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European Review for Medical and Pharmacological Sciences 2011; 15: 1256-1263 management in diabetic patients

Z. ANWER, P.K. SHARMA, V.K. GARG, N. KUMAR, A. KUMARI

Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, NH-58, Baghpat By-pass Crossing, Delhi-Haridwar Highway, Meerut (India)

Abstract. – Hypertension and are Stage two hypertension: consistent readings of becoming increasingly common. Clinical trials 160/100 mmHg or higher. have demonstrated the importance of tight Pre-hypertension: consistent readings of 120- pressure control among patients with dia- betes. However, little is known regarding the 139/80-89 mmHg. management of hypertension in patients with coexisting diabetes. Most patients with both dis- Diabetes mellitus often simply referred to as orders have a markedly worsened risk for pre- diabetes is a condition in which a person has a mature micro vascular and macro vascular com- high blood level, either because the body plications. The appropriate management of the doesn’t produce enough , or because body hypertension seen in almost 70% of patients cells don’t properly respond to the insulin that is with mellitus remains controver- 3 sial. However, over the past few years, many ran- produced . There are many types of diabetes, the 4 domized, controlled trials have provided guid- most common of which are : ance for more effective therapy. These trials have established the need for a lower goal blood : results from the body’s failure pressure (<130/80 mm Hg) than has previously to produce insulin, and presently requires the been recommended. To achieve therapy goals, person to inject insulin. multiple antihypertensive drugs are usually needed. Type 2 diabetes: results from , a condition in which cells fail to use insulin Key Words: properly, sometimes combined with an ab- solute insulin deficiency. Hypertension, Diabetes mellitus, Macrovascular, Mi- : it is when pregnant women, crovascular, Cardiovascular . who have never had diabetes before and have high blood level during . It may precede development of type 2 diabetes mellitus.

Introduction Other forms of diabetes mellitus include con- genital diabetes, which is due to genetic defects Hypertension (defined as a of insulin secretion, -related dia- ≥140/90 mmHg) is an extremely common condi- betes, induced by high doses of tion in diabetes, affecting ∼20-60% of patients gluco-corticoids, and several forms of monogenic with diabetes, depending on , ethnicity, diabetes. and age. Hypertension is a condition in which blood pressure is high. It can be caused by genet- ics, as well as . It is associated with How are Diabetes and significant health problems such as and Hypertension Related? attack1,2. The following clinical levels of hypertension1,2 have been described by The Na- Diabetes and high blood pressure tend to occur tional Heart, Lung, and Blood Institute: together because they share certain physiological traits. High blood pressure is a dangerous disease Stage one hypertension: consistent (i.e., two or that becomes even more problematic in the setting more consecutive) readings of 140-159/90-99 of diabetes. Unfortunately, many people with dia- mmHg. betes are also affected by high blood pressure, and

1256 Corresponding Author: Zaihra Anwer, MD; [email protected] Hypertension management in diabetic patients the two commonly occur together5-7. Dia- The well-studied example of the self-reinforcing betes and high blood pressure occur together so relationship between diabetes and high blood pres- frequently that they are officially considered to be sure takes place in the kidneys. The kidneys are the “” (diseases likely to be present in the body’s most important long-term blood pressure same patient). In the case of diabetes and high regulator. By balancing the amount of salt and blood pressure, these effects include: potassium in the body, the kidneys ultimately con- trol how much fluid is excreted as . This fluid Increased Fluid Volume – Diabetes increases regulating function helps to modulate long-term the total amount of fluid in the body, which blood pressure by physically controlling how much tends to raise blood pressure. liquid is present in the blood vessels. Increased – Diabetes can de- crease the ability of the blood vessels to stretch, increasing average blood pressure. Relationship Between Diabetes Impaired Insulin Handling – Changes in the and Hypertension way the body produces and handles insulin can directly increases in blood pressure. Figure 1 shows the interrelationship between the and the hypertension through Apart from above factors the two diseases are the intervention of insulin resistance, a common likely to occur together simply because they link between the two diseases. share a common set of risk factors. Some impor- tant shared risk factors are: Statistical Relationship Individuals with diabetes are at a much greater Body Mass – Being significantly in- risk for developing. Hypertension is twice as creases the risk of both diabetes and high common in those with diabetes as in non diabetic blood pressure. individuals1,2,8. Diet – High diets rich in salt and processed are known to contribute to the develop- Physical Relationship ment of organ problems that can lead to both Diabetes causes and raises diabetes and high blood pressure. the risk of hypertension. This condition increases Activity Level – A low level of physical activity the amount of sodium that the body absorbs. It makes insulin less effective (which can lead to also promotes the stimulation of the sympathetic diabetes) and can contribute to the develop- . This is thought to cause changes ment of stiff blood vessels, increasing the risk in structure, which affects the func- of high blood pressure. tion of the heart and blood pressure1,2,8.

Figure 1. .

1257 Z. Anwer, P.K. Sharma, V.K. Garg, N. Kumar, A. Kumari

Obesity Guidelines for the Management Metabolism is related to obesity, which is re- of Hypertension lated to diabetes, which is related to hyperten- sion. Reducing in weight can often lower blood Effective blood pressure control is an impor- pressure. This lowering of hypertension symp- tant goal for diabetic patients. The patients who toms is associated with a decrease in the symp- suffer from both diabetes and hypertension have toms of diabetes1,2,8. greater chances of developing cardiovascular dis- order10. The following guidelines must be consid- ered for the management of hypertension in dia- Evidences betic patients:

Hypertension as a for Measurement of Arterial Blood Pressure: The Complications of Diabetes object of identifying and treating high blood Diabetes increases the risk of coronary events pressure is to reduce the risk of cardiovascular two fold in men and four fold in women. This in- disorder and associated morbidity and mortali- crease is due to the frequency of associated car- ty. It is, therefore, necessary to provide a clas- diovascular risk factors such as hypertension, sification of blood pressure in adults so as to and clotting abnormalities. People identify the high risk individuals and to pro- with both diabetes and hypertension have ap- vide guidelines for treatment and follow up. proximately twice the risk of cardiovascular dis- Arterial blood pressure measured in the sitting ease as non-diabetic people with hypertension. position should be considered as ideal11. Hypertensive diabetic patients are also at in- Systolic and Diastolic Pressure Target Values: creased risk for diabetes-specific complications The level to which blood pressure should be including and nephropathy1,2. reduced in a diabetic hypertensive patient has not been known12. There are no specific guide- Evidence for Target Levels of lines on the exact values for hypertension con- Blood Pressure in Patients with Diabetes trol in diabetes. A number of epidemiological The UK Prospective Diabetes Studies studies suggest an inverse relationship exist (UKPDS) and the Hypertension Optimal Treat- between calcium, magnesium, potassium in- ment (HOT) trial both demonstrated improved take and blood pressure level13-15. Most of outcomes, especially in preventing stroke, in pa- these studies are cross-sectional, but none of tients assigned to lower blood pressure targets. these studies has analyzed diabetic patients Optimal outcomes in the HOT study were separately from the general hypertension pop- achieved in the group with a target diastolic ulation. There are no randomized clinical trials blood pressure of 80 mmHg. Randomized clini- on magnesium supplementation in diabetic cal trials demonstrate the benefit of targeting a subjects with hypertension. diastolic blood pressure of ≤80 mmHg. Epi- Screening and Initial Evaluation: All patients demiological analyses show that blood pres- with diabetes should have blood pressure mea- sures ≥120/70 mmHg are associated with in- sured at the time of diagnosis and at each creased cardiovascular event rates and mortality scheduled diabetes visit13. Initial assessment of in persons with diabetes. Therefore, a target a hypertensive diabetic patient should include blood pressure goal of <130/80 mmHg is rea- a complete medical history with special em- sonable if it can be safely achieved. Achieving phasis on cardiovascular risk factors and the lower levels, however, would increase the cost presence of diabetes . The physi- of care as well as drug side effects and is often cal exam should include height, weight, and difficult in practice1,2. careful evaluation of arterial circulation. Initial laboratory examination should include serum creatinine, electrolytes, fasting lipid profile, Types of Hypertension in Diabetes Mellitus and urinary albumin excretion16. Behavioral Treatments of Hypertension: Di- 1. etary management with moderate sodium re- 2. Hypertension consequent to nephropathy striction has been effective in reducing blood 3. Isolated systolic hypertension pressure in individuals with essential hyper- 4. Supine hypertension with orthostatic fall9 tension17,18. Weight reduction can reduce blood

1258 Hypertension management in diabetic patients

pressure independent of sodium intake and can hydrochlorothiazide) are generally well toler- also improve blood glucose and lipid levels19. ated and not associated with adverse metabolic Sodium restriction has not been tested in the effects31. are not as effective diabetic population in controlled clinical trials. in patients with renal insufficiency; in such pa- Reductions in daily sodium intake to levels of tients, loop diuretics are preferred. 10-20 mmol (230-460 mg) per day have re- Calcium Channel Blockers (CCB): Controver- sulted in decreases in systolic blood pressure sy exists regarding the use of CCBs, particu- of 10-12 mmHg17. cessation and larly the dihydropyridines (e.g., amlodipine, moderation of alcohol intake are also recom- nifedipine) in treating hypertension in patients mended to reduce blood pressure20-22. with diabetes. The combination of an ACE in- hibitor and a dihydropyridine CCB has been shown to reduce proteinuria2. The nondihy- Treatment Goals dropyridine CCBs (e.g., verapamil) demon- strate reductions in cardiovascular risk when In the setting of diabetes, the target blood used as monotherapy. Combining a nondihy- pressure is <130/80. Significant improvements in dropyridine CCB with an ACE inhibitor in hy- long term cardiovascular and health do pertensive patients with diabetes is associated not become apparent until blood pressure is re- with greater reductions in than if duced to this level. Because it is difficult to re- either agent was used individually2,32. duce blood pressure to this level, it is a recom- Angiotensin II Blockers (ARB): mendation usually reserved only for specific pa- Candesartan and are used to treat tients23-25. patients with type 2 diabetes, hypertension, and microalbuminuria33. Candesartan is as ef- Drug Therapy fective as lisinopril in blood pressure reduction Drug therapy is a necessary step for most pa- and minimization of microalbuminuria34-35. tients during treatment. Vast amounts of re- Losartan therapy produced a renoprotective ef- search have been done in an effort to determine fect independent of its blood-pressure-lower- which drug or drug combination is the “best” ing effect in patients with type 2 diabetes and for treating high blood pressure in patients with nephropathy35,36. Irbesartan is found to be diabetes. The best drugs to use in the setting of renoprotective in patients with type 2 diabetes diabetes are: who have . lowers urine albumin excretion to a greater degree Angiotensin Converting Enzyme (ACE) In- than amlodipine in type 2 diabetic patients hibitors: ACE inhibitors have proved benefi- with microalbuminuria37. cial in patients who have myocardial infarc- Beta Blockers: Traditionally, the use of beta tion or congestive , or who have blockers in patients with diabetes has been dis- diabetic renal disease10. ACE inhibitor thera- couraged because of adverse metabolic effects py results in 20 to 30 percent decrease in the and the masking of hypoglycemic symptoms. risk of stroke, coronary heart disease, and There is no difference in hypoglycemic major cardiovascular events26,27.ACE in- episodes in patients treated with atenolol com- hibitors are found to be more beneficial when pared with captopril, but the mean compared with other antihypertensives in the in the atenolol group was greater28. Cardio se- reduction of acute myocardial , car- lective beta blockers are preferred over the diovascular events, and mortality. Captopril non-selective type because they are associated and atenolol are similar in terms of reduction with less blunting of hypoglycemic awareness in microvascular and macrovascular compli- and less elevation of lipid and glucose levels. cations28. The alpha carvedilol causes fewer Diuretics: Thiazide diuretics have been shown to alterations in lipid and glucose levels com- benefit patients with diabetes and systolic hy- pared with traditional beta blockers38. Beta- pertension. Chlorthalidone therapy is effective blocker therapy can be advantageous in many in preventing major cerebrovascular and car- patients with diabetes because of its proven diovascular events in older non-insulin-treated ability to decrease cardiovascular morbidity patients with diabetes and isolated systolic hy- and mortality in persons with atherosclerotic pertension. Lower dosages of (e.g., heart disease39.

1259 Z. Anwer, P.K. Sharma, V.K. Garg, N. Kumar, A. Kumari

Renin Inhibitors: A new and promising ap- • Patients with a systolic blood pressure of 130- proach in rennin angiotensin aldosterone sys- 139 mmHg or a diastolic blood pressure of 80- tem blockade has been started with the de- 89 mmHg must be given lifestyle/behavioral velopment of first direct , therapy for a period of 3 months and then , recently approved by US and should be treated pharmacologically with Drug Administration (FDA) for the treatment agents that block the renin-angiotensin system. of hypertension in diabetic patients. • In addition to lifestyle/behavioral therapy pa- Aliskiren is generally well tolerated and, in tients with hypertension should receive drug contrast to ACE inhibitors, it does not induce therapy. accumulation of substance P or bradykinin. • Multiple drug therapy is generally required to Therefore, side effects such as cough and an- achieve blood pressure targets. gioedema are very rare. It has demonstrated • For those having blood pressure ≥ 140/90 a favorable safety and tolerability profile should be given drug to reduce cardio-vascular alone or in combination with other drugs39. disorder events. Aliskiren monotherapy demonstrated signifi- • All patients with diabetes and hypertension cant, dose-dependent antihypertensive effects should be treated with a regimen that includes in several placebo-controlled clinical trials40. an ACE inhibitor or ARB. If one is not tolerat- Renin inhibition seems an interesting new ed, the other should be given. If blood pressure approach for preventing the progression of targets are to be achieved, a thiazide chronic kidney disease41. should be added. • If ACE inhibitors or ARBs are used, renal Combination Therapy function and serum potassium levels should be Diabetes and hypertension constitute a par- monitored. ticularly dangerous combination with respect to • In patients with type 1 diabetes with hyperten- cardiovascular morbidity and mortality. A sig- sion and any degree of , ACE in- nificant increase in systolic blood pressure in hibitors have been shown to delay the progres- any age group leads to significant increase in sion of nephropathy. . Therefore, it is neces- • In patients with type 2 diabetes, hypertension, sary to reduce blood pressure42. Most patients and microalbuminuria, ACE inhibitors and with hypertension and diabetes require more ARBs have been shown to delay the progres- than one agent to attain adequate blood pres- sion to macroalbuminuria. sure control. In the HOT (Hypertension Opti- • In those with type 2 diabetes, hypertension, mal Treatment) trial, 68% of patients were macroalbuminuria and renal insufficiency, an maintained on combination antihypertensive angiotensin receptor blocker should be strong- therapy. The combination of ACE inhibitors ly recommended. and CCBs is associated with a reduction in car- • In elderly hypertensive patients, blood pres- diovascular events and protein-urea2,43-46. The sure should be lowered gradually to avoid combination of a dihydropyridine and a nondi- complications. hydropyridine CCB has been shown to have a • Patients not achieving target blood pressure on synergistic blood-pressure-lowering potential47. three drugs, including a diuretic and patients Caution should be used with the combination with a significant renal disease should be re- of nondihydropyridine CCBs and beta blockers ferred to a experienced in the care of because of the potential for additive negative patients with hypertension1,2. cardiac inotropic effects. Combinations of beta blockers and ACE inhibitors have shown few Non-Drug Therapy additive effects on blood pressure when used in This therapy mainly includes , salt patients with a pulse rate of less than 84 beats restriction, dietary changes, quitting smoking, per minute48. The final phase of the CALM limiting alcohol intake, etc29-31. In patients with- (candesartan and lisinopril microalbuminuria) out diabetes, strict to these rules very study examined combination treatment with often leads to significant drops in blood pressure candesartan and lisinopril33. so much that drug therapy may not be needed. In The following steps are required for combina- the Dietary Approaches to Stop Hypertension tri- tion treatment of hypertension in diabetic pa- al, lifestyle modifications such as and a tients: diet low in salt and high in potassium have clear-

1260 Hypertension management in diabetic patients

ly been shown to decrease blood pressure49. Ex- 6) HYPERTENSION IN DIABETES STUDY (HDS): I. Prevalence cessive sodium intake is particularly deleterious of hypertension in newly presenting type 2 diabet- ic patients and the association with risk factors for in patients with diabetes because it may decrease cardiovascular and diabetic complications. J Hy- the antihypertensive effects of and pertens 1993; 11: 309-317. their beneficial effects on protein urea50. Weight loss and exercise can help to lower blood pres- 7) SOWERS JR, EPSTEIN M, FROHLICH ED. Diabetes, hy- pertension, and cardiovascular disease: an up- sure and may also improve glycaemic control date. Hypertension 2001; 37: 1053. and insulin sensitivity. 8) CONY DB, TUCK ML. Advances in hypertension. Am J Nephrol 1996; 16: 223-236.

9) DAS S. Etiopathogenesis of hypertension in dia- Conclusion betes mellitus. Int J Diab Dev Count 1995; 15: 106-109. Control of hypertension and maintenance of 10) THE SIXTH REPORTOFTHEJOINT NATIONAL COMMITTEE ideal blood pressure is the moot point that would ON PREVENTION, Detection, Education and treat- ment of High Blood Pressure. Arch Int Med 1997; benefit the diabetic patient most. Pharmacists 157: 2413-2467. must become more vigilant about current guide- lines for the treatment of patients with concomi- 11) KUMAR A. Indian scenario–hypertension. In: Das S Ed. Complications of Diabetes in Indian Secnario. tant hypertension and type 2 diabetes mellitus. USV Ltd Mumbai; 2000. Strategies such as patient education and medica- tion assessment can help to optimize care for 12) RUILOPE LM, GARCI R. How far should blood pres- sure be reduced in diabetic hypertensive pa- these patients and slow the progression to diabet- tients? J Hypertens 1997; 15: 63-65. ic nephropathy. Many patients with diabetes mel- litus and hypertension are not been treated ac- 13) GELEIJNSE JM, WITTEMAN JC, BAK AA, BREEIJEN JH, GROBBEE DE. Reduction in blood pressure with a cording to guidelines. Specific risk factors deter- low sodium, high potassium, high magnesium salt mined may aid in identifying patients at high-risk in older subjects with mild to moderate hyperten- for inadequate treatment. Patient and education sion. Br Med J 1994; 309: 436-440. provider, approaches, and health 14) MOORE TJ, MCKNIGHT JA. Dietary factors and blood system changes are needed to address these is- pressure regulation. Endocrinol Metab Clin North sues. As the population grows older and contin- Am 1995; 24: 543-555. ues to gain weight, diabetes and hypertension 15) MORRIS CD, REUSSER ME. Calcium intake and blood will become even more common. It is to be pressure: epidemiology revisited. Semin Nephrol hoped that an approach similar to that outlined 1995; 15: 490-495. here can limit their serious consequences. 16) MASER RE, PFEIFER MA, DORMAN JS, KULLER LH, BECK- ER DJ, ORCHARD TJ. Diabetic and cardiovascular risk: the Pittsburgh Epidemiol- ogy of Diabetes Complications Study III. Arch Int References Med 1990; 150: 1218-1222. 17) CUTLER JA, FOHNANN D, ALLENDER PS. Randomized 1) ARAUZ-PACHECO C, PARROTT MA, RASKIN P. The treat- trials of sodium reduction: an overview. Am J Clin ment of hypertension in adult patients with dia- Nutr 1997; 65: 643-651. betes. Diabetes Care 2002; 25: 134-147. 18) MIDGLEY JP, MATTHEW AG, GREENWOOD CM, LOGAN 2) BAKRIS GL, WILLIAMS M, DWORKIN L, ELLIOTT WJ, EP- AG. Effect of reduced dietary sodium on blood STEIN M, TOTO R, TUTTLE K, DOUGLAS J, HSUEH W, pressure: a meta-analysis of randomized con- SOWERS J. Preserving renal function in adults with trolled trials. JAMA 1996; 275: 1590-1597. hypertension and diabetes: a consensus ap- proach. Am J Kidey Dis 2000; 36: 646-661. 19) STAESSEN J, FAGARD R, LIJNEN P, A MERY A. Body weight, sodium intake and blood pressure. J Hy- 3. OTHER Diabetes treatment-bridging the divide. R KI. pertens 1989; 7: 19-23. N Engl J Med 2007; 15: 1499-1501. 20) CHOBANIAN AV, BAKRIS GL, BLACK HR, CUSHMAN 4) TIERNEY LM, MCPHEE SJ, PAPADAKIS MA. Current & Treatment. 40th ed. New WC, GREEN LA, IZZO JL, JONES DW, MATERSON BJ, York: Lange Medical Books/McGraw-Hill; OPARIL S, WRIGHT JT, ROCCELLA EJ. Joint National 2001. Committee on Prevention, Detection, Evalua- tion and Treatment of High Blood Pressure: 5) EPSTEIN M, SOWERS JR. Diabetes mellitus and hyper- The Sixth Report of the Joint National Commit- tension. Hypertension 1992; 19: 403. tee on Prevention, Detection, Evaluation and

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