Hans O.L. Lithell, MD, PhD
Effect of Antihypertensive Drugs on Insulin, Glucose, and Lipid Metabolism
The close relationship between diabetes and hypertension has been recognized for decades. New information indicates that resistance to insulin action on glucose uptake in peripheral tissues is a common underlying mechanism in hypertension and diabetes. In prospective trials, the effects of antihypertensive agents on insulin sensitivity and lipoprotein metabolism have been evaluated. Both 0-blockers and thiazide diuretics worsen insulin resistance and deteriorate lipoprotein metabolism. Angiotensin-converting enzyme (ACE) inhibitors, Ca2+-channel blockers, and a-blockers are neutral or improve these factors. These data may explain the unexpectedly high incidence of the development of diabetes among treated hypertensives and the poor effect on risk for coronary heart disease in intervention trials. Diabetes Care 14:203-209, 1991
N
on-insulin-dependent (type II) diabetes mellitus is a disease well recognized as associated with life-style. In societies where the diet provides excess calories and physical activity is minimal, obesity is very prevalent and with this goes a high prevalence of diabetes mellitus (1,2). The more severe the obesity, the earlier in life diabetes is precipitated. A moderate degree of obesity has to have a duration of ~ 10-30 yr before diabetes develops. Thus, the time factor is important when the diabetogenic factor is of a moderate degree. It has become widely accepted that hypertension should be treated because of the consistent and profound decrease in risk for stroke associated with effective treatFrom the Department of Geriatrics, Uppsala University, Uppsala, Sweden. Address correspondence and reprint requests to Hans O.L. Lithell, MD, Department of Geriatrics, P.O. Box 12042, S-750 12 Uppsala, Sweden.
DIABETES CARE, VOL. 14, NO. 3, MARCH 1991
ment. Furthermore, hypertension-related states such as left ventricular hypertrophy and renal insufficiency are favorably affected by treatment. The principle of drug treatment of hypertension has become so widely accepted in 40 yr that pharmacological treatment for hypertension is by far the largest mass intervention that has occurred in history. Today ~40-50% of men and women —70 yr of age are treated for hypertension in the industrialized countries. Therefore, it is surprising that the most commonly used drugs have not been subject to postmarketing surveillance; the knowledge of any lateoccurring side effects is therefore poor. The prospective treatment trials have a fairly short duration, and few have registered the occurrence of diabetes mellitus in active-treatment and placebo-treatment groups (3,4). However, the British Medical Research Council's prospective trial comparing the effect of propranolol or thiazide with that of placebo indicated that thiazide treatment in particular was associated with a significantly increased rate of development of impaired glucose tolerance (IGT) (3). However, the average treatment time was fairly short in that trial. More long-term follow-up studies have been published from three different cohorts. In one, there was a strikingly high incidence of diabetes in a group treated for hypertension for 14 yr, but that study was short of any comparisons with findings in a control group or background population (5). A Swedish study on middle-aged women who were treated for hypertension for >12 yr related the incidence of diabetes mellitus in that group to the incidence in the nontreated background population (6). In that study, some of the hypertensive women were treated with monotherapy with thiazides or propranolol only, but some of the hypertensive population needed a combined treatment with both agents. It was found that both the propranolol-treated group and the thiazide-treated group
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had an approximately fivefold increased incidence of diabetes, whereas the incidence in the combined-treatment group was ~12-fold higher than in the background population. In a parallel study carried out in middle-aged men, the incidence of diabetes among treated hypertensive subjects was approximately fivefold higher than in a control group matched for body mass index, glucose tolerance, and serum lipid concentrations but without pharmacological treatment for hypertension over the 10yr follow-up period (7). However, it was found that those who had hypertension differed from the beginning from those in the matched control group with regard to insulin concentrations, indicating that they were more insulin resistant when treatment started. This case-control study was part of the whole health-survey cohort. In recent analyses of the whole cohort, it was found that, after adjusting for any differences in insulin concentrations, glucose concentrations, blood pressure, and body mass index, treatment for hypertension at the follow-up 10 yr after the original health survey was associated with a significant and independent risk for development of diabetes (unpublished observations). These observations initiated our studies on the metabolic consequences of different drugs. In 1984, we decided to set up techniques to evaluate the effect of the drugs on insulin secretion and insulin sensitivity to find out if any such effect could explain the increased risk for development of diabetes. This review refers to findings in six different studies involving 279 patients.
significantly between different drugs. Because insulin-mediated glucose uptake is linearly related to the prevailing insulin concentration, adjustment for the prevailing insulin concentrations was also made (mg glucose • kg body wt" 1 • min~1 • m i l " 1 , insulin sensitivity index). In some cases, adjustment for the prevailing glucose concentration (5.2 mM on the average) was made. The insulin response to glucose challenge was evaluated with the intravenous glucose tolerance test (IVGTT; 9). This has some advantages over the oral glucose tolerance test in the experimental situation. The immediate insulin response to glucose injection (the insulin increment) is reproducible, and the effect of different drugs on this variable can be accurately estimated. The insulin increment is an important factor determining the glucose tolerance. Fasting insulin concentrations were determined at three time points in duplicate and insulin concentrations every 10 min during the 90-min test. Lipoproteins were quantified with ultracentrifugation to separate very-low-density lipoproteins (VLDL) from low-density (LDL) and high-density lipoproteins (HDL). Triglyceride and cholesterol concentrations were measured in total serum, in the VLDL, and in the bottom fraction after ultracentrifugation and in HDL after precipitation of LDL from the bottom fraction. The LDL concentrations of cholesterol and triglycerides were then calculated. HbA1c was measured by fast-performance liquid chromatography (10).
RESULTS RESEARCH DESIGN AND METHODS Newly detected hypertensive subjects, in an ongoing health survey in Uppsala, Sweden, were invited to take part in the studies together with patients who were being treated for hypertension. About half of the population in several of the studies reviewed herein were nontreated hypertensive subjects earlier, and half had been on treatment for various durations. All studies started with a placebo run-in period of 4— 6 wk. Three double-blind double-dummy-controlled studies and one open study had a crossover design; the active treatment periods were of 4- to 6-mo duration. Two were parallel group-designed blinded studies of 3to 6-mo duration, and one (the prazosin study) was a pilot open study of 3-mo duration. Comparisons have been made not only between the effects of the different drugs but also between the active treatment values and the placebo run-in value. The hyperinsulinemic-euglycemic clamp technique according to DeFronzo et al. (8,9) was used to measure insulin-promoted glucose uptake in the body (insulin sensitivity, mg glucose • kg body wt" 1 • min"1) as accurately as possible. The average prevailing insulin concentrations during the clamp was —100 mU/L, but the treatments affected the insulin metabolism differently, so that the prevailing insulin concentration also differed
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The effects of selective p-blockers were evaluated in two trials. One was a trial in which the two selective (3blockers metoprolol and atenolol were compared with fixed doses of 200 and 50 mg/day, respectively (11). Both drugs reduced insulin sensitivity statistically significantly by 20 and 13%, respectively. However, the catabolism of insulin was also affected, and after adjusting for the prevailing insulin concentration during the clamp, the insulin-sensitivity index was found to be reduced by 27% during metoprolol and by 23% during atenolol treatment (not significantly different). In that study, 62 patients were enrolled. In another study in 58 patients, atenolol was titrated according to the blood pressure response up to 100 mg/day (average dose 67 mg/day; 12). The results of this study confirmed those in the previous one, insulin sensitivity being significantly reduced during atenolol treatment. In both of those studies, the increased insulin resistance was reflected in elevated fasting and insulin concentrations during the IVGTT. However, the insulin increases were not large enough to fully compensate for the reduced insulin sensitivity, so that glucose concentrations were elevated both in the fasting state and during the IVGTT. Further evidence for a certain degree of derangement of the glucose metabolism was a significant elevation of the HbA1c concentration.
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The effect of a nonselective (3-blocker (160 mg/day turn may be responsible for the reduction in insulin senpropranolol) was compared with that of a nonselective sitivity. During treatment with captopril, an angiotensin-con(3-blocker with intrinsic sympathetic activity (10 mg/day pindolol) in a cross-over study recruiting 40 patients (un- verting enzyme (ACE) inhibitor, insulin sensitivity was published observations). The main finding was a pro- improved by ~11 %; after adjustment for the prevailing found decrease by 30% in insulin-sensitivity index dur- insulin concentrations during the clamp, the improveing propranolol treatment; during pindolol treatment, ment was 18%. In that study, it was found that, when the reduction was only about half (17%). Increases in hydrochlorothiazide preceded the captopril treatment, insulin and glucose concentrations during the IVCTT there was a carryover effect from the first treatment pewere found, the patterns being very similar to those with riod to the second, despite the long duration of the treatthe selective fJ-blockers. However, the changes were ment periods. Therefore, the effect of captopril was somewhat larger during propranolol treatment than with evaluated with the first part of the trial only. Also after the other drugs. One interesting observation is that, with adjustment for the small differences in anthropometric all of the |3-blockers, particularly with propranolol, the data and other variables influencing insulin sensitivity, insulin increment was not increased in proportion to the the results clearly indicated that insulin sensitivity was changes in other insulin concentrations, indicating a significantly improved during captopril treatment (14). certain degree of inhibition of the early phase of insulin This result was supported by the findings during the IVGTT. Insulin and glucose concentrations were signifsecretion. The mechanism causing the changes in insulin sen- icantly reduced during the latter part of the IVCTT comsitivity is not clear. However, note that propranolol is pared with the results of the run-in period. The mechanisms causing the change in insulin senthe drug causing the most vasoconstriction, whereas pindolol has a vasodilating effect. It is possible, although sitivity are not clear. In studies in the forearm after innot supported by direct measurements, that blood flow jection of captopril, insulin sensitivity increased. This to skeletal muscle is an important factor influencing in- was related to an accumulation of bradykinin in the blood stream (15). Bradykinin is metabolized by ACE. sulin sensitivity. During thiazide diuretic treatment, there was a sig- Inhibition of this enzyme thus causes accumulation of nificant reduction of insulin sensitivity by 11% and of bradykinin. It has been demonstrated that the reduction insulin-sensitivity index by 16% (13). These changes were in blood pressure is significantly related to the change associated with significant elevations of insulin concen- in bradykinin concentration in blood plasma (16). In this trations in the fasting state and during the late part of study, there was a correlation (r = - 0 . 3 9 , P = 0.06) the glucose tolerance test, but the insulin increment was between the change in blood pressure and the change not elevated in proportion to the other changes of insulin in insulin sensitivity (Fig. 1). In contrast, there was no concentrations. Furthermore, glucose concentrations were relationship between the change in insulin sensitivity and the insulin-sensitivity value in the untreated state increased, reflected in an elevation of HbAlc. The mechanism behind the decrease in insulin sen- (Fig. 2). sitivity is not clear. There was no significant relationship between the change in insulin sensitivity and change in serum K+ concentration. However, serum K+ concentration changes do not reflect the changes in electrolyte concentrations in the skeletal muscle tissue well, and alterations in skeletal muscle tissue of either K+ or Mg + concentrations may explain the observed changes in insulin sensitivity. There was no relationship between the change in insulin sensitivity during hydrochlorothiazide treatment and the value of insulin sensitivity during the placebo run-in period (unpublished observations). During treatment with diltiazem, a Ca2 + channel blocker, there were no significant alterations of insulin sensitivity, fasting or late insulin, and glucose concentrations (12). Thus, this drug seems to be neutral in these respects. However, the different types of Ca2+-channel blockers may have different characteristics. Preliminary -12 - 8 - 4 0 -16 data from one study indicate that, during nifedipine treatment (given as tablets, 20 mg twice daily), insulin Diff DBP supine sensitivity was significantly reduced (unpublished observations). It is possible that this was due to the admin- FIG. 1. Relationship between change in supine diastolic istration method, the tablets causing high plasma con- blood pressure (Diff DBP supine; mmHg) and change in centrations of nifedipine, which may lead to insulin-sensitivity index (Diff Mlgo.^) during captopril compensatory increased sympathetic activity, which in treatment (r = -0.39, P = 0.06). From Pollare et al. (13).
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triglycerides and serum cholesterol increased significantly, reflecting an increase in triglycerides in VLDL by - 2 5 % and LDL-chol by - 6 % . However, HDL-chol concentration was not affected. Treatment with the Ca2+-channel blocker diltiazem or captopril or prazosin treatments did not cause any significant changes in any lipoprotein class.
3T
2
i Q
CONCLUSIONS -1 -2
2 4 6 Glucose disposal, M C A ,
10
OU •
FIG. 2. Relationship between change in insulin sensitivity (Diff M-value) during captopril treatment and insulin sensitivity (Mgo'.uo') in untreated state. From Pollare et al. (13).
During treatment with prazosin, an a,-inhibitor, insulin sensitivity was significantly improved (9). That study was carried out in previously nontreated hypertensive subjects, most of whom were women. In this pilot study, the population differed in several respects from the populations in the other studies, and the magnitude of change was difficult to compare with those obtained in the other studies. However, insulin concentrations during the IVGTT were significantly lower during prazosin treatment than before treatment, and glucose concentrations during the IVGTT were also lower. One interesting observation is that the insulin increment was significantly inhibited during prazosin treatment, which may explain the significant reduction in glucose disappearance rate during the IVGTT. However, if the prevailing glucose and insulin concentrations in blood plasma are important for the vessel wall, then the effects during prazosin treatment seem favorable despite the lower glucose disappearance rate. In a recent study, we investigated the effects of doxazosin (unpublished observations). Preliminary data indicate that the effect on insulin sensitivity was more pronounced in the patients starting with low insulin sensitivity than in those starting with a high insulin sensitivity. Previously reported effects on lipoprotein concentration, in terms of increases in serum triglycerides and decreases in HDL-cholesterol (HDL-chol) concentrations during treatment with (3-blockers, were confirmed in these studies (17). Thus, during selective (3-blocker treatment, serum triglycerides increased by - 2 0 % , during propranolol treatment serum triglycerides increased twice as much, and during pindolol treatment no significant change occurred. However, with all four (3blockers tested, significant reductions in HDL-chol concentrations were registered, which were most profound during propranolol treatment. During hydrochlorothiazide treatment, both serum
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The findings in the epidemiological long-term follow-up studies of treated hypertensive patients give rise to strong suspicion that treatment with p-blockers or diuretics is associated with an increased risk for development of diabetes. The observations by Bengtsson et al. (6,18) that the risk was much more pronounced during combined treatment than during monotherapy with a diuretic or a p-blocker are in accordance with the observations by Swislocki et al. (19) that insulin sensitivity (measured with the insulin-suppression test) and insulin concentrations during the oral glucose tolerance test were more profoundly affected during the combined treatment than during monotherapy. In our study, it was possible to show that, after accounting for the effects of other important risk factors for development of diabetes such as anthropometric data, insulin (reflecting the degree of insulin sensitivity at the outset) and glucose concentrations, and blood pressure, the treatment for hypertension at the follow-up was a significant and independent risk factor for diabetes. The studies evaluating the effect of different drugs on insulin sensitivity and insulin concentrations clearly demonstrate that both thiazide diuretics and (3-blockers decrease insulin sensitivity and also adversely affect the insulin increment. This gives us a reasonable explanation for the observed higher incidence of diabetics among treated hypertensive subjects. Both of these factors are important risk factors for development of diabetes. However, there is a much broader perspective on the importance of metabolic disorders caused by antihypertensive agents originating from the results of the prospective trials in hypertensive patients. These data indicate that, if all available studies are included, a reduction of ~11 % of coronary heart disease has been obtained, which is much less than the expected reduction of —20-25% (20). Furthermore, in trials where only pharmacological treatment was used (excluding those trials in which a combined nonpharmacological and pharmacological treatment was used) for treatment of mild to moderate hypertension, the reduction is much smaller, only 3% (NS) (21). Independent of the magnitude of the obtained decrease, it is obvious that it is smaller than expected. Against the background of epidemiological studies in which plasma insulin concentrations were found to be independent risk factors for coronary heart disease (2224) when considering the effect of all the classic risk factors, it has been suggested that the induced insulin
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resistance during (3-blocker and diuretic treatment may have an atherogenic effect as a direct consequence of the resulting elevation of insulin concentrations. Insulin has been demonstrated to be a growth factor for smooth muscle cells, thus mechanisms are known that could explain the epidemiological findings (25). Furthermore, it has been demonstrated that the risk for coronary heart disease is equally high in people with IGT as in people with diabetes (26). These two categories differ with regard to glucose concentrations. Glucose concentrations and glycosylation of different molecules, e.g., enzymes, do not seem to be the major factors responsible for the similarly increased risk for coronary heart disease among patients with diabetes or IGT. Instead, some common factor for diabetic subjects and subjects with IGT must be in operation. Insulin resistance and elevation of insulin concentrations are such factors. Elevated insulin concentrations are more pronounced in individuals with IGT than in those with diabetes (27). Several of the earlier well-recognized risk factors for coronary heart disease are related to and may be the consequences of insulin resistance. For example, development of hypertension may be associated with lifestyle or hereditary factors resulting in insulin resistance and elevated insulin concentrations. Elevated insulin concentrations are associated with increased reabsorption oi Na + and water in the kidneys, possibly resulting in a volume-dependent hypertension (28). Elevated insulin concentrations are also associated with increased sympathetic activity (29). When repeated during many years, such an increased stimulation may result in manifest hypertension. Both serum triglyceride concentrations and HDL-chol concentrations are significantly correlated with insulin sensitivity (Figs. 3 and 4). The impact of elevated serum
2.5 T
2 1.5 o
o _J Q X
.5
0
3 6 Glucose disposal, M
9 60'-120'
12 15 bw/min)
FIG. 4. Relationship between high-density lipoprotein cholesterol (HDL-chol) concentration and insulin sensitivity (M60_120) in normotensive (D; n = 49) and newly detected untreated hypertensive (•; n = 139) men and women (r = 0.41, P < 0.0001). From Pollare et al. (35).
triglyceride concentrations as a risk factor for coronary heart disease has been much discussed and disputed. However, several of the prospective epidemiological trials have demonstrated that elevation of serum triglycerides is an independent risk factor when associated with low HDL-chol concentrations (30,31). The importance of insulin resistance as a primary risk factor may not have been fully and well understood in the prospective trials where it has been evaluated together with the other risk factors such as triglycerides or HDL-chol concentrations, insulin resistance being the underlying background risk factor but serum lipoprotein concentrations being the risk factors more directly and closer correlated to atherosclerosis and consequently coronary heart dis8T ease. During treatment with (3-blockers, some of the effects on lipoprotein concentrations may be mediated via the effect on insulin sensitivity, but some of the effects are probably direct effects of the (3-blockade on enzymes o regulating lipoprotein metabolism. Anyhow, the induced lipoprotein pattern during either p-blocker or diO) uretic treatment is consistent and is present also after long-term treatment (unpublished observations). If, in V) addition, elevated insulin concentrations in themselves 2 have an atherogenic effect, these adverse alterations may well explain the lower-than-expected effect on risk for coronary heart disease in the prospective trials. This does 0 3 6 9 12 15 not rule out the possibility that a subgroup of the hypertensive population may get a beneficial effect from Glucose disposal, Mg Q t 1 2 Q . (mg/kg bw/min) (3-blocker treatment, i.e., those with manifest ischemic heart disease, as indicated from secondary prevention FIG. 3. Relationship between serum triglyceride concentrials with (3-blockers (32). However, that part of the tration (S-Tg) and insulin sensitivity (M^'-no') in normotensive (D; n = 49) and newly detected untreated hyperten- hypertensive population is not big enough to compensive (•; n = 139) men and women (r = -0.38, P < 0.0001). sate for the metabolic consequences in the larger part of the hypertensive population that is without ischemic. From Pollare et al. (35).
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heart disease, which may explain the lack of effect on risk for coronary heart disease in the prospective trials. The new recommendations for treatment of hypertension have been set against the background of the lower-than-expected reduction of risk for coronary heart disease in the prospective trials (33,34). These trials demonstrate that the risk reduction for stroke is strictly correlated to the decrease in blood pressure (20), and this effect seems to be independent of how the blood pressure reduction was obtained. Consequently, the modern strategy is to obtain, as efficiently as possible, a reduction in blood pressure to minimize the risk for stroke and at the same time to optimize the risk factor profile including the lipoprotein pattern and insulin and glucose metabolism by a combination of nonpharmacological measures and pharmacological treatment that leaves these factors unchanged or preferably improves them. At least 60% of the hypertensive population is obese, a state associated with reduced insulin sensitivity (35). The prevalence of hyperlipoproteinemia and low HDLchol concentration is higher in hypertensive than nonhypertensive subjects. This indicates that a larger proportion of the hypertensive population should have the advantage of being treated with Ca2+-channel blockers, ACE inhibitors, or a r blockers than is the case today.
6.
7. 8. 9.
10.
11.
12.
13. ACKNOWLEDGMENTS This study was supported by Grant 5446 from the Swedish Medical Research Council, the Swedish Diabetes Association, the Ernfors Fund for Diabetes Research, Ostermans Foundation, the King Gustaf V Fund, The Heart and Lung Fund, and the Swedish Society of Medicine.
14.
REFERENCES
16.
1. Sicree RA, Zimmet PZ, King HOM, Coventry JS: Plasma insulin response among Nauruans: prediction of deterioration of glucose tolerance over 6 yr. Diabetes 36:17986, 1987 2. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH: The natural history of impaired glucose tolerance in the Pima Indians. N Engl I Med 319:1500-506, 1988 3. Medical Research Council Working Party on Mild to Moderate Hypertension: Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 2:539-43, 1981 4. Amery A, Berthaux P, Bulpitt C, Deruyttere M, de Schaepdryver A, Dollery C, Fagard R, Forette F, Hellemans J, Lund-Johansen P, Mutsers A, Tuomilehto J: Glucose intolerance during diuretic therapy: results of trial by the European Working Party on high blood pressure in the elderly. Lancet 1:681-83, 1978 5. Murphy MB, Lewis PJ, Kohner E, Schumer B, Dollery CT: Glucose intolerance in hypertensive patients treated with
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diuretics: a fourteen year follow-up. Lancet 2:1293-95, 1982 Bengtsson C, Blohme G, Lapidus L, Lindquist O, Lundgren H, Nystrom E, Peterson K, Sigurdsson JA: Do antihypertensive drugs precipitate diabetes? Br Med ) 289:1495-97, 1984 Skarfors ET, Lithell HO, Selinus I, Aberg H: Do antihypertensive drugs precipitate diabetes in predisposed men? Br Med) 298:1147-52, 1989 DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am ) Physiol 237:E214-23, 1979 Pollare T, Lithell H, Selinus I, Berne C: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 31:415-20, 1988 JeppssonJO, Jerntorp P, Sundkvist G, Englund H, Nylund V: Measurement of hemoglobin A u by a new liquid-chromatographic assay: methodology, clinical utility, and relation to glucose tolerance evaluated. Gin Chem 32:186772, 1986 Pollare T, Lithell H, Selinus I, Berne C: Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Br Med I 297:1152-47, 1989 Pollare T, Lithell H, Morlin C, Prantare H, Hvarfner A, Ljunghall S: Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. / Hypertens 7:551-59, 1989 Pollare T, Lithell H, Berne C: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl I Med 321:868-73, 1989 Lithell HO, Pollare T, Berne C: Insulin sensitivity in newly detected hypertensive patients: influence of captopril and other antihypertensive agents on insulin sensitivity and related biological parameters. / Cardiovasc Pharmacol 15 (Suppl. 5):S46-52, 1990 Jauch K-W, Hartl W, Guenther B, Wicklmayr M, Rett K, Dietze G: Captopril enhances insulin responsiveness of forearm muscle tissue on non-insulin-dependent diabetes mellitus. Eur jClin Invest 17:448-54, 1987 limura O, Shimamoto K, Tanaka S, Hosada S, Nishitani T, Ando T, Masucla A: The mechanism of the hypotensive effect of captopril (converting enzyme inhibitor) with special reference to the kallikrein-kinin and renin-angiotensin systems, jpn j Med 25:34-39, 1986 Ames RP: The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Non-diuretic drugs. Drugs 32:335-57, 1986 Bengtsson C, Blohme G, Lapidus L, Lundgren H: Diabetes in hypertensive women: an effect of antihypertensive drugs or the hypertensive state per se? Diabetic Med 5:261-64, 1988 Swislocki ALM, Hoffman BB, Reaven GM: Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am j Hypertens 2:419-23, 1989 Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH: Blood pressure, stroke, and coronary heart disease. II. Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1:827-38, 1990 Holme I: Treatment for mild hypertension (Abstract). Tidsskr
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tabolism. Diabetologia 21:165-71, 1981 Nor Laegeforen 108:1932-36, 1988 22. Pyorala K: Relationship of glucose tolerance and plasma 29. Landsberg L: Diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, insulin to the incidence of coronary heart disease: results and adaptive thermogenesis. Q j Med 236:1081-90, from two population studies in Finland. Diabetes Care 1986 2:131-41, 1979 23. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude 30. Cambien F, Jacqueson A, Richard JL, Warnet JM, Ducimetiere P, Claude JR: Is the level of serum triglyceride a JR, Rosselin G: Relationship of plasma insulin levels to significant predictor of coronary death in "normocholesthe incidence of myocardial infarction and coronary heart terolemic" subjects? Am J Epidemiol 124:624-32, 1986 disease mortality in a middle aged population. Diabeto/og/a 19:205-10, 1990 31. Castelli WP: The triglyceride issue: a view from Framingham. Am Heart) 112:432-37, 1986 24. Welborn TA, Wearne K: Coronary heart disease indicence and cardiovascular mortality in Busselton with reference 32. May GS: A review of long-term beta-blocker trials in survivors of myocardial infarction. Circulation 67 (Suppl. to glucose and insulin concentrations. Diabetes Care 1): 146-49, 1983 2:154-60, 1979 25. Stout RW: Insulin and atheroma—an update. Lancet 33. 1988 Joint National Committee: The 1988 Report of the Joint National Committee on Detection, Evaluation, and 1:1077-79, 1987 Treatment of High Blood Pressure. Arch Intern Med 26. Jarrett RJ, McCartney P, Keen H: Bedford Survey: ten year 148:1023-38, 1988 mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk indices 34. Guidelines Sub-Committee of the WHO/ISH Mild Hypertension Liason Committee: 1989 guidelines for the for coronary heart disease in borderline diabetics. Diamanagement of mild hypertension: memorandum from a betologia 22:79-84, 1982 WHO/ISH Meeting. J Hypertens 7:689-93, 1989 27. Efendid S, Wajngot A, Cerasi E, Luft R: Insulin release, insulin sensitivity, and glucose intolerance. Proc Natl Acad 35. Pollare T, Lithell H, Berne C: Insulin resistance is a characteristic feature of primary hypertension independent of Sci USA 77:7425-29, 1980 obesity. Metabolism 39:167-74, 1990 28. DeFronzo R: The effect of insulin on renal sodium me-
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The close relationship between diabetes and hypertension has been recognized for decades. New information indicates that resistance to insulin action on glucose uptake in peripheral tissues is a common underlying mechanism in hypertension and diabetes. In prospective trials, the effects of antihypertensive agents on insulin sensitivity and lipoprotein metabolism have been evaluated. Both 0-blockers and thiazide diuretics worsen insulin resistance and deteriorate lipoprotein metabolism. Angiotensin-converting enzyme (ACE) inhibitors, Ca2+-channel blockers, and a-blockers are neutral or improve these factors. These data may explain the unexpectedly high incidence of the development of diabetes among treated hypertensives and the poor effect on risk for coronary heart disease in intervention trials. Diabetes Care 14:203-209, 1991
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on-insulin-dependent (type II) diabetes mellitus is a disease well recognized as associated with life-style. In societies where the diet provides excess calories and physical activity is minimal, obesity is very prevalent and with this goes a high prevalence of diabetes mellitus (1,2). The more severe the obesity, the earlier in life diabetes is precipitated. A moderate degree of obesity has to have a duration of ~ 10-30 yr before diabetes develops. Thus, the time factor is important when the diabetogenic factor is of a moderate degree. It has become widely accepted that hypertension should be treated because of the consistent and profound decrease in risk for stroke associated with effective treatFrom the Department of Geriatrics, Uppsala University, Uppsala, Sweden. Address correspondence and reprint requests to Hans O.L. Lithell, MD, Department of Geriatrics, P.O. Box 12042, S-750 12 Uppsala, Sweden.
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ment. Furthermore, hypertension-related states such as left ventricular hypertrophy and renal insufficiency are favorably affected by treatment. The principle of drug treatment of hypertension has become so widely accepted in 40 yr that pharmacological treatment for hypertension is by far the largest mass intervention that has occurred in history. Today ~40-50% of men and women —70 yr of age are treated for hypertension in the industrialized countries. Therefore, it is surprising that the most commonly used drugs have not been subject to postmarketing surveillance; the knowledge of any lateoccurring side effects is therefore poor. The prospective treatment trials have a fairly short duration, and few have registered the occurrence of diabetes mellitus in active-treatment and placebo-treatment groups (3,4). However, the British Medical Research Council's prospective trial comparing the effect of propranolol or thiazide with that of placebo indicated that thiazide treatment in particular was associated with a significantly increased rate of development of impaired glucose tolerance (IGT) (3). However, the average treatment time was fairly short in that trial. More long-term follow-up studies have been published from three different cohorts. In one, there was a strikingly high incidence of diabetes in a group treated for hypertension for 14 yr, but that study was short of any comparisons with findings in a control group or background population (5). A Swedish study on middle-aged women who were treated for hypertension for >12 yr related the incidence of diabetes mellitus in that group to the incidence in the nontreated background population (6). In that study, some of the hypertensive women were treated with monotherapy with thiazides or propranolol only, but some of the hypertensive population needed a combined treatment with both agents. It was found that both the propranolol-treated group and the thiazide-treated group
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had an approximately fivefold increased incidence of diabetes, whereas the incidence in the combined-treatment group was ~12-fold higher than in the background population. In a parallel study carried out in middle-aged men, the incidence of diabetes among treated hypertensive subjects was approximately fivefold higher than in a control group matched for body mass index, glucose tolerance, and serum lipid concentrations but without pharmacological treatment for hypertension over the 10yr follow-up period (7). However, it was found that those who had hypertension differed from the beginning from those in the matched control group with regard to insulin concentrations, indicating that they were more insulin resistant when treatment started. This case-control study was part of the whole health-survey cohort. In recent analyses of the whole cohort, it was found that, after adjusting for any differences in insulin concentrations, glucose concentrations, blood pressure, and body mass index, treatment for hypertension at the follow-up 10 yr after the original health survey was associated with a significant and independent risk for development of diabetes (unpublished observations). These observations initiated our studies on the metabolic consequences of different drugs. In 1984, we decided to set up techniques to evaluate the effect of the drugs on insulin secretion and insulin sensitivity to find out if any such effect could explain the increased risk for development of diabetes. This review refers to findings in six different studies involving 279 patients.
significantly between different drugs. Because insulin-mediated glucose uptake is linearly related to the prevailing insulin concentration, adjustment for the prevailing insulin concentrations was also made (mg glucose • kg body wt" 1 • min~1 • m i l " 1 , insulin sensitivity index). In some cases, adjustment for the prevailing glucose concentration (5.2 mM on the average) was made. The insulin response to glucose challenge was evaluated with the intravenous glucose tolerance test (IVGTT; 9). This has some advantages over the oral glucose tolerance test in the experimental situation. The immediate insulin response to glucose injection (the insulin increment) is reproducible, and the effect of different drugs on this variable can be accurately estimated. The insulin increment is an important factor determining the glucose tolerance. Fasting insulin concentrations were determined at three time points in duplicate and insulin concentrations every 10 min during the 90-min test. Lipoproteins were quantified with ultracentrifugation to separate very-low-density lipoproteins (VLDL) from low-density (LDL) and high-density lipoproteins (HDL). Triglyceride and cholesterol concentrations were measured in total serum, in the VLDL, and in the bottom fraction after ultracentrifugation and in HDL after precipitation of LDL from the bottom fraction. The LDL concentrations of cholesterol and triglycerides were then calculated. HbA1c was measured by fast-performance liquid chromatography (10).
RESULTS RESEARCH DESIGN AND METHODS Newly detected hypertensive subjects, in an ongoing health survey in Uppsala, Sweden, were invited to take part in the studies together with patients who were being treated for hypertension. About half of the population in several of the studies reviewed herein were nontreated hypertensive subjects earlier, and half had been on treatment for various durations. All studies started with a placebo run-in period of 4— 6 wk. Three double-blind double-dummy-controlled studies and one open study had a crossover design; the active treatment periods were of 4- to 6-mo duration. Two were parallel group-designed blinded studies of 3to 6-mo duration, and one (the prazosin study) was a pilot open study of 3-mo duration. Comparisons have been made not only between the effects of the different drugs but also between the active treatment values and the placebo run-in value. The hyperinsulinemic-euglycemic clamp technique according to DeFronzo et al. (8,9) was used to measure insulin-promoted glucose uptake in the body (insulin sensitivity, mg glucose • kg body wt" 1 • min"1) as accurately as possible. The average prevailing insulin concentrations during the clamp was —100 mU/L, but the treatments affected the insulin metabolism differently, so that the prevailing insulin concentration also differed
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The effects of selective p-blockers were evaluated in two trials. One was a trial in which the two selective (3blockers metoprolol and atenolol were compared with fixed doses of 200 and 50 mg/day, respectively (11). Both drugs reduced insulin sensitivity statistically significantly by 20 and 13%, respectively. However, the catabolism of insulin was also affected, and after adjusting for the prevailing insulin concentration during the clamp, the insulin-sensitivity index was found to be reduced by 27% during metoprolol and by 23% during atenolol treatment (not significantly different). In that study, 62 patients were enrolled. In another study in 58 patients, atenolol was titrated according to the blood pressure response up to 100 mg/day (average dose 67 mg/day; 12). The results of this study confirmed those in the previous one, insulin sensitivity being significantly reduced during atenolol treatment. In both of those studies, the increased insulin resistance was reflected in elevated fasting and insulin concentrations during the IVGTT. However, the insulin increases were not large enough to fully compensate for the reduced insulin sensitivity, so that glucose concentrations were elevated both in the fasting state and during the IVGTT. Further evidence for a certain degree of derangement of the glucose metabolism was a significant elevation of the HbA1c concentration.
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The effect of a nonselective (3-blocker (160 mg/day turn may be responsible for the reduction in insulin senpropranolol) was compared with that of a nonselective sitivity. During treatment with captopril, an angiotensin-con(3-blocker with intrinsic sympathetic activity (10 mg/day pindolol) in a cross-over study recruiting 40 patients (un- verting enzyme (ACE) inhibitor, insulin sensitivity was published observations). The main finding was a pro- improved by ~11 %; after adjustment for the prevailing found decrease by 30% in insulin-sensitivity index dur- insulin concentrations during the clamp, the improveing propranolol treatment; during pindolol treatment, ment was 18%. In that study, it was found that, when the reduction was only about half (17%). Increases in hydrochlorothiazide preceded the captopril treatment, insulin and glucose concentrations during the IVCTT there was a carryover effect from the first treatment pewere found, the patterns being very similar to those with riod to the second, despite the long duration of the treatthe selective fJ-blockers. However, the changes were ment periods. Therefore, the effect of captopril was somewhat larger during propranolol treatment than with evaluated with the first part of the trial only. Also after the other drugs. One interesting observation is that, with adjustment for the small differences in anthropometric all of the |3-blockers, particularly with propranolol, the data and other variables influencing insulin sensitivity, insulin increment was not increased in proportion to the the results clearly indicated that insulin sensitivity was changes in other insulin concentrations, indicating a significantly improved during captopril treatment (14). certain degree of inhibition of the early phase of insulin This result was supported by the findings during the IVGTT. Insulin and glucose concentrations were signifsecretion. The mechanism causing the changes in insulin sen- icantly reduced during the latter part of the IVCTT comsitivity is not clear. However, note that propranolol is pared with the results of the run-in period. The mechanisms causing the change in insulin senthe drug causing the most vasoconstriction, whereas pindolol has a vasodilating effect. It is possible, although sitivity are not clear. In studies in the forearm after innot supported by direct measurements, that blood flow jection of captopril, insulin sensitivity increased. This to skeletal muscle is an important factor influencing in- was related to an accumulation of bradykinin in the blood stream (15). Bradykinin is metabolized by ACE. sulin sensitivity. During thiazide diuretic treatment, there was a sig- Inhibition of this enzyme thus causes accumulation of nificant reduction of insulin sensitivity by 11% and of bradykinin. It has been demonstrated that the reduction insulin-sensitivity index by 16% (13). These changes were in blood pressure is significantly related to the change associated with significant elevations of insulin concen- in bradykinin concentration in blood plasma (16). In this trations in the fasting state and during the late part of study, there was a correlation (r = - 0 . 3 9 , P = 0.06) the glucose tolerance test, but the insulin increment was between the change in blood pressure and the change not elevated in proportion to the other changes of insulin in insulin sensitivity (Fig. 1). In contrast, there was no concentrations. Furthermore, glucose concentrations were relationship between the change in insulin sensitivity and the insulin-sensitivity value in the untreated state increased, reflected in an elevation of HbAlc. The mechanism behind the decrease in insulin sen- (Fig. 2). sitivity is not clear. There was no significant relationship between the change in insulin sensitivity and change in serum K+ concentration. However, serum K+ concentration changes do not reflect the changes in electrolyte concentrations in the skeletal muscle tissue well, and alterations in skeletal muscle tissue of either K+ or Mg + concentrations may explain the observed changes in insulin sensitivity. There was no relationship between the change in insulin sensitivity during hydrochlorothiazide treatment and the value of insulin sensitivity during the placebo run-in period (unpublished observations). During treatment with diltiazem, a Ca2 + channel blocker, there were no significant alterations of insulin sensitivity, fasting or late insulin, and glucose concentrations (12). Thus, this drug seems to be neutral in these respects. However, the different types of Ca2+-channel blockers may have different characteristics. Preliminary -12 - 8 - 4 0 -16 data from one study indicate that, during nifedipine treatment (given as tablets, 20 mg twice daily), insulin Diff DBP supine sensitivity was significantly reduced (unpublished observations). It is possible that this was due to the admin- FIG. 1. Relationship between change in supine diastolic istration method, the tablets causing high plasma con- blood pressure (Diff DBP supine; mmHg) and change in centrations of nifedipine, which may lead to insulin-sensitivity index (Diff Mlgo.^) during captopril compensatory increased sympathetic activity, which in treatment (r = -0.39, P = 0.06). From Pollare et al. (13).
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triglycerides and serum cholesterol increased significantly, reflecting an increase in triglycerides in VLDL by - 2 5 % and LDL-chol by - 6 % . However, HDL-chol concentration was not affected. Treatment with the Ca2+-channel blocker diltiazem or captopril or prazosin treatments did not cause any significant changes in any lipoprotein class.
3T
2
i Q
CONCLUSIONS -1 -2
2 4 6 Glucose disposal, M C A ,
10
OU •
FIG. 2. Relationship between change in insulin sensitivity (Diff M-value) during captopril treatment and insulin sensitivity (Mgo'.uo') in untreated state. From Pollare et al. (13).
During treatment with prazosin, an a,-inhibitor, insulin sensitivity was significantly improved (9). That study was carried out in previously nontreated hypertensive subjects, most of whom were women. In this pilot study, the population differed in several respects from the populations in the other studies, and the magnitude of change was difficult to compare with those obtained in the other studies. However, insulin concentrations during the IVGTT were significantly lower during prazosin treatment than before treatment, and glucose concentrations during the IVGTT were also lower. One interesting observation is that the insulin increment was significantly inhibited during prazosin treatment, which may explain the significant reduction in glucose disappearance rate during the IVGTT. However, if the prevailing glucose and insulin concentrations in blood plasma are important for the vessel wall, then the effects during prazosin treatment seem favorable despite the lower glucose disappearance rate. In a recent study, we investigated the effects of doxazosin (unpublished observations). Preliminary data indicate that the effect on insulin sensitivity was more pronounced in the patients starting with low insulin sensitivity than in those starting with a high insulin sensitivity. Previously reported effects on lipoprotein concentration, in terms of increases in serum triglycerides and decreases in HDL-cholesterol (HDL-chol) concentrations during treatment with (3-blockers, were confirmed in these studies (17). Thus, during selective (3-blocker treatment, serum triglycerides increased by - 2 0 % , during propranolol treatment serum triglycerides increased twice as much, and during pindolol treatment no significant change occurred. However, with all four (3blockers tested, significant reductions in HDL-chol concentrations were registered, which were most profound during propranolol treatment. During hydrochlorothiazide treatment, both serum
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The findings in the epidemiological long-term follow-up studies of treated hypertensive patients give rise to strong suspicion that treatment with p-blockers or diuretics is associated with an increased risk for development of diabetes. The observations by Bengtsson et al. (6,18) that the risk was much more pronounced during combined treatment than during monotherapy with a diuretic or a p-blocker are in accordance with the observations by Swislocki et al. (19) that insulin sensitivity (measured with the insulin-suppression test) and insulin concentrations during the oral glucose tolerance test were more profoundly affected during the combined treatment than during monotherapy. In our study, it was possible to show that, after accounting for the effects of other important risk factors for development of diabetes such as anthropometric data, insulin (reflecting the degree of insulin sensitivity at the outset) and glucose concentrations, and blood pressure, the treatment for hypertension at the follow-up was a significant and independent risk factor for diabetes. The studies evaluating the effect of different drugs on insulin sensitivity and insulin concentrations clearly demonstrate that both thiazide diuretics and (3-blockers decrease insulin sensitivity and also adversely affect the insulin increment. This gives us a reasonable explanation for the observed higher incidence of diabetics among treated hypertensive subjects. Both of these factors are important risk factors for development of diabetes. However, there is a much broader perspective on the importance of metabolic disorders caused by antihypertensive agents originating from the results of the prospective trials in hypertensive patients. These data indicate that, if all available studies are included, a reduction of ~11 % of coronary heart disease has been obtained, which is much less than the expected reduction of —20-25% (20). Furthermore, in trials where only pharmacological treatment was used (excluding those trials in which a combined nonpharmacological and pharmacological treatment was used) for treatment of mild to moderate hypertension, the reduction is much smaller, only 3% (NS) (21). Independent of the magnitude of the obtained decrease, it is obvious that it is smaller than expected. Against the background of epidemiological studies in which plasma insulin concentrations were found to be independent risk factors for coronary heart disease (2224) when considering the effect of all the classic risk factors, it has been suggested that the induced insulin
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resistance during (3-blocker and diuretic treatment may have an atherogenic effect as a direct consequence of the resulting elevation of insulin concentrations. Insulin has been demonstrated to be a growth factor for smooth muscle cells, thus mechanisms are known that could explain the epidemiological findings (25). Furthermore, it has been demonstrated that the risk for coronary heart disease is equally high in people with IGT as in people with diabetes (26). These two categories differ with regard to glucose concentrations. Glucose concentrations and glycosylation of different molecules, e.g., enzymes, do not seem to be the major factors responsible for the similarly increased risk for coronary heart disease among patients with diabetes or IGT. Instead, some common factor for diabetic subjects and subjects with IGT must be in operation. Insulin resistance and elevation of insulin concentrations are such factors. Elevated insulin concentrations are more pronounced in individuals with IGT than in those with diabetes (27). Several of the earlier well-recognized risk factors for coronary heart disease are related to and may be the consequences of insulin resistance. For example, development of hypertension may be associated with lifestyle or hereditary factors resulting in insulin resistance and elevated insulin concentrations. Elevated insulin concentrations are associated with increased reabsorption oi Na + and water in the kidneys, possibly resulting in a volume-dependent hypertension (28). Elevated insulin concentrations are also associated with increased sympathetic activity (29). When repeated during many years, such an increased stimulation may result in manifest hypertension. Both serum triglyceride concentrations and HDL-chol concentrations are significantly correlated with insulin sensitivity (Figs. 3 and 4). The impact of elevated serum
2.5 T
2 1.5 o
o _J Q X
.5
0
3 6 Glucose disposal, M
9 60'-120'
12 15 bw/min)
FIG. 4. Relationship between high-density lipoprotein cholesterol (HDL-chol) concentration and insulin sensitivity (M60_120) in normotensive (D; n = 49) and newly detected untreated hypertensive (•; n = 139) men and women (r = 0.41, P < 0.0001). From Pollare et al. (35).
triglyceride concentrations as a risk factor for coronary heart disease has been much discussed and disputed. However, several of the prospective epidemiological trials have demonstrated that elevation of serum triglycerides is an independent risk factor when associated with low HDL-chol concentrations (30,31). The importance of insulin resistance as a primary risk factor may not have been fully and well understood in the prospective trials where it has been evaluated together with the other risk factors such as triglycerides or HDL-chol concentrations, insulin resistance being the underlying background risk factor but serum lipoprotein concentrations being the risk factors more directly and closer correlated to atherosclerosis and consequently coronary heart dis8T ease. During treatment with (3-blockers, some of the effects on lipoprotein concentrations may be mediated via the effect on insulin sensitivity, but some of the effects are probably direct effects of the (3-blockade on enzymes o regulating lipoprotein metabolism. Anyhow, the induced lipoprotein pattern during either p-blocker or diO) uretic treatment is consistent and is present also after long-term treatment (unpublished observations). If, in V) addition, elevated insulin concentrations in themselves 2 have an atherogenic effect, these adverse alterations may well explain the lower-than-expected effect on risk for coronary heart disease in the prospective trials. This does 0 3 6 9 12 15 not rule out the possibility that a subgroup of the hypertensive population may get a beneficial effect from Glucose disposal, Mg Q t 1 2 Q . (mg/kg bw/min) (3-blocker treatment, i.e., those with manifest ischemic heart disease, as indicated from secondary prevention FIG. 3. Relationship between serum triglyceride concentrials with (3-blockers (32). However, that part of the tration (S-Tg) and insulin sensitivity (M^'-no') in normotensive (D; n = 49) and newly detected untreated hyperten- hypertensive population is not big enough to compensive (•; n = 139) men and women (r = -0.38, P < 0.0001). sate for the metabolic consequences in the larger part of the hypertensive population that is without ischemic. From Pollare et al. (35).
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heart disease, which may explain the lack of effect on risk for coronary heart disease in the prospective trials. The new recommendations for treatment of hypertension have been set against the background of the lower-than-expected reduction of risk for coronary heart disease in the prospective trials (33,34). These trials demonstrate that the risk reduction for stroke is strictly correlated to the decrease in blood pressure (20), and this effect seems to be independent of how the blood pressure reduction was obtained. Consequently, the modern strategy is to obtain, as efficiently as possible, a reduction in blood pressure to minimize the risk for stroke and at the same time to optimize the risk factor profile including the lipoprotein pattern and insulin and glucose metabolism by a combination of nonpharmacological measures and pharmacological treatment that leaves these factors unchanged or preferably improves them. At least 60% of the hypertensive population is obese, a state associated with reduced insulin sensitivity (35). The prevalence of hyperlipoproteinemia and low HDLchol concentration is higher in hypertensive than nonhypertensive subjects. This indicates that a larger proportion of the hypertensive population should have the advantage of being treated with Ca2+-channel blockers, ACE inhibitors, or a r blockers than is the case today.
6.
7. 8. 9.
10.
11.
12.
13. ACKNOWLEDGMENTS This study was supported by Grant 5446 from the Swedish Medical Research Council, the Swedish Diabetes Association, the Ernfors Fund for Diabetes Research, Ostermans Foundation, the King Gustaf V Fund, The Heart and Lung Fund, and the Swedish Society of Medicine.
14.
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