Over the last decade there has been increasing interest in the clinical association between hypertension and diabetes. Although a recent consensus statement has provided guidelines for the management of hypertension in Australia, this report focuses specifically on the management of hypertension in the diabetic patient.

Hypertension is twice as prevalent in diabetic as in non-diabetic individuals. Furthermore, it has been clearly shown that hypertension in diabetic patients is associated with accelerated progression of both microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) complications. Macrovascular disease accounts for the majority of deaths in patients with non-insulin-dependent diabetes mellitus (NIDDM). The presence of hypertension in this type of diabetes is associated with a 4-5-fold increase in mortality, predominantly from coronary artery disease and stroke.

Hypertension and diabetic renal disease
Hypertension is associated with microvascular complications, in particular nephropathy.5 Diabetic nephropathy is now the leading cause of end-stage renal failure in the Western world; a similar number of patients with insulin-dependent diabetes mellitus (IDDM) and NIDDM are entering end-stage renal failure programs.

In IDDM, nephropathy affects about a third of patients and antihypertensive treatment has been shown to retard its progression. In NIDDM, hypertension is not as closely linked to renal disease and often occurs before the diagnosis of diabetes. Data on the long-term effects of antihypertensive drugs on nephropathy in patients with NIDDM are still pending.

In IDDM, elevation of blood pressure is closely linked to renal disease. Longitudinal studies have shown that blood pressure is already rising in patients with IDDM before the development of overt proteinuria, in the phase known as microalbuminuria. Microalbuminuria is defined as an elevated urinary albumin excretion rate (30-300 mg/24 hours or 20-200 g/minute) when conventional dipstick tests for proteinuria (such as Albustix) are still negative, and is now regarded as an early phase of nephropathy. In patients with IDDM, the presence of microalbuminuria or overt proteinuria predicts cardiovascular disease. The increase in cardiovascular disease is about threefold in microalbuminuric patients with IDDM when compared with age- and duration- matched normoalbuminuric patients with diabetes. This increase in cardiovascular disease is even higher in patients with overt proteinuria.

Hypertension and insulin resistance or metabolic syndrome
NIDDM and hypertension commonly co-exist and may be part of the insulin resistance or metabolic syndrome. This syndrome describes a group of clinical and biochemical features which are strongly associated with accelerated atherosclerosis. These features include obesity, mixed dys- lipidaemia (high triglycerides and low HDL [high density lipoprotein] cholesterol levels) and hyperinsulinaemia, as well as hypertension. The underlying association between hypertension and diabetes in this syndrome remains unknown, but it is possible that endothelial dysfunction as a result of both hypertension and diabetes could be an important factor in the high incidence of vascular disease in individuals with both conditions.

Antihypertensive therapy and diabetic renal disease
Hypertension should be treated aggressively in diabetic patients, particularly if there is evidence of renal disease. The aim of blood pressure reduction includes retardation of the progression and prevention of diabetic complications.

Many studies have been performed over the last decade to evaluate the efficacy of antihypertensive agents on the progression of diabetic nephropathy, with particular emphasis on patients with IDDM. Recently, Lewis et al. reported that in patients with IDDM and overt proteinuria use of the angiotensin-converting enzyme (ACE) inhibitor, captopril, not only reduced proteinuria but delayed the onset of end-stage renal failure. Studies in patients with IDDM and microalbuminuria have shown that antihypertensive therapy, even in the absence of systemic hypertension, will reduce albuminuria and delay the development of overt (Albustix-positive) proteinuria. Long-term effects on renal function remain to be determined in these patients.

The role of other antihypertensive drugs, particularly calcium-channel blockers, in influencing the progression of diabetic renal disease has not been as clearly delineated. Comparisons between ACE inhibitors and other classes of antihypertensive drugs have been performed in diabetic patients. However, these studies have generally been of short duration, have concentrated only on IDDM or have included heterogeneous groups of patients (including both types of diabetes, hypertensive and normotensive patients, or patients with different stages of renal disease). At present, a significant number of large trials are in progress in patients with IDDM and NIDDM which focus not only on differ- ent antihypertensive drugs but also on different goal blood pressures.

More detailed reviews of the various studies comparing the different classes of antihypertensive drugs in IDDM and NIDDM have been recently published. The role of ACE inhibitors in patients with NIDDM and albuminuria has not been as extensively investigated as in IDDM. However, in a study of patients with NIDDM and microalbuminuria, Ravid et al. showed that enalapril prevented the rise in albuminuria and decline in renal function observed in the placebo group. Recent meta-analyses have suggested that ACE inhibitors are superior to other classes of antihypertensive agents in reducing proteinuria in diabetic patients. A recent study by Lacourci?re et al. indicated that in patients with NIDDM and microalbuminuria captopril was superior to metoprolol or hydrochlorothiazide in reducing urinary albumin excretion.

Retinopathy is closely associated epidemiologically with hypertension. However, the role of antihypertensive therapy in preventing this diabetic complication remains unknown. It is interesting that in the study by Ravid et al. ACE inhibition was associated with less retinopathy.

Antihypertensive drugs - side effects
The choice of antihypertensive drug should be determined by the drug’s capacity to lower blood pressure, to protect the diabetic patient’s kidneys from ongoing injury and its side effects.

β-Blockers and thiazide diuretics may influence glycaemic control in a deleterious manner. These agents can also have unfavourable effects on lipids by increasing triglycerides and decreasing HDL cholesterol levels. -Blockers may exacerbate symptoms of peripheral vascular disease, a condition which is more common in diabetic patients. In patients with IDDM who are at a high risk of hypoglycaemia, β-blockers may reduce the symptomatic manifestations of hypoglycaemia and inhibit the metabolic counter-regulatory response. Recently, it has been shown that the deleterious effects of thiazide diuretics on lipid and glucose metabolism are dose related and do not generally occur if low doses are used.

The α-blockers, such as prazosin, and the calcium- channel blockers do not have adverse effects on glucose or lipid levels. ACE inhibitors have been shown to enhance insulin sensitivity. However, these modest effects on insulin resistance do not appear to be associated with a dramatic improvement in glycaemic control in diabetic patients. Nevertheless, ACE inhibitors, like α-blockers and calcium-channel blockers, do not adversely affect lipid or glucose levels.

ACE inhibitors are commonly used in diabetic patients with nephropathy. However, these agents may uncommonly be associated with life-threatening hyperkalaemia, particularly when hyporeninaemic hypoaldosteronism is present - a condition often associated with renal impairment and autonomic neuropathy in diabetes. Renal artery stenosis should always be considered in the presence of recent-onset hypertension in a diabetic patient. Bilateral renal artery stenosis is often associated with rapid deterioration of renal function if ACE inhibitors are given.

Recent guidelines
There has been a recent proliferation in guidelines for the management of hypertension. Some of these reports contain specific recommendations for the treatment of the diabetic patient with hypertension. In addition, several of the organisations which advise on the management of diabetes have developed their own set of guidelines for treating hypertension in the diabetic patient. Finally, the recent results that suggest renal protection by using antihypertensive drugs (in particular, ACE inhibitors) in diabetic patients who have a “normal” blood pressure and who have evidence of early or overt nephropathy have led to recommendations on the use of antihypertensive agents in the absence of hypertension.

This position statement outlines the opinion of the Australian Diabetes Society. In particular, we have reviewed the guidelines of the Australian consensus statement on hypertension, the American Diabetes Association guidelines and the report by an ad hoc committee to the Scientific Advisory Board of the National Kidney Foundation of the United States. All of these reports state that ACE inhibitors may have a specific role in diabetic patients with proteinuria, but vary as to whether ACE inhibitors are considered the drugs of first choice in the clinical situation of diabetes, hypertension and proteinuria.

Conclusions Although the principles of management of hypertension in the diabetic patient resemble those in a hypertensive individual without diabetes, there are additional medical problems and different classes of antihypertensive drugs to consider in the diabetic patient. Individuals with both hypertension and diabetes are at high risk for both vascular and renal disease. They should therefore be treated with the appropriate antihypertensive drugs and be carefully monitored to ensure satisfactory blood pressure control and prevention of end-organ complications.

References

  1. Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992; 19: 403-418.
  2. Williams B. Insulin resistance; the shape of things to come. Lancet 1994; 344: 521-524.
  3. Williams G. Hypertension in diabetes. In: Pickup J, Williams G, editors. Textbook of diabetes. London: Blackwell Scientific Publications, 1991: 719-732.
  4. Consensus Panel. The management of hypertension: a consensus statement. Med J Aust 1994; 160 Suppl: S1-S16.
  5. Parving HH, Andersen AR, Smidt UM, et al. Diabetic nephropathy and arterial hypertension. Diabetologia 1983; 24: 10-12.
  6. Dupree EA, Mayer MB. Role of risk factors in the complications of diabetes mellitus. Am J Epidemiol 1980; 112: 100-112.
  7. Rettig B, Teutsch SM. The incidence of end-stage renal failure in type I and type II diabetes mellitus. Diabet Nephrop 1984; 3: 26-27.
  8. Krolewski AS, Warram JH, Christlieb AR, et al. The changing natural history of nephropathy in type I diabetes. Am J Med 1985; 78: 785-794.
  9. Mogensen CE. Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. BMJ 1982; 285: 685-688.
  10. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic vascular disease. Diabetes Care 1991; 14: 173-194.
  11. Cooper ME, Frauman A, O’Brien RC, et al. Progression of proteinuria in type I and type II diabetics. Diabet Med 1988; 5: 361-368.
  12. Mogensen CE, Chachati A, Christensen CK, et al. Microalbuminuria: an early marker of renal involvement in diabetes. Uremia Invest 1985; 9: 85-92.
  13. Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in type I (insulin-dependent) diabetes mellitus. Diabetologia 1985; 28: 590-596.
  14. Messent JW, Elliott TG, Hill RD, et al. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study. Kidney Int 1992; 41: 836-839.
  15. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. Diabetologia 1989; 32: 219-226.
  16. Jerums G, Allen T, Tsalamandris C, Cooper ME and the Melbourne Diabetic Nephropathy Group. Angiotensin enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy. Kidney Int 1992; 41: 904-911.
  17. Lewis EJ, Hunsicker LG, Bain RP, Rhode RD for the Collaborative Study Group. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456-1462.
  18. Mathiesen ER, Hommel E, Giese J, Parving HH. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 1991; 303: 81-87.
  19. Viberti GC, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA 1994; 271: 275-279.
  20. McNally PG, Cooper ME. Antihypertensive treatment in NIDDM, with special reference to abnormal albuminuria. In: Mogensen CE, editor. The kidney and hypertension in diabetes mellitus. Boston: Kluwer Academic, 1994: 341-352.
  21. Bs(hlen L, de Courten M, Weidmann P. Comparative study of the effect of ACE inhibitors and other antihypertensive agents on proteinuria in diabetic patients. Am J Hypertens 1994; 7: 84S-92S.
  22. Kasiske BL, Kalil RSN, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993; 118: 129-138.
  23. Rodby RA, Rohde R, Evans J, et al. The study of the effect of intensity of blood pressure management on the progression of type I diabetic nephropathy: study design and baseline patient characteristics. J Am Soc Nephrol 1995; 5: 1775-1781.
  24. Schrier RW, Savage S. Appropriate blood pressure control in type II diabetes (ABCD trial): implications for complications. Am J Kidney Dis 1992; 6: 653-657.
  25. Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118: 577-581.
  26. Lacourcie`re Y, Nadeau A, Poirier L, Tancre`de G. Captopril or conventional therapy in hypertensive type II diabetics. Three year analysis. Hypertension 1993; 21: 786-794.
  27. Klein R, Klein BEK, Moss SE, et al. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med 1989; 149: 2427-2432.
  28. Cooper ME, Doyle AE. The management of diabetic proteinuria: which antihypertensive agent? Drugs Aging 1992; 2: 301-309.
  29. Stein PP, Black HR. Drug treatment of hypertension in patients with diabetes mellitus. Diabetes Care 1991; 14: 425-448.
  30. Harper R, Ennis CN, Heaney AP, et al. A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM. Diabetologia 1995; 38: 853-859.
  31. Pollare T, Lithell H, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989; 323: 868-873.
  32. Rimmer J, Horn J, Gennari JF. Hyperkalemia as a complication of drug therapy. Arch Intern Med 1987; 147: 867-869.
  33. Hricik D, Browning P, Kopelman R, et al. Captopril-induced functional renal insufficiency in patients with bilateral renal artery stenoses or renal artery stenosis in a solitary kidney. N Engl J Med 1983; 308: 373-376.
  34. Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V). Arch Intern Med 1993; 153: 154-183.
  35. The National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group report on hypertension and diabetes. Hypertension 1994; 23: 145-158.
  36. Guidelines Sub-Committee. 1993 Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertens 1993; 11: 905-918.
  37. American Diabetes Association. Treatment of hypertension in diabetes [consensus statement]. Diabetes Care 1993; 16: 1394-1401.
  38. Viberti GC, Mogensen CE, Passa P, et al. St Vincent Declaration, 1994: guidelines for the prevention of diabetic renal failure. In: Mogensen CE, editor. The kidney and hypertension in diabetes mellitus. Boston: Kluwer Academic, 1994: 515-527.
  39. Bennett PH, Haffner S, Kasiske BL, et al. Diabetic disease recommendations: screening and management of microalbuminuria in patients with diabetes. Recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995; 25: 107-112.

Diabetes and Hypertension Sub-Committee of the Australian Diabetes Society.
Richard E Gilbert, MB BS, FRACP, Endocrinologist, Austin, Heidelberg and Western Hospitals, VIC.
Mariusz Jasik, MD, Research Fellow, Department of Medicine, Heidelberg Hospital, University of Melbourne, VIC.
Mario DeLuise, PhD, FRACP, Director of Endocrinology, Heidelberg Repatriation Hospital, VIC.
Chris J O’Callaghan, MB BS, FRACP, Lecturer, Department Of Clinical Pharmacology, Austin Hospital, University of Melbourne, VIC.
Mark E Cooper, PhD, FRACP, Senior Lecturer, Department of Medicine, Heidelberg Hospital, University of Melbourne, VIC.