Summary

Hypertensive patients are frequently overweight with impaired glucose tolerance. Thiazide diuretics and beta-blockers are commonly used as first line anti-hypertensive drugs. While effective in blood pressure lowering, these drugs have the propensity to exacerbate glucose intolerance in overweight individuals with insulin resistance resulting in new-onset diabetes. In contrast, drugs that block the renin-angiotensin system improve glucose metabolism and reduce new-onset diabetes. This article reviews evidence from recent clinical trial and discusses the potential mechanisms whereby blockade of the renin-angiotensin system improves glucose metabolism.

摘要

高血壓病者經常出現體重過重和葡萄糖耐量異常的情況。類利尿劑和受體阻滯劑是最常用的第一線抗高血壓藥物。個別有胰島素抵抗的體重過重的高血壓患者服用，這些藥物可以有效地降低高血壓，卻加劇葡萄糖耐量異常的傾向，導致糖尿病。相反，腎素—血管緊張素阻抗藥促進葡萄糖新陳代謝減少新的糖尿病。本文回顧近期臨床試驗的證據，討論以腎素血管緊張素阻抗藥來促進葡萄糖新陳代謝的可能機制。

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Introduction

Hypertension is a prominent component of the metabolic syndrome. It has been shown that approximately 40% of patients with essential hypertension are insulin-resistant.^1,2 A significant proportion of the hypertensive population is obese and given the strong association between obesity and insulin resistance, one would expect a high prevalence of impaired glucose tolerance amongst these obese hypertensive patients. With time, many of these patients will develop type 2 diabetes which further increases their cardiovascular risk.

Limitations of existing hypertension guidelines

Several well-established hypertension guidelines are currently available including the JNC-7 (USA Joint National Committee on prevention, Detection, Evaluation, and Treatment of High Blood Pressure),³ ESH-ESC (European Society of Hypertension-European Society of Cardiology),⁴ WHO/ISH (World Health Organisation-International Society of Hypertension),⁵ BHS (British Hypertension Society)⁶ and ANBP2 (The Second Australian National Blood Pressure Study).⁷ Among these guidelines, the JNC-7 guideline suggests that thiazide diuretics should be the initial drug of choice for uncomplicated hypertension.³ This recommendation is based on cost and findings of the ALLHAT (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study,⁸ which has been intensely criticized.^9,10 On the other hand, the ANBP2 suggests that angiotensin-converting enzyme inhibitors are better initial drug treatment.¹¹ The BHS guideline suggests initial treatment with any one of the 4 drug classes (the ABCD algorithm).⁶ Most guidelines emphasize blood pressure target rather than the specific initial drug treatment. Hence there is no universal rule to support the use of any class of drug as initial drug treatment, especially in specific patient groups, such as obese hypertensive patients. Furthermore, the existence of many guidelines for a single condition suggests that there are still areas of controversy yet to be agreed among experts in the field.

Old anti-hypertensive drugs and glucose intolerance

It has been well documented that antihypertensive drugs such as thiazide diuretics and -blockers may cause glucose intolerance.¹² On the other hand, blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme (ACE) inhibitors^13,14 or angiotensin receptor blockers (ARBs)^15,16 decreases incidence of new-onset diabetes. In clinical practice, multiple antihypertensive drugs are often required to lower blood pressure to target levels.³ Thus it could be argued that thiazide and -blocker would ultimately be required as part of a multiple drug regimen to achieve blood pressure goal. However, multiple drug therapy may only be required after many years of monotherapy. Hence the initial choice of antihypertensive drug is important given the potential effects of these drugs on glucose metabolism.

RAS blockade decreases new-onset diabetes: trial evidence

There is accumulating evidence that blockade of the RAS with either ACE inhibitors or ARBs reduces new-onset diabetes.^13-16 Large-scale randomized clinical trials such as LIFE (Losartan Intervention For Endpoint reduction in hypertension) and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) studies showed that treatment with losartan and valsartan decreases new-onset diabetes when compared with -blocker and calcium channel blocker based regimens respectively.^15,16 In LIFE study, there was a 25% lower incidence of new-onset diabetes in the losartan group than the atenolol group.¹⁵ This is not surprising given the well-known negative effect of -blockers on glucose metabolism. In the VALUE study, valsartan-based regimen has significantly lower incidence of new-onset diabetes (by 23%) compared with amlodipine-based regimen. Significantly, the valsartan group had a greater proportion of patients on concurrent thiazide diuretics. Despite the negative impact of thiazide diuretics on glucose metabolism, the valsartan group had a lower incidence of new-onset diabetes than the amlodipine group.¹⁶ In contrast to the above well-conducted prospective long-term follow-up study results, Padwal and co-workers recently found that there was no difference in the incidence of new-onset diabetes amongst commonly used antihypertensive drug classes, including ACE inhibitors, diuretics and -blockers.¹⁷ This study, however, was retrospective in nature with too short a follow-up duration (mean follow-up period of 9.5 - 11.6 months) for drug-induced glucose intolerance to occur. Hence the findings of this study cannot be considered to be valid.¹⁸ Taken together, current evidence supports the notion that blockade of RAS reduces risk of development of diabetes. The key question is: Does lowering the incidence of diabetes translate into lower mortality in hypertensive patients?

Does added VALUE prolong LIFE?

Although it is clear that the co-existence of hypertension and diabetes confers a 2- to 3-fold higher risk of cardiovascular disease,^19,20 surprisingly few data exist on the prognostic impact of new-onset diabetes in hypertensive subjects with initially normal glucose tolerance. The results of a recent long-term cohort study provide valuable insight. A large number (n=795) of untreated hypertensive patients were followed up for 1-16 years (median 6.0 years).²¹ New diabetes occurred in 5.8% of subjects initially without diabetes. Of these subjects who developed diabetes, 53.5% received a diuretic as antihypertensive therapy, compared to 30.4% of those in whom diabetes did not develop. The relative risk of developing a first cardiovascular event is significantly higher in the group who developed new diabetes compared to the group persistently free of diabetes after adjusting for other confounders.²¹ These results clearly have a practical implication: the risks of new-onset diabetes should be factored into recommendations of antihypertensive therapy. While taking into account the overall cardiovascular risk, reduction of blood pressure to target levels remains the key in management of hypertension. The importance of this is reflected in the VALUE study result in which there was an increase in cardiovascular mortality in the valsartan-based regimen in the first 6 months as a result of inadequate blood pressure control compared to the amlodipine-based regimen.¹⁶

RAS blockade and insulin sensitivity

The mechanisms whereby blockade of the RAS improves insulin sensitivity are complex and not fully understood. There is some evidence that ACE inhibitors decreases insulin resistance via activation of the bradykinin-nitric oxide system leading to an increase in translocation of glucose transporter 4 (GLUT4) resulting in increase glucose uptake from the blood stream.²² Bradykinin also directly potentiates insulin responsiveness of both adipocytes and muscle fibres.²³ For ARBs, the antihyperglycaemic mechanism appears to be predominantly related to effects of angiotensin II blockade. Angiotensin II has been shown to inhibit intracellular insulin signalling which can be restored by direct angiotensin II antagonism.²⁴ In addition, both temocapril (an ACE inhibitor) and candesartan have been shown in a clinical study to increase plasma adiponectin in hypertensive patients and the effect is greater with candesartan.²⁵ Adiponectin is an adipocytokine secreted exclusively by adipocytes and hypoadiponectinaemia has been consistently linked with insulin resistance.²⁶ Hence an increase in adiponectin by RAS blockade may further explain the reduced incidence of new-onset diabetes observed in clinical trials. Furthermore, the weak anti-inflammatory effects of ARBs^27,28 may also (at least to some extent) contribute to the improvement in insulin resistance.

ARB with partial PPAR-gamma effect

The relative effect of different ARBs on insulin resistance is not known since there are no data on direct comparison. However, telmisartan may have a specific antihyperglycaemic effect beyond angiotensin II receptor antagonism as it possesses partial PPAR-gamma effect, a property that is not present to the same extent in other ARBs.^29,30 High lipophilicity is required to obtain sufficiently high penetration rates to bind to intracellular PPAR-gamma. Amongst all ARBs, telmisartan has the greatest lipophilicity which is likely to account for its partial PPAR-gamma action at pharmacological doses. Animal studies showed that when compared with other ARBs of similar dosage, telmisartan significantly decreases fasting plasma glucose, fasting insulin and triglyceride, an effect similar to thiazolidinediones.³⁰ This partial PPAR-gamma effect of telmisartan suggests that it may lead to greater improvement in insulin resistance compared to other ARBs or ACE inhibitors. In this regard, the results of ongoing trials such as ONTARGET comparing effects of dual RAS blockade (telmisartan in combination with ramipril) with monotherapy (telmisartan and ramipril) would be of great interest.³¹

Conclusions

The co-existence of type 2 diabetes and hypertension is common which markedly increases CVD risk. Amongst antihypertensive drug classes, thiazide diuretics and -blockers have potential adverse metabolic effects whereas ACE inhibitors and ARBs have favourable effects on glucose metabolism. Large scale clinical studies confirmed that incidence of new-onset diabetes is decreased in ARB treatment groups when compared to other antihypertensive drug classes. New generation ARB with partial PPAR-gamma effects may have more favourable effects on glucose metabolism. In addition to blood pressure lowering efficacy, risk of developing diabetes should be taken into account when prescribing antihypertensive drugs in clinical practice.

Key messages

1. Hypertensive patients are frequently insulin resistant with impaired glucose tolerance.
2. Antihypertensive drugs such as thiazide diuretics and beta-blockers may worsen metabolic profile and induce diabetes.
3. Drugs blocking the renin-angiotensin system increase insulin sensitivity and decrease new-onset diabetes.
4. Recent large-scale clinical trials confirm that ACE inhibitors and ARBs are superior in reducing incidence of new-onset diabetes compared to antihypertensive drugs of other classes.
5. Drugs blocking the renin-angiotensin system could be considered as initial choice of antihypertensive therapy in overweight hypertensive patients.

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References