Management of High Blood Pressure in Diabetes Mellitus: Lessons from The ADA Recommendation

R E V I E W A R T I C L E Management of High Blood Pressure in Diabetes Mellitus: Lessons from The ADA Recommendation Sarwono Waspadji INTRODUCTION Type 2 Diabetes Mellitus (T2DM) is often associated with devastating diabetic complications: nephropathy, retinopathy, coronary artery disease, cerebrovascular disease, peripheral vascular disease, and neuropathy. Hypertension is a common co-morbidity in diabetes mellitus, therefore the consequences of high blood pressure on T2DM should be considered. Among diabetics, hypertension is very commonly found as part of the metabolic-cardiovascular syndrome (insulin resistance syndrome = cardio-metabolic syndrome), clustered together with microalbuminuria. Components of metabolic-cardiovascular syndrome can be found as follows: Central obesity Insulin resistance Low HDL-cholesterol levels High triglyceride levels Systolic hypertension Absent nocturnal drop in blood pressure Salt sensitivity Male sex Increased cardiovascular oxidative stress Impaired endothelial function Abnormal coagulation / fibrinolytic profiles Several studies showed that hypertension is really a bad companion of diabetes when they coexist. The occurrence of microalbuminuria, left ventricular hypertrophy, ECG signs of MCI, and prior history of overt cardiac events double in their coexistence. The risk of Jakarta Diabetes and Lipid Centre,Division of Endocrinology and Metabolism, Department of Medicine,School of Medicine, University of Indonesia, Jakarta the development of MCI, stroke/tia and LVH are higher among hypertensive males and hypertensive females as compared to their normal counterparts. The higher the blood pressure the higher the cardiovascular mortality rates. There are many studies trying to document and to prove the association between hypertension and diabetic vascular complications. Many of them give conflicting results. One of the valid and well-recognized prospective studies is the Appropriate Blood Pressure Control in Diabetes Mellitus (ABCD study), which give strong evidence as for the relationship between blood pressure and chronic complications of diabetes mellitus, as summarized below. In diabetic population, hypertension has a significant propensity for the development of chronic diabetic complications. Table 1. Appropriate Blood Pressure Control in Diabetes Relationship Between Hypertension (> 140/90) and Diabetic Vascular Complications OR 95 % CI P Diabetic Nephropathy 1.86 1.23-2.82.0033 Cardiovasc. Disease 1.39 1.00-1.93.0476 Diabetic Neuropathy 1.03 0.77-1.38 NS Diabetic Retinopathy 1.71 1.23-2.40.0016 Peripheral Vascular Disease <.05 Left Ventricular Hypertrophy <.001 *Presented at Symposium II Holistic Approach in Cardiovascular Disease, Hotel Sahid Jakarta February 8 th 2003 Local Data-Jakarta We have performed a population study in Depok, suburban area in 2001, coordinated with the WHO and the Ministry of Health, Republic of Indonesia. Total respondents were 960. The prevalence of DM (over 25 years old), based on 2 hrs blood glucose after 75 gram glucose load of > 200 mg/dl were 13.6 %, among which 4.3 % were known diabetics. Using fasting blood glucose of > 126 mg/dl yielded the prevalence of 8.3 %. The prevalence of hypertension in the population was 514/960=53.5 %. Among diabetics the preva- 31

Sarwono Waspadji Acta Med Indones-Indones J Intern Med lence of hypertension is higher (76.4 %) as compared to the total population. Among the diabetics we found that the presence of hypertension give a higher percentage of abnormal lipid profile (Total cholesterol > 200 mg/dl, LDL-chol > 100 mg/dl, HDL-chol. < 35 mg/dl and triglyceride > 150 mg/dl of 87.3 %, 94.5 %, 4.5 % and 54.5 % respectively) as compared to the lipid profile among non hypertensive diabetic patients (Total cholesterol > 200 mg/dl, LDL-chol > 100 mg/dl, HDL-chol. < 35 mg/dl and triglyceride > 150 mg/dl of 67.6 %, 73.5 %, 8.8 % and 47.1 % respectively). The WHR among hypertensive diabetics was higher (25.2 %) than among non-hypertensive diabetics (18.8 %). The occurrence of abnormal ECG was also higher (41.1 % vs. 25 %) in the hypertensive diabetics. We also evaluate newly registered patients in CiptoMangunkusumo Hospital during the years 1992, 1993, 1997 and 1998. Altogether there were 4195 attendees. Many of them were lost to follow up when we conducted the evaluation. Only 147 patients could be evaluated. Hospital data also showed that the co-morbidity of hypertension among diabetics gives a higher tendency of dyslipidemia (57.5 % vs. 45.5 %). Diabetic nephropathy, retinopathy and coronary artery disease were also more frequently found among hypertensive diabetics as compared to non-hypertensive diabetics patients (18.5 vs. 11.2 %, 22.2 vs. 16.3 %, and 21.2 vs. 11.4 respectively). Co-morbidity of hypertension and diabetes also tends to contribute to more diabetic vascular complication(s) Hospital data, 5-10 years after the initial treatment, showed that the co-morbidity of hypertension among diabetics gives a lower total cholesterol level. Co-morbidity of hypertension and diabetes tends to end with more diabetic vascular complication(s) Acknowledging the role of high blood pressure in the development of diabetic vascular complications, scientist all over the world try to prove that lowering the blood pressure is really beneficial in preventing diabetic vascular complications and its progression. Studies to answer this question are conducted, among others as follows, with the different blood pressure target and different medication used. Most of them showed promising results of lowering blood pressure in the attempt to reduce the diabetic vascular complications. HOT study proved that lowering diastolic blood pressure to the level of < 85 mm Hg resulted in a 30% risk reduction of cardiovascular events. Table 2. Studies Comparing Blood Pressure Targets and Medication(s) Used Active Placebo Treatment SHEP (1996) 143 / 68 155 / 72 (low dose diuretics) Syst-Eur (1997) 153 / 78 162 / 82 HOT (1998) 140 / 81 (Target diast. < 80) UKPDS (1998) 144 / 82 (Target BP <150/85) Tight control 143 / 85 (dihydropyridine Ca antagonist) (Target diast. < 90) 154 / 87 (Captopril vs. Atenolol) (Target BP 180/105) Less tight control UKPDS In the UKPDS group, blood pressure lowering was similarly effective for captopril and atenolol based regimens in reducing the incidence of both microvascular and macrovascular diabetic complications. It is worth to note that in UKPDS, modest reduction in blood pressure (- 10 / 5) proved to have higher DM-related events prevention as compared to modest reduction of blood glucose. Table 3. UKPDS Study: Cardiovascular Events in Intensive Blood Glucose Control vs Tight Blood Pressure Control Intensive BG Control Hb A1c 7 % vs. 7.9 % Diabetes related end-point - 12 % (p =.30) Microvascular end-point - 25 % (p=.010) MI - 16 % (p=.052) Tight BP Control 144 / 82 vs. 154 / 87 Diabetes related end-point - 24 % (p=.005) Micro vascular end-point - 37 % (p=.009) MI - 28 % (p=.10) Heart Failure - 56 % (p=.004) Stroke - 44 % (p=.013) HOPE STUDY MICRO-HOPE STUDY HOPE study was a randomized double blind evaluation of ACE inhibitor in patients at high risk for vascular disease complications without clinically evident heart failure. This study compared antihypertensive Ramipril and Placebo. Among 9297 respondents, there were 3577 Diabetics enrolled in HOPE MICRO-HOPE In keeping with the findings of the major trial, the primary and secondary outcome of MICRO-HOPE study were recorded as follows: Primary outcome Myocardial infarction, stroke, cardiovascular death Significantly decrease (25 %, p<0.0004, 95 % CI 12 36 %) Secondary outcome Total mortality, need for revascularization Significantly lower Significant reduction in progression to overt nephropathy (16 %, 95% CI 1-29 %) 32

Vol 36 Number 1 January-March 2004 Management of High Blood Pressure No difference in admission for unstable angina or heart failure. Non-significant trend toward less laser therapy for retinopathy. Less progression to ESRD. Conclusion derived from all the prominent studies showed that lowering blood pressure to a certain degree is beneficial to reduce the diabetic vascular complications. MICROALBUMINURIA Many studies have shown that microalbuminuria is an independent risk factor for the development of CVD and a predictor of cardiovascular mortality in diabetic populations. Microalbuminuria is associated with insulin resistance, central obesity, absence of nocturnal blood pressure drop. Microalbuminuria is part of metabolic-cardiovascular syndrome associated with hypertension and it is also associated with endothelial dysfunction and increased oxidative stress. The longer the presence of microalbuminuria the higher the cumulative incidence of end stage renal disease. Several studies proved the superiority of ACE inhibitors as compared to other antihypertensive agents in lowering the urinary protein and microalbumin levels. The newly developed ARBs also proved the ability to reduce the development of overt proteinuria among diabetics (e.g. IRMA 2 Study). The use of these drugs in the management of hypertension in diabetes is therefore strongly recommended especially when microalbuminuria / proteinuria has developed in diabetic patients. IDNT Pilot Study has proved that irbesartan has been found to be more beneficial in reducing the urine protein excretion and in improving the creatinine clearance as compared to amlodipine. Another study (Psaty et al.) stunned the hypertensive community by providing strong evidence albeit nondefinitive, that certain CCB when used as drug therapy for hypertension were associated with an increased risk of myocardial infarction. However the latest evidence (ALLHAT study) did not give a different clinically relevant outcome when Lisinopril, Amlodipine and Chlorthalidone were comparatively used in the treatment of hypertension. The numbers of patients who succeeded in achieving the target blood pressure of less then 140/90 were similar in the three groups, 61 %, 66 % and 68 % respectively. Chlorthalidone and amlodipine did not increase cardiovascular events and mortality. Eventhough Lisinopril has been found to increase the risk of stroke and combined cardiovascular disease among black respondents. Considering the fact that lowering blood pressure proved to be beneficial and that microalbuminuria also has an important role in the development and progression of chronic diabetic vascular complications, consensus on the threshold of starting to treat hypertensive patients and the selected blood pressure target level has been endorsed by a group of experts around the world. The authority therefore set up the threshold for treating hypertensive diabetics and also the target blood glucose level to prevent the diabetic vascular complications. Table 4. British Hypertension Society Threshold and Target BP Recommendation for Antihypertensive in Diabetes Mellitus Threshold BPs Systolic > 140 Or Diastolic > 90 Target (clinic) BPs Systolic < 140 And Diastolic < 90 Based on several guidelines, in 2002, the American Diabetes Association recommended the target BP in the treatment of DM as 130/85, with less ambitious goal for the elderly. Table 5. American Diabetes Association Recommendation for The Treatment of Hypertensionin Diabetes Mellitus Category Goal (mmhg) Initial Therapy All Non-pregnant Diabetics > 18 y.o Isolated SBP 169-179 Isolated SBP > 180 < 130 / 80 Lifestyle : weight loss, exercise,reduced salt and alcohol Lower BP by 20 Then < 130 / 80 SBP < 160, Then < 130 / 80 Lifestyle Antihypertensive Lifestyle Antihypertensive As for the treatment, they recommended open choice for the initial treatment of hypertension in Diabetes Mellitus, using any class of drugs that is used in treatment of hypertension, and add another class of antihypertensive drugs for the second line treatment. The Indonesian Society of Endocrinology has convened already, during which algorithm on the threshold of hypertension that should be treated has been agreed upon together. The recommended algorithm in the management of hypertension in diabetes mellitus, which is based fully on ADA recommendation 2002 has been developed and distributed in the medical community in the PERKENI consensus on the management of Diabetes Mellitus 2002 as can be seen below. 33

Sarwono Waspadji Acta Med Indones-Indones J Intern Med Treatment Goal < 130/85 Initiate Pharmacologic Selection (in alphabetical order), Plus Lifestyle Modifications (ACE Inhib, Beta Blockers, Ca Antagonist, and Diuretics in low dose) ACE inhibitors are drugs of choice in patients with albuminuria/ proteinuria Table 6. The Indonesian Society of Endocrinology. Threshold and Target BP Recommendation for Antihypertensive in Diabetes Mellitus Threshold BPs Systolic > 130 or Diastolic > 80 Target (clinic) BPs Systolic < 130 and Diastolic< 80 With Proteinuria Systolic < 125 and Diastolic< 75 Isolated Systolic Hypertension: gradually,upto < 140 /90 Syst. 130-139 Syst. > 140 Diast. > 90 Diast. 80-89 Inadequate Response Lifestyle Modification 3 months, inadequate response Increase drug dose Add a second agent from a different class (e.g. diuretic, if not selected initially) Life-style + ACE Inhibitors Beta Blockers Diuretics 1-2 months, target not achieved AIIRA Increase Dose Change to other - antihypert. Add other antihypert. Inadequate Response Add other antihypertensive (second, third, etc., (one of them should be diuretics) Add a second or third, one of which should be diuretic, if not already prescribed Figure 1. Algorithm for Treatment of Hypertension in Diabetics (ADA Recommendation) The Indonesian Society of Endocrinology Threshold and target BP recommendation for antihypertensive in diabetes mellitus. If microalbuminuria, or macroalbuminuria clinical nephropathy present, use ACE inhibitors, or AIIRA or non dihydropyridine Ca antagonist. Extensive discussion on the choice of treatment is beyond the scope of this presentation. However some lessons from the ADA recommendation will be mentioned. Some evidence based recommendation from the ADA 2002 and 2003 were presented together to show that even a big and prominent international organization seem to hesitate and to be very thoughtful in making recommendations as for the treatment of hypertension in diabetes mellitus since there are a lot of controversies that much be raffled and settled together before we have better, stronger and widely accepted algorithm in the treatment of hypertension in diabetes mellitus. This can be seen from the changes in their recommendations in 2002 and 2003. Figure 2. Algorithm for Treatment of Hypertension in Diabetics (The Indonesian Endocrine Society Consensus 2002) ADA RECOMMENDATIONS 2002 Initial therapy: may be with ACE inhibitor, ARB, beta-blockers or diuretics In microalbuminuria or clinical albuminuria: ACE inhibitor or ARB In diabetics > 55 y.o. with or without hyperten sion but with risk factor(s): ACE inhibitor should be considered In diabetics with recents MCI: beta-blockers should be considered. When ACE inhibitor or ARB is not tolerated, consider non-dccb When using ACE inhibitor / ARB: monitor serum creatinine and potassium In the elderly, blood pressure should be lowered gradually Patients, which do not achieve target with 3 drugs and with severe renal disease, should be referred to specialist experienced in hypertension care. ADA RECOMMENDATIONS 2003 Initial treatment: may be any drug class currently used. ACE inhibitor, Beta Blockers, Diuretics are preferred agents. 34

Vol 36 Number 1 January-March 2004 Management of High Blood Pressure Others are similar to the ADA recommendation 2002. New evidence (the ALLHAT study) provides compelling evidence that thiazide diuretics should also be used as one of the initial drug of choice in the treatment of hypertension. CONCLUSION Hypertension is a common co-morbidity in diabetes mellitus, therefore the consequences of high blood pressure on T2DM should be considered. Hypertension and diabetes mellitus are often clustered together as a part of the metabolic-cardiovascular syndrome. Treating hypertension in diabetics should take into account all aspects of the patient s condition, metabolic-cardiovascular as well as socio-aconomic aspects, especially in the elderly, avoiding multipharmacy in managing multipathology. A logical strategy that incorporate low cost agents may differ from more popular contemporary strategy which may be somewhat influenced by marketing activities to using expensive medications. In fact physician have the means to effectively control blood pressure with inexpensive medications, even among patients who require multiple drugs. This issue should be stressed as physicians have to consider cost-effectiveness in patient management 10. American Diabetes Association. Standard of medical care for patients with diabetes mellitus. Clinical Diabetes 2002; 20(1); 24-33. 11. American Diabetes Association. Standard of medical care for patients with diabetes mellitus. Diabetes Care 2003; 26(1); S33-44. 12. Pacheco CA, Parrot MA, Raskin P. The treatment of hypertension in adults patients with diabetes mellitus. Diabetes Care 2002; 25(1): 134-47. 13. Appel LJ. The verdict from ALLHAT- thiazide diuretics are the preferred initial therapy for hypertension. JAMA 2002; 288(23): 3039-44. 14. Epstein M. Recent landmark clinical trials: How do they modify the therapeutic paradigm?. AJH 2002;15: 82S-4S. 15. Supartondo. Kecenderungan polifarmasi pada multipatologi: apa masalahnya. Penatalaksanaan pasien geriatri dengan pendekatan interdisiplin. Prosiding temu ilmiah geriatri 2003. Dalam: Supartondo, Siti Setiati, Czeresna H Soejono,eds. Jakarta: Pusat Informasi dan Penerbitan Bagian Ilmu Penyakit Dalam; 2003.p. 1-5. REFERENCES 1. Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanism of diabetic vasculopathy: an overview. AJH 2001;14: 475 86. 2. Diabetes Guidelines Work Group. Massachuset guidelines for adult diabetes care. Revised June 2001. Diabetes Control Program. Hypertension 3. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001; 37:1053-9. 4. Melers PS, Jeffers BW, Estacio R, Schrier RW. Association of hypertension and complications in non-insulin dependent diabetes mellitus. AJH 1997;10: 152-61. 5. Feher MD. Hypertension in diabetes. Pract Diab Int 2001; 18(6): 197-200. 6. Adler AI, Stratton IM, Neil HAW, etal. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412-7. 7. PB Perkeni. Konsensus pengelolaan diabetes melitus di indonesia. Jakarta, 2002. 8. American Diabetes Association. Treatment of hypertension in adults with diabetes mellitus. Diabetes Care 2002; 25(1): 199-201. 9. American Diabetes Association. Treatment of hypertension in adults with diabetes mellitus. Diabetes Care 2003; 26(1): S80-2. 35