Hypertension in Diabetic Patients – Emerging Trends

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					                                     E D I T O R ’ S                     C H O I C E                      JIACM 2003; 4(2): 96-102



                Hypertension in Diabetic Patients – Emerging Trends
                                                             SN Arya*

Abstract
Hypertension (HTN) is one of the important risk factors (bad companions) for cardiovascular morbidity and mortality in diabetic
subjects. Tight control of HTN prevents or retards both microvascular and macrovascular complications, while only tight control of
hyperglycaemia prevents or retards the march, mainly of microvascular complications, e.g., nephropathy, retinopathy, and
neuropathy. Nearly 70% of deaths occur in diabetes due to macrovascular complications, e.g., myocardial infarction, stroke,
neglected gangrene of the limbs due to peripheral vascular disease, etc, and all these risks can be prevented by tight control of
HTN, alongwith optimal control of hyperglycaemia.

ACE-inhibitors and angiotensin-II-receptor-blockers have many benefits in diabetic hypertensives. Alpha blockers (long-acting)
and long-acting calcium channel-blockers may also be used. Beta blockers and low dose thiazides may be used in certain groups
of diabetic hypertensives. Aspirin 75 mg once daily and usual dose of statins reduce major cardiovascular events.They are indicated
in diabetic hypertensives upto 75 yrs of age if serum cholesterol is > 5.0 mmol/dl and 10 yrs. coronary artery disease-risk is ≥ 15%,
and the patients have target organ damage or clinical cardiovascular disease. In advanced renal failure due to diabetic nephropathy
or accelerated essential hypertension in a diabetic, insulin is the best drug. Oral hypoglycaemic agents, e.g, gliclazide, tolbutamide,
gliquidone, glimepiride, and repaglinide can be used in mild renal failure. Pioglitazone and rosiglitazone can be used in mild renal
failure if fluid retention creates no problem.

Key words: Diabetes mellitus, Hypertension, Microvascular and macrovascular complications, Life-style modification,
Antihypertensive drugs, Insulin, Oral hypoglycaemic agents, Aspirin, Statins.


Introduction                                                           triglyceride, high LDL, and low HDL.

Hypertension may precede the onset of diabetes mellitus                Both HTN and DM are recognised as independent
(DM) and in about 95% cases, it is essential hypertension              cardiovascular risks (CVR), e.g., coronary artery disease
and the rest may be secondary type. In some cases, both                (CAD), left ventricular hypertrophy (LVH), stroke, peripheral
hypertension and diabetes mellitus may be present at the               vascular disease (PVD), retinopathy, and nephropathy. In
time of initial diagnosis. Hypertension may develop later              hypertensive patient with DM, atherosclerosis gets
in a diabetic subject as a feature of diabetic nephropathy.            accelerated and its consequences get manifested earlier.

The frequency of hypertension (HTN) in diabetic                        In observational studies, people with DM and
population is almost twice as compared to non-diabetic                 hypertension have approximately twice the risk of
general population1. In India about 50% of diabetics have              cardiovascular disease as compared to non-diabetic
HTN2, 3 .                                                              people with hypertension alone. Hypertensive patients are
                                                                       also at increased risk of diabetic specific complications
About more than three decades back Harry Keen pointed
                                                                       including retinopathy.
out two bad companions of diabetes mellitus, viz.,
hyperglycaemia (glucotoxicity) and high blood pressure                 Patients of both type-1 and type-2 DM are prone to
both associated with microalbuminuria 4. The UK                        develop hypertension which accelerates cardiac, renal,
Prospective Diabetic Study drew attention to two more                  and cerebral dysfunctions which are leading causes of
bad companions, viz., dyslipidaemia and smoking4. The                  death 5. 70% of deaths in diabetics occur due to
association of obesity (specially apple type or central                macrovascular complications like myocardial infarction
obesity) and DM are well known, especially in Indian                   (MI), unstable angina, heart failure (HF), sudden cardiac
subjects, who have typical dyslipidaemia with moderately               death, stroke, and neglected gangrene due to occlusion
raised or high normal total cholesterol, but very high                 of large arteries of extremities.

* National Professor of Medicine and Dean of Studies, IMA College of GP; Consultant Physician, Vidyapati Marg, Back
Museum Road, Patna-800 001, Bihar.
This article deals with the problem of hypertension in a          the researchers soon became aware that high BP may
diabetic subject and the main focus will be on treatment          even be a stronger risk factor for microvascular and
of HTN, but the abnormality of glucose metabolism and             macrovascular complications of DM4,11. Hence the UKPDS
the other bad companions like obesity, dyslipidaemia,             group extended the study to monitor the beneficial effects
smoking, etc., cannot be lost sight of. Brief reference will      of tight control of BP in the diabetics. The UKPD study and
be made to the choice of the anti-diabetic drugs to be            other UK study groups have shown that the long term
used when hypertension ante dates, co-exists, or follows          tight BP control in hypertensive patients with type 2 DM
the onset of diabetes mellitus.                                   results in a significant reduction in all diabetes-related end
                                                                  points. Differences in all cause mortality, however, failed
Correction of hyperglycaemia                                      to reach statistical significance4. But by the tight control
                                                                  of BP, the incidence of macrovascular complications such
Depending on their specific indication, diet control, oral
                                                                  as coronary artery disease (CAD), heart failure (HF), and
hypoglycaemic agents, or insulin should be used in
                                                                  stroke were greatly reduced4. BP study also reiterates the
essential hypertension. But when one is dealing with
                                                                  importance of early treatment. A new concept is emerging
diabetic nephropathy, insulin is the best choice. In certain
                                                                  to start ACE – inhibitors early in all diabetic hypertensive
circumstances, especially if renal failure is mild,
                                                                  patients with microalbuminuria. Not only is
tolbutamide and second generation sulphonylureas like
                                                                  antihypertensive treatment more effective in preventing
gliclazide, or gliquidone, or glimepiride 6, or a non-
                                                                  micro and macrovascular complications, than tight blood
sulphonylurea meglinitide group of drugs like repaglinide
                                                                  glucose control alone, the beneficial results also come
or nateglinide can be used because these drugs are mainly
                                                                  soon. Tight BP control is more cost effective and easier for
metabolised in the liver7. In a diabetic pregnant lady with
                                                                  clinicians and patients than tight blood glucose control.
pre-existing hypertension or pre-eclampsia, or a nursing
                                                                  It is to be noted that UKPD study did not show
hypertensive mother, in severe infection, severe trauma,
                                                                  unequivocal beneficial effect of tight control of
and in peri-operative period, only insulin with appropriate
                                                                  hyperglycaemia in preventing macrovascular
hypotensive agents can be used. In type-1 DM with
                                                                  complications (CAD, HF, stroke, peripheral vascular
hypertension, it goes without saying that there is no
                                                                  disease).
escape from insulin. Thiozolidinediones (pioglitazone and
rosiglitazone) increase insulin sensitivity and thereby           The SHEP study13 using low dose diuretics, beta blockers,
provide additional anti-hypertensive efficacy8. But they          calcium channel blockers, ACE – inhibitors and the SYST –
can be used in a diabetic hypertensive only if left               EUR study14 using calcium channel blockers and ACE –
ventricular dysfunction or heart failure is not present9,10.      inhibitors with diuretics as reserve, have shown beneficial
Thiozolidinediones induce fluid retention and anaemia,            effects of BP control as concluded by extension of UKPD
and hence should not be used in severe hypertension and           study group alluded to above. It is to be noted that both
in hypertensive heart failure. In hypertensive diabetics          SHEP and SYST-EUR Study recruited diabetic
with hepatic insufficiency, thiozolidinediones and even           hypertensives also for the trials.
gliclazide and gliquidone should not be given and the
dose of repaglinide should be reduced7.                           The International Diabetic Federation CONSENSUS
                                                                  GUIDELINES 15 have anticipated reduction in stroke
Advantages of treating hypertension in DM                         morbidity and mortality, heart failure morbidity and
                                                                  mortality, in CAD events and reduction in progression of
UKPDS in type-2 DM 4,11 and Diabetes Control and                  renal disease including diabetic nephropathy by tight
Complication Trial (DCCT)12 in type-1 DM, more so the             control of hypertension in DM. Reduced left ventricular
former, started by studying the values of various strategies      hypertrophy, a marker for CAD and HF was anticipated as
to achieve tight blood glucose control for prevention of          a relevant surrogate outcome. The above list does not
the relentless march of diabetic complications. Both the          include the benefit of management of malignant HTN.
trials showed significant reduction in microvascular
complications (retinopathy, nephropathy, neuropathy). But         In the UKPDS epidemiological study, each 10 mm Hg


 Journal, Indian Academy of Clinical Medicine         Vol. 4, No. 2   April-June2003                                       97
decrease in the mean systolic BP was associated with              organ damage (TOD), clinical cardiovascular disease (CCD)
reduction in risk of 12% for any complication related to          and one or many of other risk factors like obesity,
DM, 15% for deaths related to DM, 11% for myocardial              dyslipidaemia, male-sex (older than 60 yrs.), family history
infarction, and 13% for microvascular complications17.            of cardiovascular disease in women under 65yrs and in
                                                                  men under 55, etc., are present. All diabetics with BP more
The importance of tight BP control in lowering the
                                                                  than 160/100 irrespective of CV risk factors, confirmed on
incidence and retarding the progression of macro and
                                                                  two occasions 2 weeks apart, should receive advice
microvascular complication of DM is quite obvious.
                                                                  regarding life-style modification and should be put on
                                                                  antihypertensive drugs right at the outset.
At which level of BP to start anti-
hypertensives?                                                    Life-style modification (LSM)16,18 : This should be advised
                                                                  to all diabetic hypertensives. These non-pharmacological
The Joint British Recommendations (British Hypertension
                                                                  measures take care of hyperglycaemia, lower the BP, and
Society, British Hyperlipidaemia Association and British
                                                                  reduce the doses and number of antihypertensive drugs.
Cardiac Society) 6 have suggested the initiations of
                                                                  They also correct obesity, hyperglycaemia,
treatment of hypertension in diabetics when BP is equal
                                                                  hyperinsulinaemia, and act as primary prevention against
to or more than 140/90 mm Hg. According to the WHO
                                                                  cardiovascular risks, e.g., coronary artery disease, stroke
Expert Committee Recommendation in Hypertension
                                                                  etc. The LSM constitutes the following:
Control17 treatment may be instituted at BP 130/85 mm
Hg in a patient with diabetic nephropathy.                        1. Diet: Salt restriction to 4-6 gm sodium chloride per
                                                                     day lowers BP, reduces LV mass, and decreases dose
What target level of lowering is beneficial?                         of anti-hypertensive drugs (JNC-VI). It reduces diuretic
                                                                     induced hypokalaemia, and increases effects of anti-
The Joint British recommendation6 has set the target for
                                                                     hypertensive drugs. It protects against osteoporosis
lowering BP to 140/80 or even lower, provided the patient
                                                                     and renal stone formation through reduction in
tolerates it. In diabetics with isolated systolic hypertension,
                                                                     urinary calcium excretion (JNC-VI)18.
BP should be lowered to 130/80 or even lower. In
hypertensive diabetics with pregnancy and renal                   2. Adequate intake of dietary-fibre, and K+, Ca++, Mg++
insufficiency, the target of lowering BP should be 130/80            from fresh fruit, green vegetables, and dairy products
or even lower, if the patient tolerates it. JNC VI                   should be ensured. Mg++ is provided by chlorophyll
recommends lowering BP to 130/85 or even to 120/75 in                of green leafy vegetables16,20,21.
diabetic nephropathy if proteinuria is > 1 gm in 24 hours18.      3. Obesity: Intensive efforts should be made to reduce
The lower the BP, lower is the risk of stroke or CAD. HOT            weight by diet control and exercise. Anti-obesity diet
study19 has shown that fewer major cardiovascular events             should not contain more than 1/3rd of total calories
and the lowest cardiovascular mortality were noted at                from fat. Of the fat calories, 1/3rd should be derived
average BP of 138/83 and 139/85 respectively22. Lower BP             from saturated fat and 2/3 from poly- or mono-
did not further decrease or increase adverse events except           unsaturated fat. A Canadian study16 has confirmed
for an apparent increase in mortality in those whose                 that flax-seed oil lowers total cholesterol and LDL and
diastolic pressures were reduced to 70 mm Hg8,19.                    has anti-oxidant effects. Indian studies have shown
                                                                     that our traditional cooking medium like pure
Treatment protocol                                                   unadulterated mustard oil is best in taking care of
BP control should also take into consideration the                   serum-lipids. Weight reducing drugs are not
treatment of hyperglycaemia, dyslipidaemia, obesity,                 recommended. Fenfluramine and dexfenfluramine
sedentary habits, and smoking.                                       produce pulmonary hypertension and lesions of heart
                                                                     valves6,16,18 Orlistat acts by inhibiting pancreatic lipase
Drug-therapy should be started even for high normal BP               and excreting dietary fat in stool, but is not available
(JNC-VI classification) and stage-1 HTN (JNC-VI) if target           in India6. Fluoxetine can help motivate patient for


 98                                     Journal, Indian Academy of Clinical Medicine       Vol. 4, No. 2    April-June 2003
       dieting and is safe. Sibutramine, an anti-obesity drug       effects of treatment in reducing cardiovascular mortality
       increases BP and thus cannot be given to diabetics           and morbidity4. Low dose thiazides, beta-blockers, ACE-
       with hypertension6.                                          inhibitors, dihydropyridine calcium channel blockers (long
                                                                    acting) have all shown benefits in type-2 DM6. That both
4. Exercise reduces obesity, hyperinsulinaemia, raises
                                                                    older(beta blockers, diuretics) and newer drugs(ACE-
   HDL, and prevents osteoporosis 17. Even without
                                                                    inhibitors, calcium channel blockers, alpha-blockers, and
   weight loss, exercise improves insulin sensitivity10.
                                                                    angiotension-II receptor, blockers) have equal efficacy
5. Smoking should be stopped altogether as it is an                 have been proved by various trials. They all reduce
   independent risk factor for CV events.                           mortality and morbidity of CV events in hypertensives
6. Alcohol: Stoppage or moderation to 60 ml whisky or               (even those with DM ) and they all improve the quality of
   300 ml wine, or 720 ml beer per day is considered to             life16,20,23.
   be safe.                                                         However, the author does not prefer diuretics or beta
                                         16,18
7. Yoga, relaxation, and biofeed back .They have been               blockers in diabetic hypertensives. He uses beta blockers
   shown to reduces BP in small group of patients.                  only in diabetic hypertensive with angina or in post-
   However, relaxation therapy and biofeedback have                 myocardial infarction patients.
   been shown to have little effect in lowering BP in
                                                                    ACE – inhibitors have renoprotective effect by reducing
   multiple control trials. No doubt, a study in African
                                                                    intraglomerular pressure. They reduce albuminuria in
   Americans showed significant decrease in SBP and
                                                                    diabetic nephropathy, reduce rate of renal deterioration,
   DBP in 3 months 18. Prof. BK Sahay of Hyderabad
                                                                    and have no adverse effect on lipids. They minimise
   (personal communication) has shown improvement
                                                                    adverse metabolic effects of diuretics5,6,15 and may have a
   in quality of life, lowering of blood sugar, BP, and lipids
                                                                    specific role if nephropathy is present in type-1 DM6 . They
   by yoga in diabetics.
                                                                    may potentiate the hypoglycaemic effect of insulin and
                                                                    oral antidiabetic drugs6. Irritable cough and very rarely
Choice of anti-hypertensive drugs                                   angio-oedema, are the important side effects.
Both for patients with pre-existing essential or secondary          Hypoglycaemia, hyperkalaemia, and rise of serum
hypertension who develop diabetes mellitus later on, and            creatinine should be watched. These drugs are
in patients of diabetic-induced HTN, the best drugs are:            contraindicated in bilateral renal artery stenosis,
                                                                    pregnancy, and lactation.
i.     ACE-inhibitors and angiotensin-II receptor blockers
       singly or combined.                                          Angiotensin-II receptor blockers have many properties
ii.    Alpha receptor antagonists.                                  similar to those of ACE-inhibitors. As they don’t inhibit the
iii. Calcium channel blockers.                                      breakdown of bradykinin and other kinins, cough is not a
                                                                    problem with their use1,6.These drugs (losartan potassium,
But many of the trials in diabetic hypertensives13,22 have          candesartan, valsartan, etc.) should be used with caution
concluded that ACE -inhibitors or beta blockers have no             in unilateral renal artery stenosis,aortic or mitral valve
specific advantage or disadvantage in diabetic                      stenosis and in hypertrophic obstructive
hypertensives. Some authors provide argument for the                cardiomyopathy9.
use of both these classes of drugs in DM4. The UK PDS
                                                                    Alpha-blockers: Long acting prazosin GITS (gastro-
suggests that blood pressure reduction itself may be more
                                                                    intestinal therapeutic system), doxazosin, and terazosin,
important than the measures used to achieve it, but ACE-
                                                                    increase insulin sensitivity, improve HDL-level, and reduce
inhibitors were better tolerated. Systolic hypertension in
                                                                    serum cholesterol5.
the elderly (SHEP) trial, Hypertension Optimal Study (HOT-
study)19 and SYST-EUR study used β-Blockers and/or                  They also are beneficial for diabetic hypertensives with
diuretics and many of the subjects included in the trials           benign prostatic hypertrophy (BHP) in reducing urinary
were diabetic. All these trials demonstrated beneficial             symptoms.


     Journal, Indian Academy of Clinical Medicine       Vol. 4, No. 2   April-June 2003                                     99
Calcium channel blockers 5,6,24 : Only long acting              Role of statins in DM with HTN19
dihydropyridines(nifedipine-retard, amlodipin, lacidipin)
                                                                According to Joint British Recommendation on Prevention
are used. Amlodipin does not have negative ionotropic
                                                                of CAD and Scottish Inter-Collegiate Guidelines, statins
effects and can be used in diabetic hypertensives with
                                                                lower coronary events, stroke and all cause mortality and
heart failure. Ca-channel blockers are also useful in angina,
                                                                are safe, simple, and well tolerated. Statins are indicated
especially Prinzmetals’ angina. Pedal oedema and
                                                                in diabetic hypertension upto age 75 years if serum
headache are the side effects: Gingival hyperplasia may
                                                                cholesterol is ≥ 5 mmol/L and 10 year CAD risk ≥ 30%
occur5,6. When data from all comparative trials of using
                                                                especially if patient is having angina or MI. Statins lower
various drugs in almost 5,000 hypertensive diabetics are
                                                                blood pressure also and they correct dyslipidaemia that
combined, the lowest mortality rate has been found with
                                                                commonly accompanies DM8.
calcium channel blocker based therapy8.

Low dose thiazide diuretics : They are sparingly used           The combination of ACE - inhibitor and
by the author in diabetic hypertensives. They produce           angiotensin receptors blocker (ARB)
hypokalaemia, aggravate hyperglycaemia, and worsen              Such combination promises a better outcome in the diabetic
dyslipidaemia15 and may cause impotency. Low dose               hypertensive patient as it inhibits secretion and action of
thiazides are cheap and may be used in diabetic                 angiotensin II (A II) in totality. It has been demonstrated that
hypertensive with heart failure.                                80% angiotensin II is produced in tissues through non-ACE-
Beta blockers : They worsen hyperglycaemia and                  pathways or alternative pathways involving chymase-like
blunt hypoglycaemic awareness by blocking the                   enzymes. The production of A II through alternative
adrenergic symptoms. This hypoglycaemic                         pathways is not prevented by ACE-inhibitors but will be
unresponsiveness and lack of awareness may produce              blocked by ARB. Since both ACE-inhibitors and ARB work
dangerous hypoglycaemia without giving the patient              on renin angiotensin aldosterone system (RAAS) cascade
a chance to rectify it by timely ingestion of food.             in a sequential manner at two different stages, the net block
                                                                of A II is likely to be near total and complete.
However, beta blockers inhibit early morning
outpouring of catecholamines, rise of pulse rate and            There are evidences that the combination of ACE-
BP, and prevent cardiac rupture and sudden cardiac              inhibitors and ARB reduce retinal and other ocular
death. They protect post-infarct patients against               complications and lower the level of uric acid seen in
recurrence of myocardial infarction and sudden                  diabetic nephropathy.This combination reduces both pre-
cardiac death and are a good anti-arrhythmic 6,20,21.           load and after-load in patients with subclinical or overt
Carvedilol is an unique beta-blocker as it has arteriolar       hypertensive heart failure. This combination having a low
vasodilating action and is an adjunct to diuretics, ACE-        effective dose of both these agents, the chances of dry
inhibitors and digoxin in treatment of heart failure6 in        cough are reduced much more than monotherapy with
diabetic subjects.                                              ACE-inhibitors or A II25.

                                                                In UKPDS, combination of captopril and atenolol achieved
Role of aspirin (75 mg OD) in diabetic                          reduction in diabetes related end points by 24%, in death
hypertensive19,23                                               related to diabetes by 32%, in stroke by 44%, and in
HOT study, Thrombosis Prevention Trial and ALLAHAT Trial        microvascular end points by 37%. Combination of ACE-
have shown that 75 mg aspirin OD reduces major CV               inhibitors and calcium channel blockers have been found
events by 15% but not fatal events, in hypertension             useful in diabetic hypertensives. Combination of low dose
especially in diabetes. This is indicated in patients aged      diuretics with ACE - inhibitors produce synergistic effects.
50 years or above, if 10 years CAD – risk is ≥ 15%, if serum    Adequate control of BP in diabetics to 130/80-85 can be
cholesterol is ≥ 5 mmol/L and if TOD and CCD exist. The         achieved by a combination of these drugs, of which one
incidence of CAD is definitely reduced.                         should be an ACE - inhibitor26.



 100                                  Journal, Indian Academy of Clinical Medicine       Vol. 4, No. 2     April-June 2003
Treatment of hypertensive urgencies and                                   receptor blocker is better than any of these agents
emergencies in diabetic persons9,10,27                                    alone. Long acting calcium channel blockers and
                                                                          alpha-adrenoceptor antagonists can also be used.
Hypertensive urgencies: Asymptomatic severe HTN (>
220/125 mm Hg) with papilloedema and peri-operative                  8. Diabetics can present with urgencies where oral
hypertension are situations where BP has to be brought                  medications are used to bring down BP in a few hours.
down promptly by oral medications. Nifedipine 10 mg stat                Those presenting with emergencies require
orally (not sublingually), ACE - inhibitors like captopril 12.5         parenteral anti-hypertensive drugs to bring down BP
to 25 mg sublingually or orally, and fenoldopam (a                      to 160/100 within a few minutes to 1-2 hours.
peripheral dopamine DA1 receptor agonist) orally may be              9. Life-style modifications are prescribed for all
used. Parenteral drugs are not needed as the action of                  hypertensive diabetics.
the above drugs starts in 5-30 minutes and lasts for 10              10. Various trials have shown that treatment, particularly
minutes to 6-8 hours depending on the drugs used.                        with angiotensin converting enzyme inhibitors and
                                                                         angiotensin-II receptor blockers prevent progression
Hypertensive emergencies in diabetics include
                                                                         to end-stage renal failure and should be started
hypertensive encephalopathy, pulmonary oedema,
                                                                         early28.
aortic–dissection, unstable angina, myocardial infarction
and malignant hypertension, etc. Here, BP must be
brought down to 160/100 within a few minutes to 1 to 2
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