DRUG THERAPY

Drugs & Aging 4 (5): 403-409, 1994 1170-229XJ94/0005-0403/$03.50/0 © Adis International Limited. All rights reserved.

Insulin Resistance and Hypertension in the Elderly

Optimal Drug Therapy

Giuseppe Paoiisso, Antonio Gambardella, Domenico Galzerano and Michele Varricchio Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, Naples, Italy

Contents -103 404

405 405 -106 406

407 408 -108

Summary

Summary I. Nonpharmacological Approaches 2. Pharmacological Approaches 2.1 Diuretics 2.2 ~-B1ockers 2.3 Angiotensin Converting Enzyme Inhibitors 2.4 Calcium Channel Blockers 2.5 a.1-Antagonists 3. Conclusions

Numerous trials have demonstrated the negative effects of some antihypertensive drugs upon glucose handling. Such findings seem particularly interesting in aged hypertensive patients who are also insulin resistant and affected by physiological changes in the renal and cardiovascular systems. It appears that calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors are the most appropriate drugs to lower blood pressure in aged insulin-resistant hypertensive patients. All calcium channel blockers studied have displayed similar metabolic effects, while among the ACE inhibitors studied, lisinopril was associated with the best metabolic responses. ~-Blockers and thiazide diuretics have strong negative effects on glucose handling. Further studies are needed in order to investigate the metabolic effects of aI-antagonists in aged patients with insulin resistance and hypertension.

Numerous epidemiological evidence supports a link between hypertension and insulin resistance, which is marked by hyperinsulinaemia (Ferrannini et al. 1987; Ferrari & Weidmann 1990). This association is particularly strong among obese people,

but may also be present in nonobese patients. Resistance to the blood glucose lowering action of insulin has been detected in lean patients with untreated essential hypertension, and is considered to be the origin of hyperinsulinaemia. Insulin resis-

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tance involves mostly the peripheral tissues (mainly skeletal muscle), and is apparently pathway-specific since the metabolism of lipids and proteins does not appear to be affected (Ferrannini et al. 1987) Aging is also an insulin-resistant state mainly due to endogenous factors, such as decline in lean body mass, decline in muscular blood flow, changes in the length and period of pulsatile B cell secretion and the development of post-receptor insulin resistance. Exogenous factors, such as environment, such as changes in life style, decline in physical activity and changes in dietary habits may also have a role (Fink et al. 1983; Jackson 1990). Therefore, the relationship between insulin resistance and hypertension is strengthened when such factors cluster with aging. In fact, insulin resistance and hypertension are synergistic cardiovascular risk factors for the development of coronary heart diseases in all humans, but especially in the elderly (Amery et al. 1985; Hully etal. 1985). Thus, even in aged people, hypertension needs to be treated by nonpharmacological and/or pharmacological methods in order to reduce cardiovascular morbidity (Amery et al. 1985; Hully et al. 1985). Nevertheless, in the elderly, many age-related changes in cardiac output, renal function, baroreceptor reflex activity, insulin sensitivity and peripheral vascular resistance occur. Therefore, in aged patients antihypertensive drugs must be given with more caution than in younger adults. In light of such pathophysiological age-related changes it seems important to review the main potential benefits and dangers that can be associated with the treatment of aged, insulin-resistant hypertensive patients.

1. Nonpharmacological Approaches Aging, essential hypertension and insulin resistance seem to be linked by a common intracellular ionic disorder (Paolisso et al. 1990a,b; Resnick 1992). In aged hypertensive patients, the coexistence of a low intracellular magnesium content and a high intracellular calcium content has been dem-

Drugs & Aging 4 (5) 1994

onstrated (Resnick 1992). This unbalanced intracellular magnesium to calcium ratio has been considered as a potential cause of insulin resistance. In fact, a strong relationship between intracellular magnesium and calcium content, insulin action and arterial blood pressure seems to occur. Magnesium, as a divalent cation, is an essential cofactor for many enzymatic systems utilising high energy phosphate bonds (Paolisso et al. 1990b). It has been hypothesised that magnesium losses may cause defective oxidative glucose metabolism contributing to, or potentiating insulin resistance (Paolisso et al. 1989, 1990b). Furthermore, low intracellular magnesium levels have been associated with high arterial blood pressure (Resnick 1992). A clinical application of such concepts has been provided in thiazide-treated hypertensive patients (Paolisso et al. 1992). In such patients, long term diuretic treatment depleted intracellular magnesium levels. Furthermore, long term magnesium administration (1.5g of magnesium pidolate twice daily, equivalent to 5.2 mmol/day of elemental magnesium), restored intracellular magnesium levels, lowered arterial blood pressure and improved oxidative glucose metabolism. It should be pointed out that in that study, despite the large amount of magnesium given to the patients, none had serious adverse effects related to magnesium. A possible role for intracellular calcium as a modulator of insulin action was originally proposed by Clansen and colleagues (1974). However, another investigator failed to observe a relationship between calcium and insulin action (Klip 1984). Subsequently, diverse aspects of insulin action have been demonstrated to be dependent upon extra- and intracellular calcium levels (Draznin et al. 1987, 1988). Draznin and colleagues (1988) demonstrated that hyperinsulinaemia, induced by insulin infusions for 3 and 6 hours, not only increased intracellular calcium levels in adipocytes from healthy people, but also made them unresponsive to either insulin or glibenclamide (glyburide). The diminished responsiveness of adipocytes to insulin

Insulin Resistance and Hypertension in the Elderly

Table I. Common foods with high potassium levels. All values are calculated per 100g of edible material Food

Potassium level [mmol (mg)]

Yeast

44 (1720)

Tomato sauce

30 (1173)

Cacao

23 (899)

Potato

15 (590)

Mushroom

12 (480)

Apricot

11 (435)

Banana

10 (395)

Pork

9 (352)

Bean

7 (280)

Egg

6 (250)

Apple

3 (115)

was also manifested by reduced insulin-stimulated glucose uptake. The precise mechanism by which high intracellular calcium levels induce insulin resistance is still not known. However, accumulated experimental evidence indicates that high intracellular calcium levels may inhibit insulin-mediated glucose transport (Draznin et al. 1988). Alternatively, an overload in intracellular calcium content, which frequently occurs in aged hypertensive patients (Vidt & Borazanian 1991), can also increase arterial blood pressure through an enhanced vascular reactivity to different stimuli (Vidt & Borazanian 1991). The relationship between intracellular calcium and magnesium content, insulin action and arterial blood pressure has been strengthened by the recent data showing that a slow infusion of magnesium (100 J.lmollmin) and nifedipine (1.0 J.lg/kg/min) given over 120 minutes, on different occasions or simultaneously, can significantly lower arterial blood pressure and improve glucose handling in aged hypertensive patients (Paolisso et al. 1993). Potassium supplementation has been demonstrated to be a useful nonpharmacological tool in aged insulin-resistant hypertensive patients. In fact, low intracellular potassium levels have been implicated in the development of deficient B cell responses to glucose, which in tum, could also

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have deleterious metabolic effects in aged insulinresistant patients (Beretta-Piccoli et al. 1982). An increase in daily potassium intake might be obtained through appropriate foods (table I). On the other hand, a dramatic decline in daily calcium intake should be avoided in elderly people, due to the high risk of osteoporosis, independent of gender. By contrast, sodium may have a major role in blood pressure maintenance (Ferrari & Weidmann 1990), but does not have a relevant role in the aetiology of insulin resistance in the elderly (Ferrari & Weidman 1990; Fink et al. 1983). Of course, body weight reduction and constant but not strenuous physical activity are mandatory lifestyle guidelines for aged insulin-resistant hypertensive patients (Ferrari & Weidmann 1990). In fact, physical activity might reduce protein and body fat levels and enhance fat-free body mass and peripheral vasodilation. All these factors seem to playa pivotal role in reducing arterial blood pressure and improving insulin action (table II).

2. Pharmacological Approaches 2.1 Diuretics

Diuretics are very often the first step in the treatment of aged hypertensive patients. However, diuretics are not as safe as usually believed and, therefore, they should be prescribed with greater caution in older than in younger adult patients. In fact, in aged hypertensive patients, long term diuretic treatment has been demonstrated to cause extra- and intracellular ion losses. Such changes may disturb baroreflex regulation of arterial blood pressure and cardiac rhythm, which are already affected by age-related modifications (Varricchio et al. 1988). Table II. Nonpharmacological tools which may be of use in the treatment of aged insulin·resistant hypertensive patients Decrease in bodyweight Decrease in percentage body fat Increase in physical exercise Appropriate intake of trace elements

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To date, long term thiazide treatment has been demonstrated to reduce insulin sensitivity with a carryover effect of at least 6 months after treatment discontinuation (Lithell1991; Pollare et al. 1989a). These changes were also associated with a significant increase in plasma insulin levels during a fasting state and during the oral glucose tolerance test (OGTT) [Veterans Administration Cooperative Study Group on Antihypertensive Agents 1982]. Changes in intracellular cation homeostasis are the likely mechanisms responsible for thiazide diuretic-induced insulin resistance. In particular, a reduction in intracellular potassium and magnesium levels seems to have a major role in the down regulation of insulin-mediated glucose transport after long term diuretic treatment (Paolisso et al. 1992). However, it should be pointed out that the negative effects of long term diuretic therapy on glucose handling may be only of minor clinical significance. In fact, prospective studies have demonstrated that diuretic administration is effective in reducing overall mortality in elderly patients with hypertension (Amery et al. 1985). Finally, it should be pointed out that loop diuretics should have no or only minor effects on insulin sensitivity, since extra- and intracellular sodium levels do not affect insulin action. 2.2

~-Blockers

The effects of ~-blockers upon arterial blood pressure and glucose metabolism has been extensively studied (Lithell 1991; Pollare et al. 1989b). In particular, 2 selective ~l-blockers, metoprolol (200 mg/day) and atenolol (50 mg/day), were compared (Pollare et al. 1989c). The results demonstrated that the drugs significantly reduced insulin sensitivity by 20 and 13%, respectively. Furthermore, Pollare and colleagues (1989c) demonstrated that ~-blockers disrupt insulin clearance. When the M value (insulin-mediated glucose uptake, an index of insulin sensitivity) during the glucose clamp was adjusted for the prevailing insulin level during the clamp, insulin sensitivity in-

dex was found to be reduced by 27% during metoprolol and by 23% during atenolol treatment. The decline in insulin sensitivity after ~-blocker administration was also demonstrated by the presence of elevated fasting and glucose-induced plasma insulin levels. However, the increases in insulin levels were not strong enough to fully compensate for the reduced insulin sensitivity, so that glucose levels were elevated both after fasting and during glucose load. Similar findings, although of different magnitude, were found in studies testing nonselective ~-blockers without (propranolol) and with (pindolol) intrinsic sympathetic activity (Lithell 1991). The mechanisms underlying the negative modulation of insulin sensitivity of ~-blockers is still poorly understood. Nevertheless, it has been hypothesised that ~-blockers may decrease blood flow and increase vascular resistance in skeletal muscles which is an important factor influencing insulin sensitivity (Lithell1991). 2.3 Angiotensin Converting Enzyme Inhibitors Among the antihypertensive drugs, angiotensin converting enzyme (ACE) inhibitors are very popular because of their efficacy and low frequency of adverse effects. Furthermore, many recent studies have shown that ACE inhibition, together with the subsequent antihypertensive effect, may improve insulin sensitivity (Williams 1988). Among all the ACE inhibitors, lisinopril seems to be the most effective with respect to reductions in arterial blood pressure and improvements in insulin action in aged insulin-resistant hypertensive patients (Paolisso et al. 1992). The results of a study involving 86 aged insulin-resistant, mildly hypertensive, nonobese patients with normal glucose tolerance tests, demonstrated that lisinopril 20 mg/day produced the largest decline in arterial blood pressure, and at the same time, the best improvement in insulin action (Paolisso et al. 1992) when compared with placebo, captopril (75 mg/day), enalapril (20 mg/day) and ramipril (5 mg/day). The glucose disappearance constant (Conard's K value) was significantly

Insulin Resistance and Hypertension in the Elderly

improved with lisinopril (1.98 ± 0.05%) versus placebo (1.48 ± 0.03%; P < 0.01) and the other ACE inhibitors. By contrast, no significant difference in ~-cell response to glucose was found (Paolisso et al. 1992). More recently, we have also performed an open trial of lisinopril administered for 3 months, to test the long term effects of the drug (unpublished data). Similar to the results obtained in the short term study (Paolisso et al. 1992), this new study demonstrated favourable shifts in the M values from 4.1 ± 0.3 mg/kg/min after placebo to 5.7 ± 0.4 mg/kg/min (p < 0.03) after lisinopril administration. Obviously, lisinopril produced a significant decline in arterial blood pressure (mean arterial blood pressure 118 ± 0.8 vs 101 ± 0.9mm Hg after placebo and lisinopril, respectively, p < 0.001). Nevertheless, the changes in arterial blood pressure and M values were not correlated, thus indicating that the 2 pharmacological actions were regulated by different pathophysiological mechanisms. It is widely known that ACE inhibition lowers arterial blood pressure by causing vasodilatation secondary to inhibition of the renin-angiotensin system in plasma and tissues. Less understood is the effect of ACE inhibitors on insulin action. In order to explain the positive influence of ACE inhibitors on glucose metabolism, hormonal and haemodynamic theories have been suggested. In support of the haemodynamic theory, Kodama and colleagues (1990) demonstrated an increase in forearm blood flow which may have a role in captopril-induced improvement in glucose handling. On the other hand, Laasko and colleagues (1990) demonstrated that vasodilatation or vasoconstriction may significantly reduce peripheral glucose uptake. Thus, it can be hypothesised that ACE inhibitor-induced vasodilation decreases the distance between the capillaries (capillary recruitment) with a secondary improvement in the insulin level gradient between the capillary and surrounding muscle (Lillioja et al. 1987). Such an event might give a greater stimulation of glucose uptake.

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Regarding the hormonal hypothesis, after ACE inhibition the reduced degradation of bradykinin might result in an insulin-like activity (Dietze 1982; Jauch et al. 1986). We feel this latter hypothesis is the one most likely to be correct, since we observed improvement in glucose metabolism after short term (2 hours, i.e. acute vasodilation) as well as long term (24 hours, i.e. in the absence of acute vasodilatation) lisinopril administration. Conflicting data have been reported by Santoro and colleagues (1992). Short term administration of cilazapril (2.5 mg/day) did not affect insulinmediated glucose uptake, substrate oxidation or thermogenesis. In contrast, long term administration of cilazapril was associated with a resistance to the potassium lowering-action of insulin, which in turn may heighten insulin secretory response to glucose stimulation and improve glucose tolerance. The reasons for such discrepancy between our own studies and that by Santoro and colleagues might be due to the different patients (adult vs aged) and ACE inhibitors (cilazapril vs lisinopril) studied. 2.4 Calcium Channel Blockers The calcium channel blockers were initially used to treat angina pectoris. However, the longacting agents are practical for use in hypertension as well (Block 1990). Buhler and colleagues (1982) showed that calcium channel blockers are more effective in elderly, black and low-renin hypertensive patients than in younger, white and high-renin individuals, possibly because the cardiovascular responses to vasodilatation are attenuated in the former group (Buhler & Kiowski 1987). It should be pointed out that most of the aged patients with hypertension have increased peripheral vascular resistance. Therefore, such patients would be logical candidates for treatment with calcium channel blockers (Vidt & Borazanian 1991). Particularly interesting is the relationship between the administration of calcium channel blockers and glucose metabolism. Poll are and colleagues (l989b) showed that diltiazem treatment

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does not significantly affect insulin sensitivity, or fasting or late insulin responses to glucose load. Similar results have been reported with nicardipine (Giugliano et al. 1992), lacidipine (Morris et al. 1993) and amlodipine (Ferrari et al. 1991). In contrast, opposite results were found with nifedipine (LithellI991). Lithell (1991) found that nifedipine (20mg twice daily) reduced insulin sensitivity. Nevertheless, it was suggested that the dosage regimen, which resulted in high plasma concentrations of nifedipine, may have led to compensatory increased sympathetic activity, which in turn may be responsible for the reduction in insulin sensitivity. On the other hand, our recent study (Paolisso et al. 1993), in which nifedipine was infused at very low dosages, provided evidence for a significant improvement in insulin action independently of arterial blood pressure changes. Such positive effects of nifedipine upon insulin action were associated with reduced calcium entry within cells (Paolisso et al. 1993). In light of such evidence, calcium channel blockers seem to be safe and useful antihypertensive drugs in aged insulin-resistant hypertensive patients since they produce beneficial cardiovascular effects without impairing glucose handling. 2.5 a.t-Antagonists Prazosin has been shown in obese hypertensive patients to improve insulin action and to lower blood pressure significantly (Pollare et al. 1988). Nevertheless, it should be pointed out that in this study, only an intravenous glucose tolerance test (IvGTT) was performed. Thus, the evidence for an improved insulin action was indirect, i.e. derived from the changes in plasma insulin levels achieved during the glucose bolus. Similar results were observed with doxazosin, and indicated that the improvement in insulin sensitivity was more pronounced in the patients with an initial low insulin sensitivity than in those with high insulin sensitivity (LithellI991). The different metabolic and cardiovascular patterns of obese and aged individuals do not allow us to translate the results obtained in obese to aged

hypertensive patients. Thus, further studies will need to investigate the metabolic effects of U1antagonists in aged insulin-resistant hypertensive patients.

3. Conclusions In aged hypertensive patients, the choice of optimal drug therapy should take into account the following points: • Age-related changes in cardiac output, renal function and peripheral vascular resistance make older people more sensitive to the blood pressure lowering effects of antihypertensive drugs; • Often multiple illnesses coexist in the elderly so that antihypertensive drugs should not worsen such conditions; • Many antihypertensive drugs may have adverse metabolic effects. In light of such considerations and of the results obtained in the different trials reviewed, it seems currently that calcium channel blockers and ACE inhibitors are the most effective drugs for the treatment of elderly patients with insulin-resistant hypertension.

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Correspondence and reprints: Dr Giuseppe Paolisso, Dept of Geriatric Medicine, II University of Naples, Piazza Miraglia 2, 1-80138 Napoli, Italy.