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- Research design and methods
Non-insulin-dependent diabetes mellitus (NIDDM), hypertension and dyslipidaemia, which frequently exist in the same person, are major risk factors in atherosclerotic disorders [ 1, 2]. For this reason, drugs with no adverse effects on glucose and lipid metabolic control are preferred in the treatment of hypertension in patients having NIDDM [ 3, 4]. With regard to the clinical relevance, i.e. the course of cardiovascular disorders in NIDDM, the importance of this choice of antihypertensive treatment is still unknown [ 5]. Moreover, studies on the effects of many antihypertensive drugs on glucose metabolic control in NIDDM have shown conflicting results [ 6, 7].
Angiotensin-converting enzyme (ACE) inhibitors have been observed to increase the peripheral insulin sensitivity, when estimated by the euglycaemic clamp technique [ 8–12]. In line with these findings, severe hypoglycaemic episodes have occurred only a few hours or days after starting treatment with an ACE inhibitor [ 13, 14]. However, a large number of clinical studies, usually uncontrolled, brief and covering few patients [ 15, 16], have found that ACE treatment had no significant effect on glycaemic control in NIDDM or on insulin and C-peptide levels [ 17] and only a few have indicated an improvement, with reduction in fasting blood glucose [ 18] or glycosylated haemoglobin (HbA1c) [ 19, 20].
The findings concerning the effects of beta-adrenergic blocking agents on glucose metabolism in NIDDM are equally conflicting. However, in most clinical studies, a deterioration in glucose tolerance has occurred after non-cardioselective adrenergic blocking agents [ 21–23], but not after cardioselective agents [ 21–24], some have shown a worsening also after these [ 25] and one [ 26] has shown an improvement with both types.
In view of all this, it seemed pertinent to compare the long-term effects of one ACE-inhibitor, quinapril, which is a new drug, and one cardioselective beta-adrenergic blocking agent, metoprolol, on the glycaemic control in a large group of patients with NIDDM and hypertension. The principal parameter chosen was HbA1c Fasting serum glucose, oral glucose tolerance and C-peptide and insulin responses to oral glucose load were also monitored. Moreover, the effects on serum lipids, urinary excretion of albumin and quality of life were investigated.
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- Research design and methods
Treatment with metoprolol was associated with impaired glycaemic control, as demonstrated by a gradual increase in the mean serum glucose concentration, increase in the mean HbA1c level by 0.5% and a decrease in oral glucose tolerance. In the quinapril group, only an increase (0.3%) in the HbA1c level was observed, which tended to be smaller, although not significantly so. No changes in the antidiabetic treatment, i.e. neither the doses of the drugs nor the diet, were made, according to the study protocol. Since none of the metabolic characteristics at baseline differed significantly between the two study groups, the changes during the double-blind period were essentially related to the type of antihypertensive treatment. The more pronounced blood-pressure lowering effect (supine diastolic blood pressure) in the metoprolol-treated group indicates that the doses were not fully equipotent. Although the body weight of the study groups changed in opposite directions, in agreement with previous studies, this presumably had a minor impact on the metabolic control of glucose. The 6 month changes in fasting blood glucose and body weight showed no correlation in either of the two study groups. It is of interest to note that the rates of increase in the fasting levels of the serum glucose and the HbA1c were of the same size as those observed in the obese NIDDM patients treated with oral hypoglycaemic drugs during the second and third years, in the large United Kingdom Prospective Diabetes Study [ 31], which suggests that the deterioration in glucose metabolic control to some extent was related to the natural course of diabetes.
More recently published studies [ 32–34] have shown that ACE treatment has no effect on glycaemic control. In a recent placebo-controlled study in 17 patients with NIDDM, captopril reduced the production of hepatic glucose and increased the disposal of glucose, which indicates an increased insulin sensitivity [ 35]. A decrease in the mean HbA1c level was also observed, but the mean fasting plasma glucose level remained unchanged. Similarly, an increased insulin sensitivity, leading to increased glucose storage, was demonstrated after enalapril treatment in a 4 week double-blind placebo- controlled study conducted in NIDDM patients with hypertension [ 36].
Thus, there are obvious discrepancies between findings concerning ACE inhibitors on the glycaemic control in clinical settings and on insulin sensitivity, measured by the euglycaemic clamp or comparable methods. Although the various ACE inhibitors may have different effects on glucose metabolism, there is no convincing evidence for this. One important factor may be that most clinical studies have been performed on only a few patients. In the present study, the minimal relevant difference in HbA1c level was considered to be 0.3% and the sample size required to detect such a difference, with 5% significance and 80% power, was calculated to be 64. However, the SD of HbA1c in our study was considerably greater than expected when the study was planned. Under these circumstances, 1024 patients would be required to detect the difference of 0.3% between the groups. Only a few studies seem to have more than 20 patients, although the SD of HbA1c has ranged from 1 to 3%, both in studies which have shown and those which have not shown an effect on HbA1c. An obvious and related explanation is that measurements of insulin sensitivity by clamp or comparable techniques permit detection of changes in glucose metabolism in much smaller patient groups. Thus, in a controlled study conducted in 10 non-obese patients with essential hypertension, cilazapril treatment did not improve the oral glucose tolerance, although the insulin sensitivity, measured by the somatostatin-insulin infusion test, increased significantly [ 37]. At present, the mechanisms underlying the improvement in insulin resistance, demonstrated in non- diabetic and NIDDM, subjects remain unknown. Structural and functional normalization of the alterations in the resistance arteries found in patients with essential hypertension have been demonstrated after long-term treatment with ACE-inhibitors but not after beta-adrenergic blocking agents [ 38, 39].
In the present study, the glucose tolerance and the C-peptide and insulin responses to glucose decreased during beta-adrenergic blockade. Beta-adrenergic blocking agents have been found to increase insulin resistance. However, a reduced insulin secretion due to beta-adrenergic blockade may also contribute (for review, see [ 4]). In the present study, the decrease in the C-peptide and insulin responses to a glucose load may have various explanations, such as a direct effect of metoprolol, progression of diabetes and a decrease in insulin release, secondary to increased hyperglycaemia.
Quinapril treatment was not associated with changes in the serum levels of triglycerides, cholesterol, LDL cholesterol or HDL cholesterol. However, in the metoprolol-treated patients, there was a modest but significant increase in the serum triglycerides, which correlated with the rise in HbA1c, thus suggesting that it was related to the deterioration in glycaemic control. In contrast, no changes in lipoprotein (a) concentrations occurred, which agrees with previous findings in NIDDM (for review, see [ 40]).
Several studies, particularly those carried out over a long-term, have shown that ACE-inhibitors reduce urinary albumin excretion in hypertensive [ 41–43] and normotensive [ 43–46] NIDDM patients. The effects of ACE-inhibitors were seen, whether or not the patient had microalbuminuria or macroalbuminuria, according to a recent meta-analysis [ 47]. Since it has been shown that alterations in albumin excretion are strongly related to those in glucose metabolism [ [UK Prospective Diabetes Study Group (UKPDS). ]48–51], the deterioration in glycaemic control, particularly in the metoprolol-treated patients, may partly explain the lack of an antialbuminuric effect.
In choosing first-line drugs to lower blood pressure, it is important to consider the effect/side-effect balance. In this study, the impact of two therapies on subjective side-effects was evaluated with an established quality of life instrument, the so-called ASPECT scale, in relation to the antihypertensive efficacy and the metabolic control in diabetic patients with elevated blood pressure. In another report on hypertensive patients, captopril was found to have a more favourable effect on quality of life than propranolol or methyldopa [ 52]. However, more recently, using similar quality of life parameters and comparing ACE-inhibitors with newer beta-blockers, such as atenolol, the effect of treatment had little, if any, effect on the perception of overall wellbeing [ 53–57].
The ASPECT scale is sensitive enough to detect differences concerning quality of life both between drugs and between different dose levels of a single drug [ 29, 30]. It is therefore of interest to note that in this study neither of the drugs changed the overall perception of well-being, as regards global well-being or total symptom ratings. There were no significant differences between quinapril and metoprolol in this respect at the end of the treatment period. However, regarding specific symptoms, the ACE inhibitor, as expected, increased the prevalence of cough, whereas treatment with the beta blocker was associated with an increased prevalence of cold digits. Somewhat unexpectedly, we found no differences between therapies concerning fatigue, physical capacity, sleep disturbances, insomnia, vivid dreams or nightmares. Metoprolol, however, induced muscle fatigue, taste disturbances and sweating, which was not the case with quinapril. Several symptoms were affected in different directions, without reaching significance ( Fig. 3). Although metoprolol seemed to induce more adverse effects on certain subjective symptoms, it is important to consider all the effects on subjective symptom ratings, in view of the fact that overall well-being and total symptom scores did not change with either of the drugs. The effects on quality of life measurements must be balanced against the effects of the two therapies on metabolic control and blood pressure. Furthermore, the number of patients are too few to evaluate the effects on the quality of life and the results must therefore be interpreted with caution.