabetes is standard practice, goals often are neither met nor maintained. Strategies for achieving lower targets have not been explored. The Stop Atherosclerosis in Native Diabetics Study randomized patients with diabetes to standard versus aggressive lipid and blood pressure goals for 36 months. OBJECTIVE To report strategies used to achieve and maintain lipid goals and to report adverse events (AEs). METHODS Adults with type 2 diabetes and no history of cardiovascular disease (N = 499) were randomized to standard (low-density lipoprotein cholesterol [LDL-C] ≤ 100 mg/dL, non-high-density lipoprotein cholesterol [non-HDL-C] ≤ 130 mg/dL) or aggressive (LDL-C ≤ 70 mg/dL, non-HDL-C ≤ 100 mg/dL) targets. An algorithm was started with statin monotherapy, with intestinally acting agents added as required to reach LDL-C targets.Triglyceride [TG]-lowering agents were next used to reach non-HDL-C goals. Lipid management was performed by mid-level practitioners, with physician consultation, by the use of point-of-care lipid determinations. RESULTS On average, both groups achieved the LDL-C and non-HDL-C goals within 12 months and maintained them throughout the study. At 36 months, mean (SD) LDL-C and non-HDL-C were 72 (24) and 102 (29) mg/dL in the aggressive group (AGG) and 104 (20) and 138 (26) mg/dL, respectively, in the standard group (STD); systolic blood pressure targets were 115 and 130 mmHg, respectively. A total of 68% of participants reached target LDL-C for greater than 50% of the visits and 46% for greater than 75% of visits. At 36 months, the AGG averaged 1.5 lipid lowering medications and the STD 1.2. Statins were used in 91% and 68% of the AGG and STD; ezetimibe by 31% and 10%; fibrates by 8% and 18%. No serious AEs were observed; AEs occurred in 18% of the AGG and 14% of the STD. CONCLUSION Standard and aggressive lipid targets can be safely maintained in diabetic patients. Standardized algorithms, point-of-care lipid testing, and nonphysician providers facilitate care delivery.