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Hypertension in diabetic patients

Hypertension in diabetic patients

Keeping blood pressure controlled in diabetic patients reduces the risk of cardiovascular, heart, kidney and eye problems. The medication of choice is an angiotensin-converting enzyme inhibitor (ACEI)

Background

  • Hypertension and diabetes are indelibly linked because of genetics and environmental factors.
  • Hypertension occurs twice as frequently in those with diabetes compared with those with normal glucose levels.
  • Ultimately, 50% of patients with diabetes become hypertensive; those with hypertension are prone to type 2 diabetes mellitus (T2DM).1,2
  • The prevalence of hypertension increases with longer diabetes duration.3
  • In patients with T2DM, hypertension may precede or follow their diabetes.

Pathophysiology of hypertension in patients with diabetes

Before complications:

In those with hypertension and diabetes, there is an expansion of the extracellular fluid volume caused by excessive sodium retention, which is hyperglycaemia-induced and enhanced by hyperinsulinaemia.4

In addition, the patient is hyper-reactive to both norepinephrine and angiotensin II, which increase peripheral vascular resistance.
Insulin resistance leads to the ‘calcium pump defect’, which increases calcium levels and blood pressure.5

Evaluation and management of diabetic hypertensive patients 

In evaluation and management of these patients, emphasis should be placed on their metabolic state, with assessment of end-organ damage. The possible presence of secondary hypertension should be considered, as should the possibility of lability in blood pressure.6

Complications:

  • When hypertension and diabetes co-exist, the cardiovascular risk is doubled.7
  • The combination of diabetes and hypertension increases the incidence of transient ischaemic attack, cardiovascular disease and peripheral artery disease.7
  • High blood pressure increases the incidence of both microalbuminuria and clinical proteinuria.8
  • Retinopathy occurs more frequently in hypertensive compared with normotensive diabetic patients.9,10

Antihypertensive therapy selection

There are certain therapeutic considerations in the management of hypertensive diabetic patients, which include nonpharmacological measures, antidiabetic pharmacotherapy, the search for remediable causes and the selection of antihypertensive drugs.

Nonpharmacological measures include encouraging the patient to adopt an antidiabetic diet, one that is high in fibre and low in fat, and ensuring strict glycaemic control. Nutritional modification to promote weight reduction has an antihypertensive effect. Physical exercise promotes glycaemic control and has an antihypertensive effect.  

Restricting sodium intake with a diet low in sodium, strongly discouraging smoking and restricting protein intake to 0.6 gm/kg/day for patients with diabetic nephropathy are all helpful for hypertension control.11

Remedial causes can be removed by adjusting the patient’s prescription to stop any drugs with pressor potential (corticosteroids, oral contraceptives, nonsteroidal anti-inflammatories), checking patients for renal artery stenosis and other parenchymal renal diseases, and checking for, e.g., primary aldosteronism, Cushing’s syndrome.

Conventional antidiabetic pharmacotherapy involves an unresolved dilemma: patients need an effective level of insulin to achieve euglycaemia, but this is balanced by the harmful effects of hyperinsulinaemia, which promotes atherosclerosis, is a coronary risk factor and facilitates hypertension.12

Effects of antihypertensive drugs beyond blood pressure control

Different classes of antihypertensive drugs affect glucose metabolism in different ways. Simplistically, thiazides, loop diuretics and b-blockers reduce glucose tolerance, ACEI and angiotensin-receptor blockers improve insulin sensitivity,13 α 1-blockers improve glucose control, and calcium antagonists, sympatholytic agents, serotonin antagonists and indapamide are metabolically neutral or have no adverse metabolic effects.14,15

Different antihypertensive drugs have varying effects on left ventricular hypertrophy (LVH) – ACEI and calcium antagonists reduce the incidence of LVH, diuretics are less effective, and direct arteriolar vasodilators tend to increase the rate of LVH.15

Drugs for hypertension generally reduce proteinuria and nephropathy, with the exception of diuretics, which accelerate diabetic nephropathy,15 and nifedipine, which increases protein excretion in those with nephropathy.16

In terms of antihypertensive potency, diuretics are effective for resistant high blood pressure, calcium antagonists, ACEI and b-blockers provide roughly equivalent long-term control, and a 1-blockers and sympatholytics are most effective in hypertensive diabetic patients.17

Diabetic patients are prone to autonomic dysfunction and ischaemic angiopathy.

Calcium antagonists and ACEI are beneficial to these patients as they do not alter the autonomic homeostatic mechanism so the patient experiences less orthostatic hypotension, less sexual dysfunction and less coronary or peripheral angiopathy.18

In contrast, b-blockers can delay the recovery from an insulin-induced hypoglycaemic episode, and are implicated in Raynaud’s syndrome and claudication in these patients. Each class of antihypertensive medication can cause orthostatic hypotension.18

The ultimate goal of treatment is to improve life prognosis, which, for a patient with hypertension and diabetic nephropathy can be a reduction in the 10-year mortality rate of between 20 and 65%.19,20 Use of a diuretic in these patients can lead to excess mortality.19,20 

Practical antihypertensive therapy in patients with diabetes

In practice, all patients with diabetes with blood pressure >140/90 mmHg should be treated with antihypertensives, with the aim of reducing cardiovascular morbidity and mortality. The aim of treatment is a stable blood pressure <140/90 mmHg.

Antihypertensive drugs should also be used in those with persistent borderline hypertension and in those with diabetic nephropathy, even if their blood pressure is normal. Patients should also be instructed, motivated and supervised in nonpharmacological measures.

With the considerations outlined above, the first choice of antihypertensive drug should be an ACEI. When selecting a calcium antagonist, verapamil or diltiazem should be selected, not nifedipine. Serum creatinine, potassium and proteinuria should be monitored. If a diuretic is indicated, a metabolically neutral one should be selected, e.g., indapamide. In resistant cases, an α-blocker, α-methyl dopa or a selective β-blocker could be prescribed.

Is cardioprotection a valid concept in these patients?

Various large-scale studies of ACEI use in patients with heart failure have found a reduction in the rate of recurrent coronary events, reducing both morbidity and mortality.21–23

Analysis of the 15–20% of diabetic patients in the EUROPA study showed that the risk of recurrent coronary events was approximately six times greater in these patients than in those without diabetes. The use of an ACEI was shown to have beneficial effects on diabetic micro-albuminuria and diabetic retinopathy and was also effective in avoiding recurrent coronary events in patients with diabetes.24 In the CAPPP study where ACEI was compared with conventional antihypertensive therapy, it was found that in diabetic patients the primary endpoint (fatal and nonfatal myocardial infarction, stroke) was dramatically lower in the ACEI-treated group.25

In the HOPE study, the effect of an ACEI (ramipril) on the onset of cardiovascular and diabetic events in a wide range of high-risk patients who had no evidence of left ventricular systolic dysfunction, heart failure or uncontrolled hypertension was assessed. The results showed a 22% risk reduction.26 Further analysis of the Hope study data investigated the effect of ramipril on the likelihood of renal and cardiovascular outcomes in a broad range of high-risk diabetic patients – the MICRO-Hope study.26 Ramipril significantly prevented microvascular complications, overt nephropathy and major cardiovascular outcomes by lowering the albumin:creatinine ratio. New cases of diabetes were significantly lower with ramipril than with placebo; this is because of the beneficial effect of ACEI as it causes an increase in the blood supply to the pancreas, increased insulin sensitivity and a positive effect on hepatic metabolism and an anti-inflammatory response. ACEI are also thought to have a renal protective effect as they reduce plasma thrombomodulin, which is a useful maker for assessing the efficiency of drugs protecting the vessel wall.     

The captopril prevention project (CAPPP) found that the greatest benefit of ACEI therapy was in patients with the highest diastolic blood pressure and those with the highest fasting blood glucose level. ACEI treatment also reduced the incidence of new cases of diabetes.25

In the Hypertension Optimal Treatment (HOT) study, patients with diabetes benefited more than normoglycaemic patients from intensive blood pressure lowering using combined antihypertensive therapy. Reducing diastolic blood pressure to <80 mmHg rather than <90 mmHg resulted in a 67% reduction in cardiovascular mortality and a 52% reduction in major cardiovascular events.27

In conclusion, the WHO-ISH guidelines28 quote diabetic nephropathy as a compelling indication for the use of an ACEI.


References

1. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607.

2. Epstein M, et al. Diabetes mellitus and hypertension. Hypertension 1992;19:403–18.

3. Krokwaki AS et al hypertension, or the orthostatic type hypotension and the micro vascular complications of diabetes J Chronic Dis 1985 38-432.

4. Sowers JR, et al. Hypertension associated with diabetes mellitus, hypercalcaemic disorders, acromegaly and thyroid disease. Clin Endocrinol Metab 1981;10:631–56.

5. Zemel MB, et al. Altered cacion transport in diabetic hypertension. Clin Res 1987;35:853.

6. Chicago Year Book Medical, 1987; pp 87-132.

7. Christlieb AR. Diabetes and hypertensive vascular disease. Mechanisms and treatment. Am J Cardiol 1973;32:592–606.

8. Wiseman M, et al. Glycaemia, arterial pressure and microalbuminuria in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1984;26:401–405.

9. Knowler WC et al. Increased incidence of retinopathy in diabetics with elevated blood pressure. A six-year follow-up study in Pima Indians. N Engl J Med 1980;302:645–50.

10. Mogenson CE. Long term antihypertensive treatment inhibiting progression of nephropathy. BMJ 1982;285:685. 

11. Zeller K, et al. Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991;324:78–84.

12. Ferrannini E, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317:350–7.

13. Bergemann R, et al. (Improved glucose regulation and microalbuminuria/proteinuria in diabetic patients treated with ACE inhibitors. A meta-analysis of published studies 1985-1990). Schweiz Med Wochenschr 1992;122:1369–76. [Article in German, English abstract.]

14. Ferrari P, et al. Antihypertensive agents, serum lipoproteins and glucose metabolism. Am J Cardiology 1991;67:26B–35.

15. Weidman P, et al. Sodium volume factor, cardiovascular reactivity and hypotensive mechanism of diuretic therapy in mild hypertension associated with diabetes mellitus. Am J Med 1979;67:779–84.

16. Weidman P, et al. Treatment of the hypertensive diabetic: focus on calcium channel blocker. Herdelberg springer-Vertag 1989:85-99

17. Weidman P, et al. Presser factors and responsiveness in hypertension accompanying diabetes mellitus hypertension. Hypertension 1985;7(suppl 2):11–33.

18. Trost BN, et al. Antihypertensive therapy in diabetic patients. Hypertension 1985;7(6Pt 2):II 102–8.

19. Parving HH, et al. The impact of hypertension and antihypertensive treatment on the course and prognosis of diabetic nephropathy. J Hypertens Suppl 1990;8:S187–91.

20. Cruickshank JM, et al. Benefits and potential harm of lowering high blood pressure. Lancet 1987;1;581–4.

21. Rutherford JD, et al. Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation 1994;90:1731–8.

22. Greenberg B, et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 1995;91:2573–81.

23. Fox KM, et al. The European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA). Eur Heart J 1998;19(Suppl J):J52–5.

24. Daly CA, et al. The effects of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J 2005:26:1369–78.

25. The captopril prevention project: a prospective intervention trial of angiotensin converting enzyme inhibition in the treatment of hypertension. The CAPPP study. J Hypertens 1990;8:985–90.

26. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000,355:253–9.

27. Hansson L, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT study group. Lancet 1998;351:1755–62.

28. WHO-ISH hypertension guidelines. J Hypertens 2003;21:1983–92.

Omar Salah Awwad

Professor of Cardiology, Vice President
Cardiology department
Ain Shams University
Hypertension
Diabetes
blood pressure
Antihypertensive therapy
Angiotensin-converting enzyme inhibitors