S c a d J CLin Lab Invest 1990; 50 , Suppl 199: 49-54

ANTIHYPERTENSIVE THERAPY AND BLOOD LIPIDS: CALCIUM ANTAGONISTS

Aapo Lehtonen Turku City Hospital, Department of Medicine, Finland.

INTRODUCTION

The major challenge for the future is the prevention of the high in- cidence of coronary heart disease in hypertension. It seems therefore reasonable to examine the hypothe- sis that agents that are equally effective in lowering blood pres- sure have equally beneficial ef- fects on life expectancy. Because the available agents have been shown to have different effects on plasma lipids, it should be consid- ered that they have different ef- fects on the development of corona- ry artery disease. There is now a large body of evidence describing the disturbances in lipoproteins that may be produced by antihyper- tensive agents (1,2,3). Often these drug-induced lipid changes exag- gerate an atherogenic lipid profile which is of importance because both in treated and untreated hyperten- sion, compared to normotensives, there are abnormalities in lipids and lipoproteins (4).

If cell necrosis is an important process in the formation of athero- ma, and if cell death is mediated in part by changes in membranes that facilitate the intracellular accumulation of calcium, drugs cap- able of reducing calcium uptake might exert antiatherogenic ef- fects. Calcium antagonists such as verapamil, diltiazem, nifedipine and nicardipine have been demon- strated to exert antiatherogenic effects in cholesterol-fed rabbits (5). Some investigators, however, have failed to demonstrate these effects. In addition, in vitro mod- els have shown that certain calcium

antagonists interfere with lipopro- tein metabolism by human cells (6).

GLUCOSE METABOLISM

Impaired glucose tolerance may also contribute to the risk of coronary heart disease independently of the other factors (7). Reports of the metabolic effects of calcium an- tagonist have been reviewed by Trost and Weidmann (8). Calcium antagonists may affect glucose hom- eostasis through several mechan- isms. Calcium antagonists can in- terfere with insulin release and can also inhibit the secretion and effect of counter-regulatory hor- mones such as adrenal catechol- amines, glucagon, growth hormone and adrenocorticotrophic hormone ( 8 ) . In addition, calcium an- tagonists can affect glycogenolys- is. Currently, available data indi-

cate that calcium antagonists do not alter glucose homeostasis at a clinically relevant degree in eith- er non-diabetic subjects or pati- ents with diabetes mellitus type 11. With higher doses, the pattern of increased blood glucose and de- creased insulin levels found in vitro may sometimes also occur in man. Furthermore, results of long- term trials, and particularly, un- changed levels of glycosyloted haemoglobin show that in both non- diabetics and patients with diabe- tes mellitus type 11, the use of a calcium antagonist is not likely to affect carbohydrate metabolism ad- verse1 y .

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SERUM LIPIDS

Short term studies

Eight short-term ( 5 2 months) stud- ies are listed on Table 1. In these studies the effects of nifedipine, nitrendipine, diltiazem and vera- pamil on plasma lipids were inves- tigated. Some studies were double- blind placebo controlled studies and some open placebo-controlled or non-placebo controlled studies. In six studies, no alterations were found in the levels of serum chol- esterol, HDL-cholesterol or trigly- cerides. Franz and Wievel (9) in- vestigated the effect of nifedipine and nitrendipine on plasma lipids in a randomized cross-over therapy study. They found a decrease of about 10% in low density lipopro- tein cholesterol levels after nife- dipine treatment, whereas the lev- els of total cholesterol, HDL-chol- esterol and triglycerides remained unchanged. Fagan et al. (19) found an increase in serum total chol- esterol levels after treatment with nitrendipine 10 mg twice a day whereas no significant change in total cholesterol level was found after once daily treatment with nitrendipine. In one study, the concentrations of serum apoproteins have been investigated (ll), and an increase in the levels of apopro- tein A1 after six weeks and apo A1 and apo A11 after three months treatment with nifedipine was found. The changes in serum lipids during short-term therapy with cal- cium antagonists were so small that it appears reasonable to conclude that none of the calcium antagon- ists have any clear effect upon serum lipids.

Long-term studies

Ten long-term studies are listed in Table 2. Serum lipid changes were reported in only four of these. In two studies, slightly adverse al-

teration in Berum lipids during calcium antagonist therapy was re- ported. In my own open, non-con- trolled study where the antihyper- tensive treatment was changed from hydrochlorthiazide to verapamil, serum concentrations of total chol- esterol and LDL-cholesterol were significantly higher after 3, but not after 1 and 6 months of vera- pamil treatment, compared to basal concentrations before diuretic treatment (12). All other lipid levels were unchanged and there were no significant differences between plasma lipid levels during therapy with thiazide or verapamil. In the other randomized, cross-over study the effects of once daily sustained-release verapamil (200- 400 mg/day) and low dose hydro- chlorthiazide (25 mg/day) on meta- bolic parameters were compared (13). Plasma lipids did not change significantly from the values at the end of the drug free run-in period either on verapamil or on hydrochlorthiazide. Serum insulin decreased significantly when com- pared with both the wash-out and thiazide periods. The second "neg- ative" study (14) reported a de- crease in high-density lipoprotein cholesterol after 12 months of tre- atment with nitrendipine. In the open uncontrolled study of Walldius (15), a fall in serum total chol- esterol and LDL-cholesterol con- centrations was reported after 6 months of treatment with verapamil.

Pool et al. (16) found that dil- tiazem treatment was associated with an increase in high-density lipoprotein cholesterol (from 52 to 60 mg/dl) and a decrease in the total cholesterol: HDL-cholesterol ratio both after 3 months and 7 months of treatment. In a ran- domized, double-blind study the metabolic effects of diltiazem and atenolol were compared (17). During atenolol treatment the concentra- tion of HDL-cholesterol decreased and that of serum triglycerides

51

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TABLE 2. Serum

lipids

dur

ing

long-term

(>2

mont

hs) th

erap

y wi

th c

alci

um antagonists

.

Reference

No of

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mont

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Tota

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tal

HDL

Apop

rote

ins

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A1

A11

B st

erol

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ride

s ster

ol

Wada et

al.

1982

10

Lehtonen and Gordin 19

84 15

Hsu

et al.

1984

16

16

11

Walldius 1984

11

9 Faergeman et al.

1984

13

Landmark 1985

16

Pool et

al.

1985

18

31

Francischetti et al.

1987

22

Lehtonen et

al.

1987

13

Poll

are et al.

1989

26

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6

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74

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180

- 80

-160

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0 t.i.d.

- 90

- 30

- 298

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-40

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0 b

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40

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329

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1, de

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Lehtonen A

increased significantly, but during diltiazem treatment there were no significant changes in lipoprotein lipid concentrations. There was a significant difference in the ef- fects of the two drugs on the lev- els of serum cholesterol, trigly- cerides and high-density lipopro- tein cholesterol.

CONCLUSION

The main conclusion from these studies, in which the duration of treatment with calcium antagonist varied from 2 to 12 months, is that there is no consistent trend of changes in serum lipids. It is however still not clear how much, if at all, an antihypertensive med- ication with a potential for an unwanted modification in the serum lipid profile would be able to counteract the beneficial effect on the heart of lower blood pressure. However, if it is accepted that the risk of coronary artery disease increases by more than 2% with eve- ry 1% increase in LDL-cholesterol or 1% decrease in HDL-cholesterol, the changes caused by antihyperten- sive medication may be of con- siderable significance. According to many short-term and

long-term studies calcium an- tagonists appear to be lipid neu- tral. Although direct benefits have not been defined, it would seem reasonable that the achievement of optimum plasma lipids should be an important therapeutic aim in the management of the hypertensive patient.

REFERENCES

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2. Lehtonen A. Effect of beta-

blockers on plasma lipids dur- ing antihypertensive therapy. J Cardiovasc Pharmacol 1985; 7:

3. Ames RP. The effects of anti- hypertensive drugs on serum lipids and lipoproteins. Drugs1986; 32: 335-357.

4. Multiple Risk Factor Interven- tion Trial Research Group. Hy- pertension management in the Multiple Risk Factor Interven- tention Trial (MRFIT). Six year intervention results for men in special intervention and usual care groups. Arch Intern Med

5. Henry PD, Bentley KL. Suppres- sion of atherogenesis in chol- erol-fed rabbit treated with nifedipine. J Clin Invest 1981; 68: 1366-1369.

6. Henry PD. Atherosclerosis, cal- cium and calcium antagonists. Circulation 1985; 72: 456-45

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7. Fuller IH, Shipley MJ, Rose G, Jarrets JR, Keen H. Coronary heart disease risk and impaired glucose tolerance. Lancet 1980; 1: 1373-1376.

8. Trost BN, Weidmann P. Effects of calcium antagonists on glu- cose homeostaeis and serum lip- ids in non-diabetic and diabet- ic subjects: A review. J Hyper- tension 1987; 5 (Suppl 4): 81- 104.

9. Franz IW, Wievel D. Antihyper- tensive Wirkung von Nitren- dipin, Nifedipin und Acebutolol und deren Kombination auf den Ruhe- und Belastungsblutdruck bei Hochdruckkranken. Z Kardiol

10. Fagan TC, Nelson EB, Lasseter KC, Crook J, Morledge J, Konrad KA. Once- and twice-daily nitrendipine in patients with hypertension and non-insulin dependent diabetes. Pharmaco- therapy 1986; 6: 128-136.

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13. Lehtonen A, Gordin A, Salo H. Comparison of sustained release verapamil and hydrochlorothiaz- ide in hypertension - effect on blood pressure and metabolic variables. Int J Clin Pharmacol Ther Toxicol 1987; 25: 301-305.

14. Francischetti EA, Oigman W, Fagundee VGA, Sanjuliani AF, Cunha MC. Long-term therapy with nitrendipine: evaluation of its antihypertensives and metabolic effects. J Cardiovasc

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15. Walldius G. Effect of verapamil on serum lipoproteins in pati- ents with angina pectoris. Acta Med Scand 1984; 681 (Suppl): 43-48.

16. Pool PE, Seagren SC, Sale1 AF, Skalland ML. Effects of dil- tiazem on serum lipids, exer- cise performance and blood pressure: randomized, double- blind, placebo-controlled eval- uation for systemic hypertens- ion. Am J Cardiol 1985; 56:

17. Pollare T, Lithell A, Morlin C, Prantare H, Hvarfner A, Ljung- hall S. Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. J Hypertension 1989; 7: 551-559.

86H-91H.

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