Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study

OBJECTIVE: The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS: A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS: End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58-0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48-0.98], P = 0.037) and any cardiovascular event (0.85 [0.73-1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS: Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.     

Serum levels of advanced glycation end products are increased in patients with type 2 diabetes and coronary heart disease.

OBJECTIVE: To investigate whether serum levels of advanced glycation end products (AGEs) and the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML) are increased in patients with type 2 diabetes compared with nondiabetic control subjects and whether levels of AGEs and/or CML differ in patients with type 2 diabetes with or without coronary heart disease (CHD). RESEARCH DESIGN AND METHODS: Serum levels of AGEs and CML were measured with an immunoassay in 32 men and 21 women aged 59.3+/-6.2 years (means +/- SD) with type 2 diabetes for 7.3 + 3.1 years and in 17 men and 17 women aged 56.2+/-4.2 years without diabetes. Of the patients with diabetes, 18 had CHD. RESULTS: The serum levels of AGEs and CML were significantly increased in patients with type 2 diabetes compared with nondiabetic control subjects (median [5th-95th percentile]: AGEs 7.4 [4.4-10.9] vs. 4.2 [1.6-6.4] U/ml, P < 0.0001; CML 15.6 [5.6-29.9] vs. 8.6 [4.4-25.9] U/ml, P < 0.0001). The median level of AGEs but not CML was significantly increased in patients with type 2 diabetes and CHD compared with patients without CHD (8.1 [6.4-10.9] vs. 7.1 [3.5-9.8] U/ml, P = 0.03). There were significant positive correlations between serum levels of AGEs and CML in both patients and control subjects. CONCLUSIONS: Levels of AGEs and CML were significantly increased in patients with type 2 diabetes compared with nondiabetic control subjects, and levels of AGEs but not CML were significantly higher in patients with type 2 diabetes and CHD than in patients without diabetes. These results may indicate a role for non-CML AGEs in the development of macrovascular disease in patients with type 2 diabetes.     

Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study

OBJECTIVE: Inflammatory activity is increased in type 1 diabetes and may predispose to vascular disease. Its origin is not clear. We therefore investigated determinants of inflammation in type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed a nested case-control study from the EURODIAB Prospective Complications Study of 543 European individuals having type 1 diabetes (278 men), diagnosed at <36 years of age. Case subjects (n = 348) were those with one or more complications of diabetes; control subjects (n = 195) were all those with no evidence of any complication. We determined levels of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, combined them in a "general score of inflammatory markers," and investigated their associations with vascular risk factors and markers of endothelial dysfunction by use of multiple linear regression analysis. RESULTS: Measures of inflammation were associated with sex, diabetes duration, glycemic control, the advanced glycation end product pentosidine, BMI, HDL cholesterol, triglycerides, and systolic blood pressure (standardized betas with the general score of inflammatory markers 0.15 [P = 0.002], 0.15 [P = 0.006], 0.18 [P < 0.0001], 0.12 [P = 0.005], 0.10 [P = 0.057], -0.15 [P = 0.001], 0.16 [P < 0.0001], and 0.09 [P = 0.042], respectively). In addition, measures of inflammation were strongly associated with markers of endothelial dysfunction, soluble vascular cell adhesion molecule-1, and soluble E-selectin (standardized betas with the general score of inflammatory markers 0.28 [P < 0.0001] and 0.19 [P < 0.0001]). CONCLUSIONS: We have shown that conventional risk factors for vascular disease and endothelial adhesion molecules are important determinants of inflammation in type 1 diabetic individuals, suggesting that strategies to decrease inflammatory activity in type 1 diabetes should focus not only on control of conventional risk factors, but also on improvement of endothelial function.     

Persistent platelet activation in patients with type 2 diabetes treated with low doses of aspirin

BACKGROUND: The percentage of diabetic patients who do not benefit from the protective effect of aspirin is larger than in other populations at cardiovascular risk. OBJECTIVE: We compared the ability of aspirin to suppress TxA2 and platelet activation in vivo, in type-2 diabetics vs. high-risk non-diabetic patients. METHODS: Urinary 11-dehydro-TXB2, plasma sCD40 L, and sP-selectin were measured, together with indices of low-grade inflammation, glycemic control, and lipid profile, in 82 patients with type-2 diabetes and 39 without diabetes, treated with low doses of aspirin. RESULTS: Urinary 11-dehydro-TxB2, plasma sCD40L and sP-selectin were significantly higher in diabetics than in controls: [38.9 (27.8-63.3) vs. 28.5 (22.5-43.9) ng mmol(-1) of creatinine, P = 0.02], [1.06 (0.42-3.06) vs. 0.35 (0.22-0.95) ng mL(-1); P = 0.0001], [37.0 (16.8-85.6) vs. 20.0 (11.2-35.6) ng mL(-1), P = 0.0001], respectively. The proportion of individuals with diabetes increased across quartiles of 11-dehydro-TxB2, sCD40L, and sP-selectin, with the highest quartiles of 11-dehydro-TxB2, sCD40L and sP-selectin, including 66%, 93.3%, and 93.3% of individuals with diabetes. Markers of platelet activation positively correlated with indices of glycemic control but not with markers of low-grade inflammation. CONCLUSIONS: Platelet dysfunction associated with insufficient glycemic control, may mediate persistent platelet activation under aspirin treatment.     

Joint effects of antibody to heat shock protein 60, hypertension, and diabetes on risk of coronary heart disease in Chinese

BACKGROUND: Several studies have suggested an association between antibody to human heat shock protein 60 (anti-Hsp60) and coronary atherosclerosis, but the results have been inconsistent. The aim of this study was to investigate the association between anti-Hsp60 and coronary heart disease (CHD) and to determine whether anti-Hsp60, hypertension, and diabetes have joint effects on CHD risk. METHODS: We measured the concentrations of anti-Hsp60 in 1003 CHD patients and 1003 age- and sex-matched control subjects without CHD events. RESULTS: Concentrations of anti-Hsp60 were significantly higher in CHD patients than in controls. Increasing concentrations of anti-Hsp60 were significantly associated with higher risk of CHD (P for trend <0.0001) and with increasing severity of CHD as assessed by number of diseased vessels detected with angiography [odds ratio (OR) 3.67, 95% CI 1.56-8.64, P = 0.003] after multivariate adjustment for traditional CHD risk factors. There were strong joint effects of high concentrations of anti-Hsp60 and hypertension (OR 5.17, 95% CI 3.95-6.75, P < 0.0001) and diabetes (OR 6.49, 95% CI 4.52-9.33, P < 0.0001) on CHD risk; simultaneous occurrence of high anti-Hsp60 concentrations, hypertension, and diabetes conferred a dramatically higher risk of CHD (OR 20.99, 95% CI 12.50-35.24, P < 0.0001) in multivariate analyses. CONCLUSIONS: Anti-Hsp60 is independently associated with CHD risk, and a combination of high anti-Hsp60, hypertension, and diabetes is particularly detrimental for CHD risk.     

Should diabetes be considered a coronary heart disease risk equivalent?: results from 25 years of follow-up in the Renfrew and Paisley survey

OBJECTIVE: The purpose of our study was to confirm or refute the view that diabetes be regarded as a coronary heart disease (CHD) risk equivalent and to test for sex differences in mortality. RESEARCH DESIGN AND METHODS: This was a prospective cohort study of 7,052 men and 8,354 women aged 45-64 years from Renfrew and Paisley, Scotland, who were first screened in 1972-1976 and followed for 25 years. All-cause mortality was calculated as death per 1,000 person-years. A Cox proportional hazards model was used to adjust survival for age, smoking habit, blood pressure, serum cholesterol, BMI, and social class. RESULTS: There were 192 deaths in 228 subjects with diabetes and 2,016 deaths in 3,076 subjects with CHD. The highest mortality was in the group with both diabetes and CHD (100.2 deaths/1,000 person-years in men, 93.6 in women) and the lowest in the group with neither (29.2 deaths/1,000 person-years in men, 19.4 in women). Men and women with diabetes only and CHD only formed an intermediate risk group. The adjusted hazard ratio (HR) for CHD mortality in men with diabetes only compared with men with CHD only was 1.17 (95% CI 0.78-1.74; P = 0.56). Corresponding HR for women was 1.97 (1.27-3.08; P = 0.003). CONCLUSIONS: Diabetes without previous CHD carries a lifetime risk of vascular death as high as that for CHD alone. Women may be at particular risk. Our data support the view that cardiovascular risk factors in diabetes should be treated as aggressively as in people with CHD.     

Migraine and coronary heart disease in women and men

OBJECTIVE: We evaluated migraine as an independent risk factor for subsequent coronary heart disease (CHD) events among women in the Women's Health Study (WHS) and men in the Physicians' Health Study (PHS). BACKGROUND: Although several studies have suggested that migraine is associated with increased risk of stroke, there are few and conflicting data on whether migraine predicts risk of future CHD events. METHODS: The WHS is an ongoing randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in 39876 women health professionals aged > or =45 years in 1993, and the PHS is a completed randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in the primary prevention of cardiovascular disease and cancer in 22071 men physicians aged 40 to 84 years in 1982. Primary endpoints were defined as major CHD (nonfatal myocardial infarction [MI] or fatal CHD) and total CHD (major CHD plus angina and coronary revascularization). RESULTS: After adjusting for other CHD risk factors, female health professionals and male physicians reporting migraine were not at increased risk for subsequent major CHD (women: relative risk [RR], 0.83; 95% confidence interval [CI], 0.53 to 1.29; men: RR, 1.02; 95% Cl, 0.79 to 1.31) or total CHD (women: RR, 1.01; 95% Cl, 0.76 to 1.34; men: RR, 0.98; 95% Cl, 0.82 to 1.18). When considered separately, there was also no increase in risk of MI or angina. CONCLUSION: These prospective data suggest that migraine is not associated with increased risk of subsequent CHD events in women or men.     

Awareness and treatment of dyslipidemia in young adults with type 1 diabetes

OBJECTIVE: Dyslipidemia is a preventable major risk factor for coronary heart disease (CHD). Despite an increased risk of CHD in type 1 diabetes, little is known concerning awareness and adequacy of dyslipidemia treatment in this population. In this report, we describe the prevalence of dyslipidemia and adequacy of pharmacological treatment in patients with type 1 diabetes and comparable nondiabetic subjects. RESEARCH DESIGN AND METHODS: From 2000 to 2002, the Coronary Artery Calcification in Type 1 Diabetes study obtained fasting lipid profiles in 1,416 individuals aged 19-56 years with no history of CHD: 652 type 1 diabetic patients (46% men, mean age 37 +/- 9 years) and 764 nondiabetic control subjects (50% men, mean age 39 +/- 9 years). These data combined with patient questionnaire results were used to determine prevalence of dyslipidemia and adequacy of pharmacological treatment. For all subjects, dyslipidemia was defined using National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: Type 1 diabetic subjects had significantly less dyslipidemia than nondiabetic control subjects (47 vs. 58%, P < 0.001), and a higher percentage of those with abnormal lipids were aware of (52 vs. 34%, P < 0.0001), on medication for (36 vs. 9%, P < 0.0001), and in control of their lipid levels (15 vs. 1.4%, P < 0.001). Of those on treatment, control was achieved in 41% of type 1 diabetic subjects and 15% of nondiabetic participants (P < 0.01). CONCLUSIONS: Dyslipidemia, a major risk factor for CHD, remains largely undiagnosed and undertreated in high-risk populations, such as patients with type 1 diabetes.     

The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men

In the present study, we have determined the relative frequency of the R46L, I474V and E670G variants in the PCSK9 (protein convertase subtilisin/kexin type 9) gene and its association with plasma lipid levels and CHD (coronary heart disease) in healthy U.K. men and patients with clinically defined definite FH (familial hypercholesterolaemia). Genotypes were determined using PCR and restriction enzyme digestion in 2444 healthy middle-aged (50-61 years) men from the prospective NPHSII (Second Northwick Park Heart Study), with 275 CHD events (15 years of follow-up), and in 597 U.K. FH patients from the Simon Broome Register. In the NPHSII healthy men, the R46L genotype distribution was in Hardy-Weinberg equilibrium and the frequency of 46L was 0.010 [95% CI (confidence interval), 0.007-0.013], with one man homozygous for the 46L allele. There was significant association of the 46L allele with lower mean (S.D.) total cholesterol [5.74 (1.01) mmol/l for RR compared with 5.26+/-1.03 mmol/l for RL; P=0.001], apolipoprotein B [0.87 (0.24) g/l for RR compared with 0.75 (0.26) g/l for RL; P<0.0001] and low-density lipoprotein cholesterol [4.01 (0.95) mmol/l for RR compared with 3.62 (0.97) mmol/l for RL; P=0.02]) levels, after adjustment for age, general medical practice, smoking, body mass index and systolic blood pressure. As expected, 46L carriers had a low risk of definite or possible CHD [hazard ratio, 0.46 (95% CI, 0.11-1.84)], but this was not statistically significant (P=0.27). Two other common PCSK9 variants I474V [V allele frequency, 0.179 (95% CI, 0.17-0.19)] and E670G [G allele frequency, 0.034 (CI, 0.03-0.04)] were not associated with any significant effects on lipid levels or CHD risk. In FH patients, the frequency of 46L was 0.003 (95% CI, 0.00-0.01), which was significantly lower (P=0.037) than the healthy subjects. In the four FH patients carrying 46L, mean untreated total cholesterol levels were not different (P=0.91) in carriers and non-carriers (median, 10.3 mmol/l compared with 10.2 mmol/l respectively, after adjustment for age, gender and mutation type). In conclusion, the PCSK9 46L allele is more frequent in healthy U.K. men than in FH patients and is strongly associated with a protective plasma lipid profile risk for CHD. Its low frequency (approx. 2% carriers) means that it does not make a major contribution to determining population CHD risk in the U.K.     

Mixed dyslipidemia among patients using lipid-lowering therapy in French general practice: an observational study

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) are associated with an increased incidence of coronary heart disease (CHD). However, limited data are available about the prevalence of dyslipidemias related to LDL-C, HDL-C, and TGs among French patients treated with lipid-lowering agents. OBJECTIVE: This paper describes the prevalence of various types of dyslipidemias among patients treated with lipid-lowering agents in French general practice. METHODS: This was a cross-sectional, observational study conducted using retrospective data collection at the time of enrollment. Eligible patients were those treated pharmacologically for dyslipidemia in the Cegedim Strategic Data general practice network. Fasting lipid values and cardiovascular (CV) risk factors were gathered by investigators using an ad hoc questionnaire. European guidelines were used to define various types of dyslipidemias. Polytomous logistic regression was used to assess the associations between different dyslipidemias and diabetes mellitus, a history of CHD, and the number of CV risk factors. RESULTS: A total of 946 patients had a complete lipid profile and valid data for determining CV risk status. The mean (SD) age of these patients was 64.0 (9.9) years, and 55.7% of the patients were men. At least 1 abnormality in LDL-C, HDL-C, or TGs was present in 791 (83.6 %) of the 946 patients. The rates of elevated LDL-C, low HDL-C, and elevated TGs were 73.2%, 16.9%, and 30.3%, respectively (these groups are not mutually exclusive). Among those who did not reach the LDL-C goal, 38.7% had dyslipidemias with low HDL-C, elevated TGs, or both. Compared with having a normal lipid profile, each additional CV risk factor increased the likelihood of the following types of dyslipidemias: low HDL-C and/or elevated TGs, but normal LDL-C (odds ratio [OR], 1.36; 95% CI, 1.03-1.79); elevated LDL-C and TGs, but normal HDL-C (OR, 1.58; 95% CI, 1.24-2.02); and all 3 lipid abnormalities (OR, 1.54; 95% CI, 1.10-2.14). Patients with diabetes had a similarly increased risk of mixed dyslipidemias, whereas patients with a history of CHD did not. CONCLUSIONS: Among these patients treated with lipid-lowering agents, 38.7% had mixed dyslipidemias, including low HDL-C, elevated TGs, both low HDL-C and elevated TGs, or all 3 lipid abnormalities. Patients with a greater number of nonlipid CV risk factors or with diabetes had a significantly increased risk of mixed dyslipidemias involving elevated TGs and/or low HDL-C in addition to elevated LDL-C.     

Increased urinary albumin excretion, insulin resistance, and related cardiovascular risk factors in patients with type 2 diabetes: evidence of a sex-specific association

OBJECTIVE: While the relevant role of insulin resistance in the pathogenesis of increased urinary albumin excretion (UAE) is well established in type 1 diabetes, its contribution in type 2 diabetes is controversial. Our aim was to investigate whether insulin resistance was associated with increased UAE in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 363 men and 349 women, aged 61 +/- 9 years, with a disease duration of 11 +/- 9 years and HbA(1c) levels of 8.6 +/- 2.0% were included. Insulin resistance was derived from the homeostasis model assessment of insulin resistance (HOMA(IR)), and UAE was derived from the albumin-to-creatinine ratio (ACR) defined as increased if the value was > or =2.5 mg/mmol in men and > or =3.5 mg/mmol in women. ACR was correlated with HOMA(IR) (r = 0.15, P = 0.0001), independently of age, disease duration, blood pressure, HbA(1c), triglycerides, waist circumference, and smoking. RESULTS: When the two sexes were investigated separately, a significant correlation between ACR and HOMA(IR) was reached in men (n = 363; r = 0.21, P = 0.0001) but not women (n = 349; r = 0.08, P = 0.14), suggesting that insulin resistance and sex may interact (P for interaction = 0.04) in determining UAE. When men were subgrouped into quartiles of HOMA(IR), those of the third and fourth quartile (i.e., the most insulin resistant) were at higher risk to have increased ACR than patients of the first quartile (third quartile: odds ratio 2.2 [95% CI 1.2-4.2], P = 0.01) (fourth quartile: 4.1 [2.2-7.9], P = 0.00002). Finally, ACR was significantly higher in men with two or more insulin resistance-related cardiovascular risk factors (i.e., abdominal obesity, dyslipidemia, and arterial hypertension) than in men with fewer than two insulin resistance-related cardiovascular risk factors (0.90 [0.2-115.1] vs. 1.56 [0.1-1367.6], respectively, P = 0.005). CONCLUSIONS: In type 2 diabetic patients, increased UAE is strongly associated with insulin resistance and related cardiovascular risk factors. This association seems to be stronger in men than in women.     

Increased plasma markers of oxidative stress are associated with coronary heart disease in males with diabetes mellitus and with 10-year risk in a prospective sample of males

BACKGROUND: Increased oxidative stress is associated with coronary heart disease (CHD). We examined the association between plasma markers of oxidative stress and CHD in a cross-sectional sample of patients with diabetes and prospective CHD risk in a sample of men predominantly without diabetes. METHODS: Plasma total antioxidant status (TAOS) and the ratio of oxidized LDL (Ox-LDL) to LDL-cholesterol (LDL-C) were determined in a cross-section of 761 Caucasian individuals with diabetes (UDACS study). Plasma TAOS was also determined in 310 baseline samples from a 10-year prospective cohort of 3012 healthy males (NPHSII). RESULTS: Within UDACS, males with CHD had lower mean (SD) plasma TAOS [no CHD, 43.4 (13.2)%; CHD, 40.3 (13.8)%; P = 0.04]. The prevalence of CHD was higher in the lowest compared with the upper quartiles (32.7% vs 19.7%; P = 0.004). We observed a significant association between plasma Ox-LDL:LDL-C and CHD status [no CHD vs CHD, 16.9 (3.1) vs 19.3 (5.0) units/mmol; P = 0.04], with the prevalence of CHD being higher among men in the upper compared with lower quartiles (18.4% vs 35.1%; P = 0.003). No association was observed in females. In NPHSII, TAOS was lower in those who developed CHD [35.1 (8.0)% vs 37.1 (7.9)%; P = 0.04]. The odds ratio for CHD in the lowest compared with the upper quartile was 1.91 (95% confidence interval, 0.99-3.70; P = 0.04). This remained unchanged after adjustment for classic risk factors. CONCLUSIONS: A cross-sectional and prospective association exists between baseline plasma measures of oxidative stress and CHD risk. The association with prospective CHD risk remained after adjustment for "traditional" risk factors, implying an independent role for oxidative stress in CHD risk.     

Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study.

BACKGROUND: Increased plasma lipoprotein(a) [Lp(a)] concentrations have been reported to be an independent risk factor for coronary heart disease (CHD) in some prospective studies, but not in others. These inconsistencies may relate to a lack of standardization and the failure of some immunoassays to measure all apolipoprotein(a) isoforms equally. METHODS: We measured plasma Lp(a)-cholesterol [Lp(a)-C] in a Caucasian population of offspring and spouses of the Framingham Heart Study participants, using a lectin-based assay (LipoproTM). We compared the prevalence of increased Lp(a)-C to the presence of sinking pre-beta-lipoprotein (SPB). We also related Lp(a)-C concentrations to the prevalence of CHD risk in the entire population. RESULTS: The mean (+/- SD) Lp(a)-C concentration in the Framingham population (n = 3121) was 0.186 +/- 0.160 mmol/L, with no significant gender or age differences. The mean Lp(a)-C concentrations in the absence or presence of SPB were 0.158 +/- 0. 132 mmol/L and 0.453 +/- 0.220 mmol/L, respectively (P <0.0001). The mean Lp(a)-C concentration in men with CHD (n = 156) was 0.241 +/- 0. 204 mmol/L, which was significantly (P <0.001) higher, by 34%, than in controls. The odds ratio for CHD risk in men with Lp(a)-C >/=0. 259 mmol/L (>/=10 mg/dL), after adjusting for age, HDL-cholesterol, LDL-cholesterol, smoking, diabetes, blood pressure, and body mass index, was 2.293 (confidence interval, 1.55-3.94; P <0.0005). Lp(a)-C values correlated highly with a Lp(a)-mass immunoassay [ApotekTM Lp(a); r = 0.832; P <0.0001; n = 1000]. CONCLUSIONS: An increased Lp(a)-C value >/=0.259 mmol/L (>/=10 mg/dL) is an independent CHD risk factor in men with a relative risk of more than 2, but was inconclusive in women. Lp(a)-C measurements offer an alternative to Lp(a)-mass immunoassays and can be performed on automated analyzers.     

Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat

OBJECTIVE: Previous reports of an association between low testosterone levels and diabetes risk were often confounded by covariation of sex hormone-binding globulin (SHBG) and testosterone measurements. Measurements of bioavailable and free testosterone, more reliable indexes of biologically active testosterone, were examined for their associations with markers of insulin resistance and body fat measures in 221 middle-aged nondiabetic men. RESEARCH DESIGN AND METHODS: Bioavailable and free testosterone were calculated from the concentrations of total testosterone, SHBG, and albumin, and they were not significantly correlated with SHBG (r = 0.07-0.1). In contrast, total testosterone correlated significantly with SHBG (r = 0.63). We evaluated the relationship between these measures of circulating testosterone and markers for insulin resistance (i.e., fasting insulin, C-peptide, and homeostasis model assessment for insulin resistance [HOMA-IR]) as well as total body fat (assessed by dual-energy X-ray absorptiometry [DEXA]) and abdominal fat distribution (assessed by single-slice computed tomography [CT]). RESULTS: Bioavailable, free, and total testosterone and SHBG all correlated significantly with fasting insulin (age-adjusted r = -0.15 [P = 0.03], -0.14 [P = 0.03], -0.32 [P < 0.0001], and -0.38 [P < 0.0001], respectively), fasting C-peptide (r = -0.18 [P = 0.009] to -0.41 [P < 0.0001]), HOMA-IR (r = -0.15 [P = 0.03] to - 0.39 [P < 0.0001]), and body fat measures (r = -0.17 [P = 0.008] to -0.44 [P < 0.0001]). Only SHBG and total testosterone were significantly associated with fasting glucose (r = -0.20 [P = 0.003] to -0.21 [P = 0.002]). In multivariate analysis, bioavailable or free testosterone was significantly and inversely associated with insulin, C-peptide, and HOMA-IR, but this was not independent of total body or abdominal fat. SHBG was a significant determinant of insulin, C-peptide, and HOMA-IR, independent of body fat. The associations between total testosterone and insulin resistance were confounded by SHBG. CONCLUSIONS: The inverse association between testosterone and insulin resistance, independent of SHBG, was mediated through body fat.     

Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease

BACKGROUND: Adiponectin, an adipocyte-derived hormone, appears to be a modulator of lipid metabolism and systemic inflammation and is present in particularly low concentrations in patients with coronary heart disease (CHD). However, the clinical importance of adiponectin in individuals at markedly high risk for future cardiovascular morbidity and mortality has not been fully elucidated. We examined the associations between serum adiponectin and several biomarkers related to cardiovascular disease and heart failure in a large high-risk population comprising patients with prevalent CHD. METHODS: We measured fasting adiponectin, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and markers of lipoprotein metabolism in 1174 patients with CHD. RESULTS: After adjustment for age and sex, adiponectin was associated with HDL-cholesterol (HDL-C; r = 0.25; P <0.0001), NT-proBNP (r = 0.17; P <0.0001), and plasma triglyceride (r = -0.21; P <0.0001) concentrations. There was, however, no statistically significant association between adiponectin and markers of systemic inflammation. In partial correlation analyses further adjusted for body mass index, alcohol intake, smoking status, presence of diabetes and/or hypertension, lipid-lowering drug therapy, and fasting plasma glucose, adiponectin remained significantly associated with HDL-C (r = 0.21; P <0.0001), NT-proBNP (r = 0.15; P <0.0001), and plasma triglycerides (r = -0.16; P <0.0001). CONCLUSIONS: Serum adiponectin is associated with the presence of atherogenic dyslipidemia and with NT-proBNP concentration but not with markers of systemic inflammation in patients with manifest CHD. Thus, atherogenic dyslipidemia may link adiponectin with the progression of atherosclerosis. Moreover, serum adiponectin may be related to BNP in patients with CHD.     

Risk perception for developing diabetes: comparative risk judgments of physicians

OBJECTIVE: To assess personal risk perceptions for developing diabetes among practicing physicians. RESEARCH DESIGN AND METHODS: Little is known about comparative risk perceptions concerning diabetes among medical experts. We administered the new Risk Perception Survey for Developing Diabetes to 535 nondiabetic physicians. The participants were 86% male, had a mean age of 49 years, and were 66% white and 24% Asian. Almost 37% were considered at higher risk for developing diabetes based on self-reported risk factors. Over 91% of respondents were either internal medicine or family medicine physicians. RESULTS: Of the four subscales, Comparative Disease Risk and Environmental Risk indicated moderate risk perceptions, whereas Personal Control scores indicated a robust sense of control over developing diabetes. Optimistic Bias scores showed a tendency toward participants' being optimistic that they were less likely to develop diabetes. Based on self-reported risk factor categories, a comparison of scores between physicians at higher risk (n = 196) and those at lower risk (n = 313) for developing diabetes showed greater comparative disease risk perception among the higher risk physicians (P < 0.01), as well as greater perception of diabetes risk (P < 0.001). Nearly 50% of higher risk physicians, however, reported an optimistic bias that they were less likely to develop diabetes than other people of their same age and sex. Women (n = 75) reported greater perception of environmental risks than men (P < 0.001). Asian respondents (n = 126) reported greater perception of environmental risk (P < 0.001) and greater worry about developing diabetes (P < 0.0001) than white respondents (n = 355). Regression analyses showed that scores for nondiabetes comparative disease risks (0.39) and level of optimistic bias (0.31) were predictive of diabetes risk perception (P < 0.0001). CONCLUSIONS: The data gathered on physicians' perception of their personal risk for developing diabetes and other comparative risk judgments provided an expert comparison for future analyses of at-risk or lay individuals' perceptions of diabetes risk. Effective communication of diabetes risk among physicians, patients, and the general public relies on knowledge of and sensitivity to group differences in these perceptions.     

Steroids in adult men with type 1 diabetes: a tendency to hypogonadism

OBJECTIVE: To compare steroids and their associations in men with type 1 diabetes and healthy control subjects. RESEARCH DESIGN AND METHODS: We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample. RESULTS: In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute. CONCLUSIONS: Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.     

Weight change and duration of overweight and obesity in the incidence of type 2 diabetes.

OBJECTIVE: To examine the relationship between weight change and duration of overweight and obesity and the incidence of type 2 diabetes in a cohort of middle-aged British men. RESEARCH DESIGN AND METHODS: We carried out a prospective study of cardiovascular disease in men aged 40-59 years at screening (1978-1980), drawn from one general practice in 24 British towns, who completed a postal questionnaire 5 years later (Q5) and for whom data on BMI at year 1 (Q1) and Q5 were available (n = 7,100). Men with diabetes at Q1 or Q5 and men with hyperglycemia at Q1 were excluded from the study (n = 184). The main outcome measure was type 2 diabetes (physician-diagnosed) during a mean follow-up period of 12 years starting at Q5 (1983-1985). RESULTS: In the 6,916 men with no history or evidence of diabetes, there were 237 incident cases of type 2 diabetes during the mean follow-up period of 12 years, a rate of 3.2/1,000 person-years. Substantial weight gain (>10%) was associated with a significant increase in risk of type 2 diabetes compared with that in men with stable weight (relative risk [RR] 1.61 [95% CI 1.01-2.56]) after adjustment for age, initial BMI, and other risk factors. Excluding men who developed diabetes within 4 years after the period of weight change increased the risk further (1.81 [1.09-3.00]). After adjustment and exclusion of men who developed diabetes early in the follow-up, weight loss (> or =4%) was associated with a reduction in the risk of type 2 diabetes, compared with that in the stable group, that reached marginal significance (0.65 [0.42-1.03], P = 0.07). A test for trend that fitted weight change as a continuous covariate showed the risk of diabetes to increase significantly from maximum weight loss to maximum weight gain (P = 0.0009). The lower risk associated with weight loss was seen in obese (> or =28 kg/m2) and nonobese subjects and in men with normal (<6.1 mmol/l) and high (> or =6.1 mmol/l) nonfasting blood glucose levels. Although not statistically significant, this is consistent with a benefit from weight loss. Risk of type 2 diabetes increased progressively and significantly with increasing levels of initial BMI and also with the duration of overweight and obesity (P<0.0001). CONCLUSIONS: This study confirms the critical importance of overweight and obesity, particularly of long duration, in the development of type 2 diabetes. The data support current public health recommendations to reduce the risk of type 2 diabetes by preventing weight gain in middle-aged men who are not overweight and by encouraging weight loss in overweight and obese men.     

Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study.

OBJECTIVE--To determine coronary heart disease (CHD) incidence among dyslipidemic subjects with non-insulin-dependent diabetes mellitus (NIDDM) and to assess the effect of lipid-modifying treatment on serum and lipoprotein lipids and the CHD incidence in these patients. RESEARCH DESIGN AND METHODS--Of the 4081 men participating in the Helsinki Heart Study, a coronary primary prevention trial with gemfibrozil in middle-aged men with high non-high-density lipoprotein (HDL) cholesterol (greater than 5.2 mM; 200 mg/dL), 135 had NIDDM at entry. The incidence of definite myocardial infarction and cardiac death and changes in serum and lipoprotein lipids were determined during the 5-yr trial in the NIDDM patients and compared with those observed in nondiabetic trial participants. RESULTS--Compared with nondiabetic subjects, NIDDM patients had lower HDL cholesterol (P less than 0.001), higher triglyceride concentration (P less than 0.0001), and greater body mass index (P less than 0.001), there were more hypertensive patients (P less than 0.001) among them. The incidence of myocardial infarction and cardiac death was significantly higher among diabetic than nondiabetic participants (7.4 vs. 3.3%, respectively, P less than 0.02). CHD incidence in the gemfibrozil-treated diabetic men (n = 59) was 3.4% compared with 10.5% in the placebo group (NS). In multivariate analysis, diabetes (P less than 0.05), age (P less than 0.0001), smoking (P less than 0.0001), low HDL cholesterol (P less than 0.05), and high low-density lipoprotein cholesterol (P less than 0.005) were independently related to CHD incidence. Gemfibrozil-induced serum and lipoprotein lipid changes in diabetic patients were similar to those observed in nondiabetic subjects. CONCLUSIONS--Compared with similarly dyslipidemic nondiabetic subjects, patients with NIDDM are at markedly increased risk of CHD. This elevated risk can be somewhat reduced by gemfibrozil.