THE ISSUE

Diabetes mellitus and hypertension are amongst the most common non-communicable diseases in Pakistan effecting nearly 2.7 and 10.8 million individuals respectively¹. Both diseases are risk factors for cardiovascular disease and death². The prevalence of hypertension is double among diabetics as compared to non-diabetics in the western world³. Similar findings have also been reported from Pakistan⁴. The risk of Cardio-vascular death in a hypertensive diabetic is twice that of a non-diabetic hypertensive and four times that of a non-diabetic without hypertension⁵. However it is distressing to know that a very low percentage of the Pakistani population is aware as well as treated for these conditions¹.

Beta-blockers (β-blockers) are well established in the treatment of coronary heart disease and hypertension⁶. However until recently they were considered relatively contraindicated among diabetic patient^7-10.  A recent meta-analysis by Psaty et al¹¹, which was based on the results of 18 Randomized Controlled Clinical Trials with 50,000 patients, indicated that low dose thiazides (diuretics) and β-blockers are more effective as compared to other agents in reducing total mortality, cardiovascular mortality, stroke and myocardial infarction in individuals with hypertension. The results of this meta-analysis make β-blockers potentially a drug of choice among diabetic individuals with hypertension. Prospective studies have, however, indicated an increased risk of mortality in diabetic patients treated with diuretics^12,13. As a result of these findings, the use of diuretics as the first line treatment for hypertension in diabetes mellitus has not been recommended¹⁴.

This commentary aims to critically assess the common misconceptions held regarding the use of β-blockers among diabetic hypertensive patients and to explore the recent literature on use of β-blockers among hypertensive diabetic patients.

Misconceptions

A review of the relevant literature shows that the most common misconceptions about the use of β-blockers among diabetic hypertensive patients are  (1) fear of developing Insulin resistance or hyperglycemia (2) masking of hypoglycemic symptoms and (3) development of lipid abnormalities.

Insulin resistance or hyperglycemia

Increased insulin resistance with subsequent increased blood glucose levels are frequently cited as an argument in favor of withholding β-blockers from patients with diabetes mellitus. This impression is usually based on two major studies conducted in early eighties; MRC Mild Hypertensive Study¹⁵ and Beta Blocker Heart Attack Trial Research Group (BHAT)¹⁶. MRC Mild Hypertensive Study¹⁵ indicated that non-selective β-blockers tend to cause a small increase in blood glucose while Beta Blocker Heart Attack Trial Research Group (BHAT)¹⁶ reported an increased prescription of hypoglycemic agents in the Propranalol treated group. This resistance appears to be the result of decreased β_2-stimulated insulin secretion and partly by reduced peripheral uptake of glucose¹⁷. This effect is diminished with the use of beta selective agents¹⁸, especially if concomitant changes in potassium and weight are avoided¹⁹. Although this effect seems potentially important, there is little evidence that it is clinical problem. Jonas et al followed a prospective cohort of 2,723 patients with diabetes mellitus and established Coronary Artery Disease (CAD), and found that patients on β-blockers achieved the same levels of glycemic control and had a lower mortality, as compared to diabetics not using β-blockers²⁰. The UK Prospective Diabetes Study Group (UKPDS), whose results were published in 1998, has shown no difference in HbA₁C levels between Atenelol (β-blockers) and Captopril (ACE Inhibitor) groups, indicating comparable glycemic control²¹.

Masking of hypoglycemic symptoms

One of the most widely used reason for withholding beta blockers for use in diabetic patients is that it may mask the symptoms of hypoglycemia, which may prove fatal^{11, 13, 14, 18}. This action is mainly a characteristic of non-selective β-blockers by delaying the return of low blood glucose to normal, along with modifying hypoglycemic signs and symptoms²³. However, the fact is ignored that hypoglycemic unawareness to a level that may prove dangerous is a problem only in a small number of patients with IDDM. Apart from this, the use of selective β_1-blockers reduces this concern further^{5, 13, 18}. A prospective study of 778 elderly diabetic patients with hypertension and CAD found no increased risk of hypoglycemia with use of beta-blocker ²⁴. UKPDS also, in a nine-year follow-up comparing the efficacy of Propranalol with Captopril, found no difference between the number and severity of hypoglycemic events in either treatment arms²¹, which should be a sufficient evidence to clear this misconception.

Lipid abnormalities

Changes in plasma lipid levels are also one of the grounds for withholding β-blockers in diabetic patients. β-blockers have little effect on LDL cholesterol, but do increase plasma VLDL as well triglyceride levels, along with lowering HDL concentration²⁵. Kasiske et al, in a meta-analysis that included 474 trials found that use of β-blockers is associated with an increase of triglycerides by 30mg/dl and decrease of HDL cholesterol by 4 mg/dl on average²⁶. This negative surrogate end point (a lab measurement or a physical sign used as a substitute to a clinical endpoint) has been a strong argument used to withhold β-blockers in diabetic patients. These changes are more apparent with non-selective beta-blockers, which may be due to the interference with peripheral lipoprotein lipase, an enzyme responsible for the removal of endogenous triglycerides¹³. However, the clinical significance of β₂-blockade on changing lipid levels is not clear, as non-selective agents such as Timolol and Propranalol have been found very effective in reducing post-MI mortality and re-infarction²⁷, a benefit that is undiminished in the presence of adverse changes in lipid levels²⁸. Samuelsson et al in a prospective study of 686 hypertensives, of which 76% used β-blockers, found that although baseline triglyceride level elevation predicted future CVD events, treatment induced hypertriglycedemia (>15 years of follow-up) did not add to the initial risk²⁹. However, even if this argument cannot eliminate the concern regarding these adverse surrogate endpoints, the newer β-blockers such as Labetalol, Acebutalol, Carvedilol and Bisprolol could be considered. It has been observed that blood lipid level changes with these agents are minimal or absent^{30, 31}. The use of these agents is favored since β₁- blockade appears to be the active ingredient in cardiovascular protection, and their use can also prevent the emergence of the adverse surrogate endpoints by non selective beta blockade.

DISCUSSION

Apart from blood pressure lowering effect, β-blockers have anti-anginal, anti ischemic and anti-arrhythmic properties, which have been effective in reducing CHD events and deaths as shown by a number of studies^{32, 33, 34}. Yusuf et al in a meta-analysis demonstrated 20-25% reduction in recurrent CHD events and mortality in post-MI patients²⁷. Interestingly Gunderson et al showed a greater benefit derived by diabetic patients in a secondary prevention trial of myocardial infarction as compared to non-diabetics³⁵. Such evidence is compelling to re-think that the potential role of β-blockers in treatment of diabetic hypertensive patents.

Few would now disagree that β-blockers have a useful role in the treatment role of heart failure, which was regarded a contraindication until fairly recent times. However, the role of beta-blockers regarding the treatment of hypertensive diabetics is still emerging. There has been a long held bias against the use of β-blockers in diabetes, especially in favor of ACE- inhibitors. The more frequent and liberal use of ACE inhibitors in diabetes mellitus is mainly due to a) their insignificant effects on triglcerides, HDL and LDL levels³⁶, b) delayed diabetic nephropathy³⁷ which appears to be an independent effect of blood pressure control³⁸, and c) ability to reduce insulin resistance³⁶. Thus, it has been advocated that ACE inhibitors should be the first line therapy for hypertension in diabetic patients, due to the lack of ACE inhibitors effecting the above mentioned surrogate end-points. Study results favoring more liberal use of beta-blockers in type II diabetics come from the UKPDS^{21, 39}. The UKPDS study has shown that tight control of hypertension in diabetic patients resulted in fewer cardiovascular events and is more important than glycemic control in reducing CVD events and mortality. Importantly, β-blockers were as effective as ACE inhibitors, and there were trends favoring the use of β-blockers, such as fewer myocardial infarctions, fewer strokes and micro vascular diseases, and lower total mortality²¹ in β-blockers. β₁ selective blockade appeared to be the active ingredient for these benefits⁴⁰.

This review does not advocate the use of β-blockers in every hypertensive diabetic. Reviewing the results of the HANE study⁴¹ in 886 young to middle aged men and women (21-70 years) and the Veteran Affairs Cooperative study in 1105 men⁴², Atenolol was found to be best for younger individuals (<60 years) while hydrocholorothiazide and dialtizam were best for older individuals with hypertension.  As a result β-blockers should not be the first line therapy for older hypertensives. These conclusions also apply to elderly hypertensive diabetic patients.

In the UKPDS study the most common reason for non-compliance with Atenelol was brochoconstriction²¹; a risk which is greatest with the use of non-selective agents without intrinsic symptomatic activity²³. Although this risk is minimized with the use of highly selective β₁ blockers, but patients are not totally safe from reversible airway changes⁴³. In hypertensive diabetic patients with severe airway conditions, alternative therapy should be offered. Similarly in those patients with IDDM who suffer from hypoglycemic symptom unawareness, β-blockers may be contraindicated with an ACE inhibitor or calcium channel blocker considered^12-14. In patients with diabetic nephropathy (mainly seen in IDDM patients), ACE inhibitors are recommended to delay the onset of end stage renal-disease^{44, 45}. However β-blockers can now be considered for the same role as the results of SOLVD Heart Failure Study⁴⁶ indicated that β-blockers offered more reno-protection as compared to ACE inhibitor. Finally among patients with autonomic dysfunction, the use of β-blockers may be challenginge^{13, 14}.

An important aspect to consider is the quality of life for the patient. Hypertension in most cases, even associated with type II diabetes is asymptomatic. Thus it is very important to ensure compliance, which can be significantly enhanced with agents that do not produce side effects that impairs quality of life⁴⁰. Although Croog et al looking into quality of life with antihypertensives demonstrated that propranalol, but not captopril decreased quality of life⁴⁷, many similar studies comparing beta selective agents with ACE inhibitors found no difference between their effects on quality of life^48-50.

Anticipation of surrogate end points has lead to hesitancy for using beta-blockers in diabetic hypertensives. Despite widely held beliefs, the literature supports the notion that β-blockers should be among the preferred therapy for hypertensive diabetic patients. They cause the reduction of the most important complications of diabetes with hypertension, such as CVD events, strokes and mortality. This paper calls on practitioners to reconsider the role of β-blockers on their menu of options for hypertensive diabetics.

REFERENCES

1.        Pakistan Medical Research Council. National Health Survey of Pakistan. Islamabad : Pakistan Medical Research Council , 1997 : 48,54. 

2.        Kaukua J, Turpeinen A, Uusitupa M, Niskanen L. Clustering of cardiovascular risk factors in type 2 diabetes mellitus: prognostic significance and tracking. Diabetes Obes Metab 2001; 3: 17-23

3.        Epstien M, Sowers JR. Diabetes Mellitus and Hypertension. Hypertension 1992;19:403-418

4.        Haider Z, Obaidullah S, Maqbool K. Hypertension in Pakistani patients with diabetes mellitus. J Trop Med Hyg 1980; 83:251-3

5.        Statement on hypertension in diabetes mellitus: Final report. Arch Int Med 1987; 147:830-842

6.        National High Blood Pressure Expert panel working group. Hypertension in Diabetes. Hypertension 1994;23:147-162

7.        Physician Desk Reference, 50^th edition. New York : Medical Economics Data Production Company, 1996

8.        Leese GP, Savage MW, Chattington PD, Vora JP. The diabetic patient with hypertension. Postgrad Med J 1996;72:263-268

9.        Kaplan NM. Clinical Hypertension. 6^th edition. New York : Williams & Wilkins.

10.     Kaplan NM, Rosetock J, Ruskin P. a differing view of treatment of hypertension in patients with diabetes mellitus. Arch Int Med 1987;147:1160-1162

11.     Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemaitre RN, Wagner EH, Furberg CD.. Health outcomes associated with anti-hypertensive therapy used as first-line agents: A systemic review and meta-analysis. JAMA 1997;277:1886-1892

12.     Warram JH, Laffel LM, Valsania P, Christlieb AR, Krolewski AS. Excess mortality associated with diuretic therapy in diabetes mellitus. Arch Int Med 1991;151:1350-1356

13.     Klein R, Klein BE, Moss SE, Davis MD, DeMets DL.. Relation of ocular and systemic factors to survival in diabetes. Arch Int Med 1989;149:266-272

14.     Myers MG, Carruthers SG, Leenen FH, Haynes RB. Recommendations from the Canadian Hypertension Society Consensus Conference on pharmacological treatment of hypertension. CMAJ 1989;140:1141-1146

15.     Report of Medical Research Council Working Party on mild to moderate hypertension. Adverse reactions to bendrofluazide and propanalol for the treatment of mild hypertension. Lancet 1981;2:539-43

16.     Beta Blocker Heart Attack Trial Research Group (BHAT). A randomized clinical trial of propranolol in patients with acute myocardial infarction. JAMA 1982;247:1707-1714

17.     Giugliano D, Acampora R, Marfella R, De Rosa N, Ziccardi P, Ragone R, De Angelis L, D'Onofrio F. Metabolic and cardiovascular effects of carvedilol and atenolol in NIDDM and hypertension: A randomized controlled clinical trial. Ann Int Med 1997;126:955-959

18.     Sowers JR, Zemal MB. Clinicla implications of hypertension in the diabetic patient. Am J Hyper 1990;3:414-424

19.     Heinemann L, Heise T, Klepper A, Ampudia J, Bender R, Starke AA. Four-week administration of an Ace-inhibitor and a cardio selective Beta blocker in healthy volunteers: no influence on insulin sensitivity. Eur J Clin Invest 1995;25: 595-600

20.     Jonas M, Reicher-Reiss H, Boyko V, Shotan A, Mandelzweig L, Goldbourt U, Behar S. Usefulness of beta-blocker therapy in patients with non-insulin diabetes mellitus and coronary artery disease. Am J Cardiol 1996;77:1273-1277

21.     UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risks of microvascular and macrovasvular complications in type 2 diabetes mellitus: UKPDS 39. BMJ 1998;317:713-720

22.     Manolio TA, Cutler JA, Furberg CD, Psaty BM, Whelton PK, Applegate WB. Trends in pharmacological management of hypertension in the United States. Arch Int Med 1995;155:829-837

23.     Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice. 2^nd edition. New York : Churchill Livingstone, 1994; 950-957

24.     Shorr RI, Ray WA, Daugherty JR, Griffin MR. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA 1997;278:40-43

25.     Day JL, Metcalf J, Simpson CN. Adrenegenic mechanisms in control of plasma lipid concentrations. BMJ 1982;284:1145-1148

26.     Kasiske BL, Ma JZ, Kalil RS, Louis TA. Effects of anti-hypertensive therapy serum lipid levels. Ann Intern Med 1995;122:133-141

27.     Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta-blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985 xxvii (5):335-371

28.     Byington RP, Worthy J, Craven T, Furberg CD. Propranolol-induced changes and their prognostic significance after myocardial infarction: the Beta-blocker Heart Attack Trial experiences. Am J Cardiol 1990; 65:1287-1291

29.     Samuelsson O, Hedner T, Persson B, Andersson O, Berglund G, Wilhelmesen L. The role of diabetes mellitus and hypertriglycedemia as coronary risk factor in treated hypertension: 15 years of follow-up of antihypertensive treatment in middle-aged men in the primary prevention trial in Goteberg, Sweden. J Int Med 1994;235;217-227

30.     De Bono G, Kaye CM, Roland E, Summers AJ. Acebutolol : Ten years of experience. Am Heart J 1985;109:1211-1223

31.     Fritz G, Weiner L. Effects of bisoprolol dosed once daily, on blood pressure and serum lipids and HDL cholesterol in patients with mild to moderate hypertension. Eur J Clin pharmacol 1987;32:77

32.     O'Connor R, Persse D, Zachariah B, Ornato JP, Swor RA, Falk J, Slovis CM, Storrow AB, Griswell JK.. Acute coronary syndrome: pharmcotherapy.  Prehosp Emerg Care. 2001; 5: 58-64.                

33.     Prasad A, Reeder G. Modern adjunctive pharmcotherapy of myocardial infarction. Expert Opin Pharmacother. 2000 ; 1: 405-18

34.     Brachmann J. The role of class III antiarrhythmic agents in maintaining sinus rhythm. Europace. 2000 l;1 Suppl C:C10-5

35.     Gundersen T, Kuekshus J. Timolol treatment after myocardial infarction in diabetic patients. Diabetic Care 1983;6:285-290

36.     Pollare T, Litthle H, Berne C. A comparison of the effects of hydrocholorthiazide and captropril on glucose and lipid metabolism in patients with hypertension. N Eng J Med 1989;321:868-873

37.     Mathiesen ER, Hommel E, Giese J, Parving HH. Efficacy of captropril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 1991;303:81-87

38.     Mognensen CE. Angiotensin converting enzyme inhibitors and diabetic nephropathy BMJ 1992;304:327-328

39.     UK Prospective Diabetes Study Group. Tight blood pressure control and risk of microvascular and macrovascular complications in type II diabetes: UKPDS 38. BMJ 1998;317:703-713

40.     Cruickshank JM. Beta-blockers continue to surprise us. Eur Heart J 2000;21:354-363

41.     Philipp T, Anlauf M, Distler A, Holzgreve H, Michaelis J, Wellek S. Randomized, double-blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendepine and enalapril in antihypertensive treatment, results of the HANE study. BMJ 1997;315:154-159

42.     Preston RA, Materson BJ, Reda DJ, Williams DW, Hamburger RJ, Cushman WC, Anderson RJ. Age-race, subgroup compared with rennin profile as predictors of blood pressure response to antihypertensive therapy. JAMA 1998;279:1168-1172

43.     Dorrow P. Effects of single oral dose of bisoprolol and atenolol on airway functions in non-asthmatic chronic obstructive lung disease and angina pectoris. Eur J Clinic Pharmacol 1986;21: 127-133

44.     Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Eng J Med 1993;829;1456-1462

45.     Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P.  Effect of the angiotensin converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Eng J Med 1996;334:939-945

46.     Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J. Predictors of decreased renal function in patients with heart failure during ACE-inhibitor therapy; results from the SOLVD study. Am Heart J 1999; 138: 849-855

47.     Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins CD, Klerman GL, Williams GH. The effects of antihypertensives on         quality of life. N Eng J Med 1986;314:1657-1664

48.     Steiner SS, Friedhoff AJ, Wilson BL, Wecker JR, Santo JP. Antihypertensive therapy and quality of life; a comparison of atenolol, captropril, enalapril and propranolol. J HumHypertens 990;4:217-225

49.     Fletcher AE, Bulpitt CJ, Hawkins CM. Quality of life on antihypertensive therapy; a randomized double blind controlled trial of atenolol and captropril. J Hyper 1990;8: 463-466

50.     Prichard BNC, Saul PA. Comparison of beta blockade and ACE inhibition in the treatment of hypertension. J Cardiovasc Pharmcol 1989; 16 (Suppl 15): 81-85