Ingemar Selinus

Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension

SummaryThe aim of this study was to determine whether insulin sensitivity measured by the euglycaemic insulin clamp technique is lower in patients with primary hypertension than in matched healthy control subjects, and whether this sensitivity was affected after 12 weeks of antihypertensive treatment with the alpha 1-adrenoceptor blocking drug prazosin. Twelve moderately obese normoglycaemic patients (four men), with hypertension not previously treated with pharmacological agents and diastolic blood pressure above 100 mm Hg, and 12 healthy matched control subjects participated. Supine blood pressure decreased 12/5 mmHg (p<0.01) and standing blood pressure 14/9 mmHg (p=0.001) during prazosin treatment (mean dosage 5.3±1.6 mg/day (SD)). During euglycaemic insulin clamp studies the control subjects showed a higher mean glucose uptake than the untreated hypertensive patients (7.5±1.0 and 5.8±1.9 mg·kg b.w.−1·min−1, respectively, p<0.01). During prazosin treatment there was no significant difference between the hypertensive patients and the control subjects in this respect (6.6±2.8 and 7.5±1.0, respectively, p=0.21). During prazosin treatment, however, the disappearance rate of glucose decreased during the intravenous glucose tolerance test (from 1.7±0.9 to 1.3±0.6, p<0.02) and the area under the glucose concentration-time curve decreased by 38% (from 473±119 to 294±99, p<0.001). The peak insulin concentration decreased from 55±35 to 46±32 mU/l (p<0.006) and the area under the insulin concentration-time curve was suppressed by 38% (from 2368±1597 to 1479±940, p<0.01). This study shows that treatment of moderately obese hypertensive patients with prazosin is associated with an increase of the insulin-mediated glucose disposal and a decrease of the insulin response to an intravenous glucose load.

Risk factors for the development of hypertension : a 10-year longitudinal study in middle-aged men

A group of middle-aged men (n = 2322) were examined at a health screening which included an intravenous glucose tolerance test (IVGTT) with insulin determinations, and were then re-examined approximately 10 years later. At the first survey, 19.6% of the participants had hypertension, defined as diastolic blood pressure greater than or equal to 95 mmHg or were receiving drug treatment for hypertension. At follow-up survey, the corresponding figure was 34.7%. Baseline blood pressures were the strongest predictors of future development of hypertension. In the absence of baseline blood pressures, fasting and late insulin levels at IVGTT, difference in body mass index between the surveys and heredity for hypertension were significant risk factors for hypertension. When a difference in diastolic blood pressure was used as an independent variable, the only significant risk factor was the difference in body mass index. Thus, insulin resistance (as reflected by fasting, late insulin levels and body mass index) seems to be related to the development of hypertension.

Do antihypertensive drugs precipitate diabetes in predisposed men

OBJECTIVE--To evaluate the influence of antihypertensive treatment and metabolic characteristics on the development of diabetes mellitus in middle aged men. DESIGN--Prospective study over an average of nine years. SETTING--Community based health survey of middle aged men carried out at the University of Uppsala. SUBJECTS--Seventy three hypertensive men aged 49-54 and 65 normotensive controls matched for body mass index, glucose disappearance rate (k value) at an intravenous glucose tolerance test, and serum triglyceride and cholesterol concentrations. INTERVENTIONS--Hypertensive group was treated with beta blockers, thiazides, hydralazine, or combinations of these drugs. Treatment was not randomised. MEASUREMENTS and MAIN RESULTS--Intravenous glucose tolerance, fasting blood glucose and serum lipid and insulin concentrations, body weight and height, three skinfold measurements, and blood pressure were recorded both during an initial health screening survey in 1970-3 and at a follow up survey in 1980-3. In the period between the two surveys 12 hypertensive men and two controls developed diabetes. Review of values obtained at the initial survey showed that the hypertensive men who developed diabetes or impaired glucose tolerance could be distinguished from those hypertensive men who did not by virtue of a higher fasting serum insulin concentration (26.1 v 15.2 mU/l (confidence interval of difference -15.2 to -6.2)), a lower peak serum insulin concentration (78.9 v 94.3 mU/l (confidence interval of difference -1.1 to 41.1)), and a lower k value (1.29 v 1.68 (confidence interval of difference -0.02 to 0.68)). The insulin index (peak insulin concentration divided by fasting insulin concentration), however, decreased significantly in the hypertensive men over time irrespective of whether they developed diabetes but did not change in the controls. Furthermore, the serum triglyceride concentration increased in the treated group and decreased in the controls. CONCLUSION--A severalfold difference in the incidence of diabetes between treated hypertensive and non-treated, normotensive men may be a consequence of the treatment, which may be particularly deleterious in men predisposed to diabetes.

Serum triglycerides are a risk factor for myocardial infarction but not for angina pectoris: Results from a 10-year follow-up of Uppsala primary preventive study

At a follow-up 7-10 years after a health survey of men born in 1920-1924 in the municipality of Uppsala, 31 of the participants (n = 2322) had died from ischaemic heart disease (IHD). In response to a letter to all men alive in 1980, 106 men declared that they had had a myocardial infarction (MI) (verified or suspected). In 58 cases MI was verified from the hospital records. 28 other men had had typical central chest pain (angina pectoris) only. In another 20 men other diagnoses explained the chest pain for which they were treated in hospital. The health screening values for S-cholesterol and S-triglycerides, blood pressure and smoking habits were analysed in relation to the occurrence of IHD. In this prospective study, smoking, hypertension, S-cholesterol and S-triglycerides were identified as risk factors for fatal and non-fatal MI. The risk factor values were similar in subjects suffering from angina pectoris only to those in subjects who also developed ECG and/or transferase changes, with the exception of S-triglyceride concentration, which was normal in the group with angina pectoris. The subjects who had a fatal MI had a significantly higher blood pressure than those with non-fatal MIs, but otherwise these two groups did not differ. The results emphasize the importance of scrutinizing questionnaire data with regard to chest pain and of selection of end-points when risk factor patterns are described for cardiovascular diseases.

Physical training as treatment for Type 2 (non-insulin-dependent) diabetes in elderly men. A feasibility study over 2 years

SummaryAt a health examination of men approximately 60 years old, 48 were found to have Type 2 (non-insulin-dependent) diabetes. All had been healthy 10 years earlier. The intention was to randomly allocate those with mild diabetes to a training or a control group and study the long-term influence of regular training on the progress of the disease. However, it was found that the majority — 39 of 48 — had other diseases or were on treatment which made regular training difficult and would have complicated the interpretation of the metabolic effects of training. Eight men took part in a physical training programme for up to 2 years. Aerobic capacity, glucose tolerance and serum lipoproteins were measured before and at the end of the training period. Another group of eight men with Type 2 diabetes, of similar weight, age and relative aerobic capacity, who did not undergo the physical training, served as control subjects. The oxygen uptake increased by 16% in the training group and decreased by 12% in the control group but no significant changes could be demonstrated in body weight, fasting blood glucose, serum lipoproteins, glucose tolerance or insulin values at a 75-g oral glucose tolerance test between the two groups. Two patients in the training group developed coronary heart disease, two deteriorated metabolically (drug treatment had to be added), and there were two drop-outs. The results cast doubts on the feasibility and efficacy of physical training as a long-term treatment for the majority of Type 2 diabetic patients, who are older than 60 years.

Unaltered lipoprotein and carbohydrate metabolism during treatment with contraceptive subdermal implants containing ST-1435

Abstract Nine healthy, fertile women were treated for six months with subdermal contraceptive implants of two different sizes containing a potent progestogen, ST-1435. Lipoprotein cholesterol and triglyceride concentrations were not influenced by the treatment. Similarly, the main apolipoproteins in low- and high-density lipoproteins were not changed, which further supports the interpretation that the lipoprotein metabolism is not affected by this type of treatment. An oral glucose tolerance test (OGTT) including insulin determinations was performed in five of the volunteers with the largest implants. Blood glucose and insulin concentrations during the OGTT remained unchanged during treatment, indicating that the treatment with ST-1435 did not affect carbohydrate metabolism.

Alcohol intemperance and sudden death.

Ten years after a health screening examination was offered to 50 year old men 32 of the 2322 participants and 12 of the 454 nonparticipants had died of ischaemic heart disease. Of these, 26 and 11 respectively had suffered sudden death, for which necropsy was performed. Half of the men who had died suddenly had been registered for alcohol intemperance up to 1973, which was four times the prevalence of such registrations in the general population. Registration at both the Swedish Temperance Board and the Bureau of Social Services was associated with an odds ratio of 3.74 for sudden death as compared with not being registered at either. Logistic analysis including the classical risk factors for ischaemic heart disease together with registration for alcohol intemperance and at the Bureau of Social Services showed only the two types of registration and systolic blood pressure to be independent risk factors. On the other hand, there was no overrepresentation of subjects entered in the registers among those surviving a myocardial infarction. For non-fatal myocardial infarction blood pressure and serum triglyceride concentration were significant risk factors and serum cholesterol concentration, smoking, and body mass index probable risk factors; the two types of registration were not independent risk factors. Alcohol intemperance is strongly associated with an increased risk of sudden death after myocardial infarction.

Unaltered Lipoprotein and Carbohydrate Metabolism during Treatment with Contraceptive Subdermal Implants Containing ST-1435

Nine healthy, fertile women were treated for six months with subdermal contraceptive implants of two different sizes containing a potent progestogen, ST-1435. Lipoprotein cholesterol and triglyceride concentrations were not influenced by the treatment. Similarly, the main apolipoproteins in low- and high-density lipoproteins were not changed, which further supports the interpretation that the lipoprotein metabolism is not affected by this type of treatment. An oral glucose tolerance test (OGTT) including insulin determinations was performed in five of the volunteers with the largest implants. Blood glucose and insulin concentrations during the OGTT remained unchanged during treatment, indicating that the treatment with ST-1435 did not affect carbohydrate metabolism.

Pharmacodynamics of a contraceptive vaginal ring releasing norethindrone and estradiol: Ovarian function, bleeding control and lipoprotein patterns

Abstract A new contraceptive vaginal ring (CVR), releasing ~700 μg of norethindrone (NET) and ~140 μg of estradiol (E2) daily, was studied in eleven women for a total of 61 21-day cycles. Ovarian function, as judged by plasma progesterone (P) and E2 levels, and plasma NET levels were studied by weekly blood samples in 30 cycles. The lipoprotein pattern was studied before, after two and six months of treatment and one month after completed treatment. The CVR gave rise to stable plasma NET levels which however varied considerably between individuals. Signs of luteal activity/ovulation were encountered in 430 cycles, all in subjects with the lowest NET plasma levels. E2 levels above 250 pmol/l, indicating follicular activity, were encountered in 2230 cycles. Breakthrough bleeding and spotting appeared in 4061 cycles and in 12 per cent of the treatment days. Bleeding control was significantly better in the same subjects when using a CVR releasing levo-Norgestrel and E2. Serum and HDL cholesterol concentrations decreased significantly by 10–12 per cent during treatment. The ratios between apolipoproteins A-I and A-II on one hand and HDL cholesterol on the other increased significantly and the ratio apolipoprotein A-I:A-II decreased significantly, indicating a change in the lipoprotein composition. These changes are qualitatively similar but quantitatively not as pronounced as with the more extensively studied l-Ng/E2 CVR. The difference in clinical performance and in the effects on the lipoprotein pattern between the presently studied CVR and the l-Ng/E2 CVR is most likely the result of not using equipotent doses of gestagen in the CVRs.

Metabolic effects of a change in antihypertensive treatment

Twenty hypertensive men, aged 58 to 62 years, who had been treated with a combination of different drugs for many years, had their therapy changed in a stepwise manner to a combination of 50 mg of atenolol per day and 2 to 15 mg of prazosin per day. The effects of each change of treatment were assessed separately five to six months after the change. Serum lipids and high-density lipoprotein concentrations were determined, and an intravenous glucose tolerance test was performed at the start of the study and after each change. In the group in which therapy was changed from a diuretic to prazosin, serum cholesterol and triglyceride concentrations decreased significantly by 11 and 42 percent, respectively, but in the group in which therapy was changed from hydralazine to prazosin, there were no alterations in serum lipids or lipoproteins. The changes in therapy had no overall effects on glucose or insulin parameters evaluated with an intravenous glucose tolerance test. However, prazosin was associated with an increase in the fasting blood glucose level and a decrease in the peak insulin value after glucose injection, both of which were dose-related effects. The data indicate that the glucose turnover was at least as good after a switch from diuretic to prazosin treatment as before at lower insulin values. In those patients in whom therapy was switched from propranolol to 50 mg of atenolol per day, the serum triglyceride concentration decreased by about 10 percent, whereas in the group in which therapy was changed from 100 to 50 mg of atenolol per day, there were no serum lipid or lipoprotein alterations. The results show that a combination of 50 mg of atenolol per day and prazosin has metabolic advantages over combined diuretic and propranolol treatment. Such advantages may be of importance in the long-term treatment of hypertensive patients.