Bengt Scherstén

Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study

BACKGROUND The efficacy of new antihypertensive drugs has been questioned. We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients. METHODS We did a prospective, randomised trial in 6614 patients aged 70-84 years with hypertension (blood pressure > or = 180 mm Hg systolic, > or = 105 mm Hg diastolic, or both). Patients were randomly assigned conventional antihypertensive drugs (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily) or newer drugs (enalapril 10 mg or lisinopril 10 mg, or felodipine 2.5 mg or isradipine 2-5 mg daily). We assessed fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease. Analysis was by intention to treat. FINDINGS Blood pressure was decreased similarly in all treatment groups. The primary combined endpoint of fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group (19.8 events per 1000 patient-years) and in 438 of 4401 in the newer drugs group (19.8 per 1000; relative risk 0.99 [95% CI 0.84-1.16], p=0.89). The combined endpoint of fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs (0.96 [0.86-1.08], p=0.49). INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events. Decrease in blood pressure was of major importance for the prevention of cardiovascular events.

Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study.

OBJECTIVE To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Of 165 patients (fasting blood glucose [FBG] ≥ 6.7 mmol/l) initially treated with diet alone, 144 (FBG still ≥6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, withFBG <6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration. RESULTS The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG ± SE was reduced (P = 0.001) from 9.1 ± 0.4 to 7.0 ± 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 ± 0.8 to 7.8 ± 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 ± 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups. CONCLUSIONS Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM.

Ten-year Follow-up of Subjects with Impaired Glucose Tolerance: Prevention of Diabetes by Tolbutamide and Diet Regulation

In a diabetes detection survey carried out between 1962 and 1965, 2477 (1.1%) of 228,883 subjects had Clinistix-positive glucosuria after a carbohydrate-rich luncheon meal. Of these 2477, 578 displayed impaired tolerance to oral glucose without having manifest diabetes. From this group, 267 men were divided into five groups and subjected to the following treatments and controls: (a) diet regulation and 0.5 g tolbutamide t.i.d. (N = 49), annual oral glucose tolerance test (OGTT); (b) diet regulation and one placebo tablet t.i.d. (N = 48), annual OGTT; (c) diet regulation only (N = 50), annual OGTT; (d) no treatment (N = 61), annual OGTT; and (e) no treatment, OGTT at follow-up (N = 59 at follow-up). In addition, a control group was included comprised of men with normal OGTT (N = 52). At follow-up, 29% of those without diet regulation and medication (group e; N = 59) had developed diabetes. Of those on diet regulation, but without active medication (group b plus group c, N = 98), 13% had diabetes. No individual maintaining tolbutamide and diet regulation (N = 23) had progressed to diabetes. In this group, 80% of those later examined (N = 11) had serum tolbutamide concentrations in the therapeutic range. No individual with initially normal OGTT developed diabetes or impaired OGTT. The findings suggest that normal oral glucose tolerance signifies little risk of progress to impaired glucose tolerance and manifest diabetes, whereas impaired glucose tolerance is associated with a high risk of progression to diabetes. In addition, it seems possible that treatment with diet regulation, in combination with tolbutamide, may prevent or postpone progression from impaired glucose tolerance to manifest diabetes.

Preventing Non-Insulin-Dependent Diabetes

Many risk factors for non-insulin-dependent diabetes mellitus (NIDDM), such as obesity, physical inactivity, and high-fat diet, can potentially be modified. Furthermore, some of the metabolic abnormalities, such as insulin resistance and impaired glucose tolerance, that predict diabetes can be improved by behavior modification and drug treatment. Thus, at least to some extent, NIDDM may be preventable. Several small clinical trials have addressed the hypothesis that NIDDM can be prevented by dietary modification, physical activity, or drug treatment. Some studies suggest a preventive effect, but the conclusions are limited by considerations of sample size, randomization, or intensity of the interventions. Consequently, the hypothesis that NIDDM is preventable requires further testing.

Socio‐demographic and psychosocial factors are associated with features of the metabolic syndrome. The Women's Health in the Lund Area (WHILA) study

Aim: The aim was to analyse any associations between socio‐demographic and psychosocial factors and different features of the metabolic syndrome in a geographically well‐defined population of middle‐aged women.

Serum glibenclamide in diabetic patients, and influence of food on the kinetics and effects of glibenclamide

SummaryThe steady state concentrations of glibenclamide in serum were measured radioimmunologically in 37 diabetic patients after administration for at least a year. No other antidiabetic drugs had been given. The interindividual variation in glibenclamide concentrations was extremely large (0 to 1520 nmol/l), greatly exceeding the variation in dosage (2.5–25 mg daily). There was no relation between dose and serum concentration of glibenclamide. Only four (9%) patients had fasting blood glucose concentrations below 5.5 mmol/l, and fewer than half had values below 8 mmol/l. In most cases, therefore, the therapy was inadequate. Single-dose kinetics of glibenclamide was assessed in healthy volunteers. Food intake did not influence the bioavailability of a 5 mg dose of glibenclamide. There was no insulin increase in response to glibenclamide unless a meal was also given, and this increase was not significant until 1 h after administration of drug and meal, when the mean serum concentration of glibenclamide had reached 100nmol/l. Even in the fasting state, however, there was a progressive fall in blood glucose after glibenclamide administration, significant within 45 min and with a nadir at 2–2 1/2 h.

Relation between drug treatment and cancer in hypertensives in the Swedish Trial in Old Patients with Hypertension 2: a 5-year, prospective, randomised, controlled trial

BACKGROUND Is cancer related to hypertension and blood pressure? Do antihypertensive drugs promote cancer? Do antihypertensive drugs protect against cancer? We previously analysed the frequency of cardiovascular mortality and morbidity in elderly people who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension-2). We have also looked at the frequency of cancer in these patients. METHODS We randomly assigned 6614 elderly patients with hypertension (mean age 76 years, median time of follow-up 5.3 years) to one of three treatment strategies: conventional drugs (diuretics or b-blockers), calcium antagonists, or ACE inhibitors. We matched the patients to the Swedish Cancer Registry and compared our findings with expected values based on age, sex, and calendar-year-specific reference frequencies for the general Swedish population. We also compared the number of cancers between the three treatment groups. FINDINGS At baseline, 607 (9%) patients had previous malignant disease. Diagnoses were closely similar to the distribution of cancer types that might be seen in elderly patients. During follow-up, there were 625 new cases of cancer in 590 patients. The frequency of cancer did not differ significantly between the treatment strategies, including all cancers and those at individual sites. The standardised incidence ratios (SIRs) for all cancers were also close to unity: 0.92 (95% CI 0.80-1.06) for conventional drugs, 0.96 (0.83-1.10) for calcium antagonists, and 0.99 (0.86-1.13) for ACE inhibitors. INTERPRETATIONS No difference in cancer risk was seen between patients randomly assigned to conventional drugs, calcium antagonists, or ACE inhibitors. Thus, the general message to the practising physician is that more attention should be given to getting the blood pressure down than to the risk of cancer.

Antihyperglycaemic efficacy, response prediction and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination

The short‐term (2–12 weeks) antihyperglycaemic efficacy of metformin (M), glibenclamide (G), and their primary combination (MG) was assessed in a double‐blind study including 165 unselected patients with Type 2 diabetes. Patients with diet failure were randomized to M, G or MG. The dose was titrated with a fasting blood glucose concentration (FBG) of < 6.7 mmol I−1 as the target, using at most six dose levels, the first three comprising increasing monotherapy (M or G) or low‐dose primary combination (MGL), and the second three add‐on therapies (M/G and G/M) and primary combination therapy escalated to high dose (MGH). Success rates were higher on MGL than on monotherapy. The difference in achieving acceptable control (FBG ≤ 7.8 mmol I−1) was 70% versus 51% (95% confidence interval 3–36%, p = 0.032). When the drugs were combined, a slightly greater FBG reduction (p = 0.026) was observed, at lower dosage (p = 0.013). The response could not be predicted from body weight, but depended upon initial FBG (p = 0.019) and meal‐stimulated C‐peptide (p = 0.007). FBG declined progressively with increasing doses of metformin, whereas glibenclamide exerted most of its effect at low dose. Primary combination therapy with metformin and sulphonylurea may be clinically useful.

STOP-Hypertension 2: a prospective intervention trial of "newer" versus "older" treatment alternatives in old patients with hypertension. Swedish Trial in Old Patients with Hypertension.

It is well established that hypertensive patients benefit from drug treatment of their disorder. In recent years three major out-come studies of antihypertensive treatment in elderly hypertensives have shown substantial benefits, i.e. a reduction in the risk of stroke and other cardiovascular mortality and morbidity. In all these studies beta-blockers and/or diuretics were used in comparison with placebo. Newer therapeutic alternatives have, however, at least theoretically, many advantages which could result in further improvements in prognosis. The initial Swedish Trial in Old Patients with Hypertension (STOP-Hypertension 1) was conducted in men and women aged 70-84 years. STOP-Hypertension 2 will evaluate the therapy used in STOP-Hypertension 1 against therapy based on either ACE-inhibitors (enalapril and lisinopril) or on calcium antagonists (isradipine and felodipine), using the PROBE design (Prospective, Randomised, Open, Blinded Endpoint evaluation). The primary aim will be to assess the effect on cardiovascular mortality. Statistical calculations indicate that 6,600 patients, followed for four years will be needed (2p < 0.05, power 90%) to obtain significance if there is a 25% difference between the new and the established therapy. Patients in primary health care (300 centres) will be included if their supine blood pressure is > or = 180/105 mmHg (and/or). Recruitment of patients started in September 1992 and so far more than 100 patients/week have been included.

The impact of health care advice given in primary care on cardiovascular risk

Abstract Objective: To evaluate the additional benefit of “intensive” health care advice through six group sessions, compared with the advice usually offered to subjects with multiple risk factors for cardiovascular disease. Design: Prospective, randomised controlled clinical study lasting 18 months. Setting: 681 subjects aged 30-59 years, with at least two cardiovascular risk factors in addition to moderately high lipid concentrations: total cholesterol >/=6.5 mmol/l on three occasions, triglycerides <4.0 mmol/l, and ratio of low density lipoprotein cholesterol to high density lipoprotein cholesterol >4.0. Most (577) of the subjects were men. Main outcome measure: Percentage reduction in total cholesterol concentration (target 15%); quantification of the differences between the two types of health care advice (intensive v usual) for the Framingham cardiovascular risk and for individual risk factors. Results: In the group receiving intensive health care advice total cholesterol concentration decreased by 0.15 mmol/l more (95% confidence interval 0.04 to 0.26) than in the group receiving usual advice. The overall Framingham risk dropped by 0.068 more (0.014 to 0.095) in the group receiving intensive advice, and most of the risk factors showed a greater change in a favourable direction in this group than in the group receiving usual advice, but the differences were seldom significant. The results from questionnaires completed at the group sessions showed that the subjects improved their lifestyle and diet. Conclusion: Limited additional benefit was gained from being in the group receiving the intensive health care advice. It is difficult to make an important impact on cardiovascular risk in primary care by using only the practice staff. Better methods of communicating the messages need to be devised. Key messages Key messages This multicentre study examined the effects of “usual” or “intensive” health care advice on 681 subjects aged 30-59 years with a moderately high cholesterol concentration and two or more other cardiovascular risk factors The intensive advice programme was based mainly on group sessions led by doctors and nurses from health centres The study found that after 18 months of intervention limited additional benefit was derived from the intensive health care advice Messages and the means of delivering them to individuals in need should be customised for each person