R.S. Elkeles

Cardiovascular Outcomes in Type 2 Diabetes: A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study

OBJECTIVE To determine whether serum lipid intervention, in addition to conventional diabetes treatment, could alter cardiovascular outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS There were 164 type 2 diabetic subjects (117 men, 47 women) without a history of clinical cardiovascular disease randomized to receive either bezafibrate or placebo daily on a double-blind basis in addition to routine diabetes treatment and followed prospectively for a minimum of 3 years. Serial biochemical and noninvasive vascular assessments, carotid and femoral artery B-mode ultrasound measurements, and those pertaining to coronary heart disease (CHD)—clinical history, the World Health Organization (WHO) cardiovascular questionnaire, and resting and exercise electrocardiogram (ECG)—were recorded. RESULTS Bezafibrate treatment was associated with significantly greater reductions over 3 years in median serum triglyceride (−32 vs. 4%, P = 0.001), total cholesterol (−7 vs. −0.3%, P = 0.004), and total−to-HDL cholesterol ratio (−12 vs. −0.0%, P = 0.001), and an increase in HDL cholesterol (6 vs. −2%, P = 0.02) as compared with placebo. There was a trend toward a greater reduction of fibrinogen (−18 vs. −6%, P = 0.08) at 3 years. No significant differences between the two groups were found in the progress of ultrasonically measured arterial disease. In those treated with bezafibrate, there was a significant reduction (P = 0.01, log-rank test) in the combined incidence of Minnesota-coded probable ischemic change on the resting ECG and of documented myocardial infarction. CONCLUSIONS Improving dyslipidemia in type 2 diabetic subjects had no effect on the progress of ultrasonically measured arterial disease, although the lower rate of “definite CHD events” in the treated group suggests that this might result in a reduction in the incidence of coronary heart disease.

High Prevalence of Gestational Diabetes in Women from Ethnic Minority Groups

The influence of ethnic origin, body mass index, and parity on the frequency of gestational diabetes was assessed in 11205 consecutive women attending a multiracial antenatal clinic in London, where all women were screened for gestational diabetes. Logistic regression was used to model the relationship between gestational diabetes and ethnic origin, age, body mass index (BMI), and parity. Results were presented as adjusted odds ratios, where the reference categories are White women, age < 25 years, BMI < 27, and parity < 3. Ethnic origin was the dominant influence on the prevalence of gestational diabetes. Women from ethnic groups other than White had a higher frequency of gestational diabetes than White women (2.9% vs 0.4%, p < 0.001). Compared to White women the relative risk of gestational diabetes in the other ethnic groups was: Black 3.1 (95% confidence limits 1.8–5.5), South East Asian 7.6 (4.1–14.1), Indian 11.3 (6.8–18.8), and miscellaneous 5.9 (3.5–9.9). Increasing age was an independent risk factor. The relative risk was higher in women ≥ 35 years in all ethnic groups other than in South East Asian women. Obesity (BMI ≥ 27) was a further independent risk factor in all ethnic groups except in the Indian and South East Asian women. Parity ≥ 3 increased the relative risk of gestational diabetes in the White, Black, and South East Asian women only. Age and obesity were factors of particular importance in Black women in whom the risk was 4.1 fold greater in those ≥ 35 years compared with women ≥ 35 years, and 5.0 fold higher if the BMI was ≥ 27 compared with ≥ 27. Ethnic origin has a major influence on the prevalence of gestational diabetes and the importance of other risk factors varies between ethnic groups. These findings have important implications for the screening of women in pregnancy.

Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study

AIMS The PREDICT Study is a prospective cohort study designed to evaluate coronary artery calcification score (CACS) as a predictor of cardiovascular events in type 2 diabetes (T2DM). METHODS AND RESULTS A total of 589 patients with no history of cardiovascular disease and with established T2DM had CACS measured, as well as risk factors, including plasma lipoprotein, apolipoprotein, homocysteine and C-reactive protein concentrations, homeostasis model assessment insulin resistance (HOMA-IR), and urine albumin creatinine ratio. Participants were followed for a median of 4 years and first coronary heart disease (CHD) and stroke events were identified as primary endpoints. There were 66 first cardiovascular events (including 10 strokes). CACS was a highly significant, independent predictor of events (P < 0.001), with a doubling in CACS being associated with a 32% increase in risk of events (29% after adjustment). Hazard ratios relative to CACS in the range 0-10 Agatston units (AU) were: CACS 11-100 AU, 5.4 (P = 0.02); 101-400 AU 10.5 (P = 0.001); 401-1000 AU, 11.9 (P = 0.001), and >1000 AU, 19.8 (P < 0.001). Only HOMA-IR predicted primary endpoints independently of CACS (P = 0.01). The areas under the receiver operator characteristic curve for United Kingdom Prospective Diabetes Study (UKPDS) risk engine primary endpoint risk and for UKPDS risk plus CACS were 0.63 and 0.73, respectively (P = 0.03). CONCLUSION Measurement of CACS is a powerful predictor of cardiovascular events in asymptomatic patients with T2DM and can further enhance prediction provided by established risk models.

The Effects of Metformin on Glycemic Control and Serum Lipids in Insulin-Treated NIDDM Patients With Suboptimal Metabolic Control

OBJECTIVE To test the hypothesis that metformin therapy, given as an adjunct to insulin therapy, improves metabolic control in insulin-treated NIDDM patients with suboptimal glycemic control. RESEARCH DESIGN AND METHODS A total of 33 subjects with insulin-treated NIDDM were investigated; all had commenced insulin after secondary failure of antihyperglycemic agents. Two randomized double-blind placebo-controlled crossover studies were run. In study 1 (n = 19), insulin-treated subjects with suboptimal glycemic control received 12 weeks of metformin 1 g b.i.d. and 12 weeks of placebo. In study 2 (n = 14), subjects already established on adjunctive metformin/insulin therapy stopped the metformin component and received 12 weeks of metformin at their baseline dosage (range 1–2.5 g) and 12 weeks of equivalent placebo. Fasting plasma glucose, HbA1c, and serum lipids were measured at baseline and midway through and at the end of each treatment phase. The effect of 12 weeks of metformin treatment was compared with the effect of 12 weeks of placebo in each study and in both studies combined. RESULTS In study 1, metformin treatment was associated with significant improvements in fasting plasma glucose (mean 12-week difference fromplacebo [95% CI]: 5.8 mmol/1 [3.5–8.1], P < 0.001) and HbA1c (1.6% [0.9–2.4], P < 0.001). In study 2, metformin treatment was associated with significantly lower fasting plasma glucose (5.3 mmol/1 [0.6–9.9], P = 0.029) and lower HbA1c(2.4% [1.0–3.8], P = 0.003) compared with those for placebo. Study 2 also showed metformin treatment to be associated with significantly lower total cholesterol than that for placebo (1.0 mmol/1 [0.1–1.9], P = 0.032) and lower LDL cholesterol (1.0 mmol/1 [0.1–1.9], P = 0.028). This significant difference in serum lipids seen in study 2 was not seen in study 1, but was present when both sets of data were combined (n = 33, mean total cholesterol difference at 12 weeks [95% CI]: 0.6 mmol/1 [0.1–1.1], P = 0.015). Metformin had no significant effect on triglyceride, HDL cholesterol, weight, or blood pressure. Twosubjects on metformin withdrew because of side effects. CONCLUSIONS Metformin, when given as adjunctive therapy, was well tolerated and improved glycemic control and lipid concentrations in patients with insulin-treated NIDDM whose diabetes was poorly controlled. These improvements could be maintained over the long term.

Smoking is associated with increased hepatic lipase activity, insulin resistance, dyslipidaemia and early atherosclerosis in Type 2 diabetes

We have studied the relationships between hepatic lipase activity, smoking, dyslipidaemia insulin resistance, and early atherosclerosis in 67 Type 2 diabetic subjects, 47 non-smokers and 20 smokers. Insulin resistance was measured using an insulin modified frequently sampled intravenous glucose tolerance test. Early atherosclerosis was assessed using high-resolution ultrasound to measure carotid intima media thickness (IMT) and an arterial ultrasonic score (AUS). Smokers had higher serum cholesterol and triglyceride, lower HDL and HDL2 cholesterol as well as increased hepatic lipase activity. They were also more insulin resistant than non-smokers. Smokers also had higher patient AUS scores. On multiple regression analysis, hepatic lipase activity emerged as the most significant variable affecting patient AUS. We suggest that smoking accentuates the dyslipidaemia of Type 2 diabetic subjects and this is associated with increased hepatic lipase activity. This may be one mechanism whereby smoking further increases the risk of cardiovascular disease in Type 2 diabetes.

The Effect of Glibenclamide and Metformin on Serum Lipoproteins in Type 2 Diabetes

In a cross‐over study, the effects of 3 months treatment with metformin or glibenclamide on body weight, blood glucose control, and serum lipoproteins were compared in 35 Type 2 diabetic patients, inadequately controlled by dietary therapy alone. Glibenclamide alone increased body weight (mean change + 2.75 kg; 95% confidence intervals − 1.95 to + 3.55 kg; p < 0.0001). Glibenclamide and metformin achieved equivalent blood glucose control, independent of initial body mass index. Neither drug affected serum triglyceride concentration. Metformin alone significantly reduced low density lipoprotein cholesterol (mean change − 0.34 mmol l−1; 95% confidence intervals − 0.12 to − 0.57 mmol l−1; p < 0.01). Neither drug altered high density lipoprotein or subfraction cholesterol.

The association of coronary calcium score and conventional cardiovascular risk factors in Type 2 diabetic subjects asymptomatic for coronary heart disease (The PREDICT Study)

Aim To determine the association between coronary calcification score (CACS) obtained by electron beam computed tomography (EBCT) and cardiovascular risk factors in Type 2 diabetic subjects entered into a prospective cohort study.

Arterial wall changes in type 2 diabetic subjects

Arterial ultrasonic appearances using high resolution ultrasound were studied in 97 subjects with Type 2 diabetes and age‐ and sex‐matched controls. The intima‐media thickness of both common carotid arteries was measured 2 cm proximal to the bifurcation and the presence or absence of plaque on both common and femoral bifurcations was recorded. The mean intima‐media thickness in subjects with diabetes was 0.82 ± 0.22 mm while in the controls 0.66 ± 0.13 mm (p < 0.001). Multiple regression in diabetic subjects only showed no correlation between age, sex, body mass index, smoking, duration of diabetes, systolic or diastolic blood pressure, cholesterol, HDL, LDL, triglycerides, HbA, and the common carotid artery intima‐media thickness. Type 2 diabetes is associated with increased intima‐media thickness which has been found to be a marker of cardiovascular events in the general population.

Serum lipids, lipoproteins and macrovascular disease in non-insulin-dependent diabetics: a possible new approach to prevention

The relationship between macrovascular disease and serum lipids, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL), and subfraction cholesterol, and apolipoproteins has been examined in 53 female and 95 male patients with non‐insulin‐dependent diabetes mellitus (NIDDM). In males, those with macrovascular disease had higher serum and LDL cholesterol concentrations than those without. In females, those with macrovascular disease had higher levels of serum triglyceride, cholesterol, LDL cholesterol, as well as lower HDL, HDL2, and HDL3 cholesterol and apoprotein A‐1, than those without. On multivariate analysis, LDL cholesterol was the most important association with macrovascular disease in males and apoprotein A‐1 in females.

The response of hepatic lipase and serum lipoproteins to acute hyperinsulinaemia in type 2 diabetes

Abstract. Hepatic lipase has a putative role in the catabolism of HDL particles and, while its activity is dependent upon insulin in the rat, no such insulin responsiveness has been demonstrated in man. We studied 21 patients with type 2 diabetes to examine whether hepatic lipase activity was influenced by hyperinsulinaemia during a 2–4 h isoglycaemic clamp study. Acute changes in lipids, lipoproteins and apoli‐poproteins were also documented in pre‐ and post‐clamp serum. Hepatic lipase activity during hyperinsulinaemia was compared with activity measured after an equivalent period without insulin. For comparison, nine non‐diabetic subjects (matched for age and body mass index) underwent similar clamp studies. In the control experiment without insulin, hepatic lipase activity did not change significantly (mean 9.7 {range 2.3–22.3} in the morning and 9.9 {3.0–22.5} mmol h‐1 l‐1 in the afternoon, NS). In contrast, after the hyperinsulinaemic clamp, hepatic lipase activity fell significantly in diabetic subjects from 12.8 {4.4–30.6} to 10.4 {3.3–31.3} mmol h‐1 l‐1, P<0.0002 along with serum triglycerides and total and LDL cholesterol. The change in hepatic lipase activity was positively related to the fasting apoprotein B concentration (Spearman r = 0.54, P= 0.016). In the normal subjects, a similar decline in hepatic lipase activity was observed during hyperinsulinaemia (from 15.1 {9.8–32.7} to 12.6 {6.3–28.3} mmol h‐1 l‐1, P<0.01) along with decreases in total, HDL and LDL cholesterol, triglycerides and apoproteins A1 and B. The change in hepatic lipase activity was positively related to fasting apoprotein B and total cholesterol concentration (both r= 0.72, P= 0.042) and both the fasting LDL cholesterol (r = 0.82, P=0.021) and the change in LDL cholesterol during the clamp study (r = 0.81, P= 0.022). Thus, acute physiological hyperinsulinaemia in normal and type 2 diabetic man causes a decrease in hepatic lipase activity. This may reflect a direct effect of insulin or, alternatively, it may be secondary to insulin‐mediated alterations in lipopro‐tein metabolism.