Importance of blood pressure control in patients with diabetes mellitus

Shigehiro Katayama*, Munemichi Inaba

The Fourth Department of Medicine, Saitama Medical School, 38 Morohongo, Moroyamacho, Iruma, Saitama 350-0495, Japan

Received 25 June 2001; accepted 2 July 2001

1. Introduction

Patients with diabetes mellitus are at high risk of

cardiovascular disease. Many epidemiological studies

have shown that the risk of cardiovascular mortality is

two to three times higher than in people without

diabetes mellitus (Kannel & McGee, 1979; Stamler

et al., 1993). Hypertension is very frequently associated

with diabetic subjects (The Hypertension in Diabetes

Study Group, 1993), i.e., about 50% of diabetics, irre-

spective of whether they are Type 1 or Type 2, are

hypertensive. Hypertensive diabetics have been reported

to have more cardiovascular disease when compared to

normotensive diabeteics. Total mortality in many epide-

miological studies is two to three times higher in

hypertensive diabetics when compared to that in normo-

tensive diabetics. The total mortality in hypertensive

diabetics is six to seven times higher than that in

normotensive nondiabetics. In addition, despite decreases

in the incidence of heart disease in the general popu-

lation, the decline is much smaller in people with Type 2

diabetes and may even be rising in women with diabetes

(Gu, Cowie, & Harris, 1999).

2. Pathogenesis of hypertension in diabetes mellitus

One of the reasons that hypertension is very often

associated with diabetes is that hyperglycemia accelerates

atherosclerosis. We have previously demonstrated that

patients with Type 2 diabetes mellitus showed diminished

forearm blood flow due to increased vascular resistance

even at younger ages (Ide et al., 1991). Although Japa-

nese diabetics are not so obese, obesity-related sympa-

thoadrenergic stimulation might be another reason for

hypertension. Insulin resistance is also one of the reasons

for hypertension. We previously reported that 36% of

hypertensive patients demonstrated hyperinsulinemia of

more than 78 mU/ml, which is the mean + 2S.D. of

20 young lean females, 1 h after 75 g oral glucose

tolerance (OGTT), while only 16% of normotensives

showed such a hyperinsulinemia. Very recently, we

reported that insulin resistance, which is estimated by a

higher fasting IRI ( > 15 mU/ml), the sum of IRI during

75 g OGTT (>150 mU/ml h) or Homa-R (>4), is a good

predictor of the subsequent development of hypertension

in normotensive subjects with impaired glucose tolerance

or a mild diabetes mellitus, the odds ratio of which is five

to nine times higher than that in the group with fasting

IRI < 10 mU/ml, the sum of IRI during 75 g OGTT

< 100 mU/ml h or Homa-R < 2 (Kashiwabara et al.,

2000). Volume expansion derived from diabetic nephro-

pathy is another cause of hypertension. Endothelial dys-

function possibly due to hyperglycemia and/or oxidative

stress may be also very important to increase blood

pressure (Tooke & Goh, 1998). Diminished bradykinin

and NO synthesis in endothelial cells may also cause

hypertension. Although the renin–angiotensin system is

not augmented as evidenced by normal to low plasma

renin activity, the tissue renin–angiotensin system might

be activated in diabetes mellitus.

3. Recent guidelines of hypotensive treatment for

hypertensive diabetics

Based on the insufficient efficacy of antihypertensive

treatment described above, recent guidelines stratified

hypertensive patients by their risks and/or target organ

damages/clinical cardiac disease and recommended more

vigorous blood pressure lowering. In fact, the sixth Joint

National Committee guideline (JNC VI), which was

published in 1997, stratified patients into three groups

(Joint National Committee, 1997). In Risk Groups A and

B, hypotensive agents are recommended at more than

160/100 mmHg. In patients with their blood pressure of less

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* Tel.: +81-492-76-1204; fax: +81-492-94-9752.

E-mail address: skataya@saitama-med.ac.jp (S. Katayama).

Journal of Diabetes and Its Complications 16 (2002) 87–91

than 160/100 mmHg, lifestyle modification is recommen-

ded for 6 months to 1 year. If their blood pressure is not

decreased to less than 140/90 mmHg, hypotensive agents

will be started after lifestyle modification. However, in

patients in Risk Group C associated with target organ

disease and clinical cardiac disease, and/or diabetes mellitus

with or without other risk factors, hypotensive agents are

immediately recommended even at high normal blood

pressure. This is a large difference from Risk Groups A

and B. In patients with essential hypertension, the target

blood pressure is less than 140/90, while in diabetics,

130/85, and in patients with renal dysfunction associated

with proteinuria of more than 1 g/day, 125/75. However, at

that time, there was not so much evidence to support these

target blood pressures.

In a Hypertension Optimal Treatment (HOT) study

(Hansson et al., 1998), 19,000 hypertensives with a

diastolic blood pressure of 100–115 mmHg were treated

with the Ca-antagonist, felodipine. They were separated

into three groups: the target blood pressure of which were

85–90, 80–85, and less than 80. Since the achieved

blood pressures in three groups were very close, the

incidence rates of the major cardiovascular events in the

three classes were not different (Fig. 1). However, when

analyzed according to the achieved blood pressure, the

lowest incidence of the major cardiovascular events was

observed at around 83 mmHg in diastolic, and 139 mmHg

in systolic. However, as shown in Fig. 1, in diabetics, the

relationship of ‘‘the lower, the better’’ is evident, i.e., the

incidence of the major cardiovascular events in the group

of their target blood pressure of less than 80 mmHg was

50% of the group of 85–90 mmHg. However, please note

that the risk of cardiovascular events in diabetics was still

30% higher when compared to the whole group, 92% of

which were nondiabetics. In the same year, the results of

the UK Prospective Diabetes Study Group (UKPDS) were

published (UKPDS Group, 1998). Blood pressure control

in the newly diagnosed Type 2 diabetics was very

efficient in reducing not only microvascular, but also

macrovascular, diseases such as myocardial infarction

and stroke to the same extent as blood glucose control.

The results of the HOT study and UKPDS supported the

lower target blood pressure in high-risk patients such as those

with diabetes mellitus. These results were incorporated into

the guideline by the World Health Organization/International

Society of Hypertension (WHO/ISH) in 1999 (WHO/ISH,

1999). The target blood pressure of less than 130/85 was

recommended not only in diabetics but also in the younger

and middle-aged hypertensives without diabetes mellitus.

In JNC VI, diuretics and b-blockers were recommended

as the first-line drugs, since much evidence indicates that

these two classes of drugs reduce cardiovascular events.

Other newer drugs such as angiotensin-converting enzyme

inhibitors (ACEIs) and Ca-antagonists were recommended

in specific situations as compelling indications. For

example, for heart failure, ACEIs and diuretics were

strongly recommended. For diabetics especially associated

with diabetic nephropathy, ACEIs were recommended.

However, in the guideline by WHO/ISH, six classes of

hypotensive drugs were regarded as the first-line drugs,

Fig. 1. Incidence rate of major cardiovascular events in all hypertensive subjects (about n= 19,000) and diabetics (n= 1501) in the HOT study (Hansson

et al., 1998).

S. Katayama, M. Inaba / Journal of Diabetes and Its Complications 16 (2002) 87–9188

since there was no evidence to show that one class is

superior to another class.

4. Japanese guideline for treatment of hypertension 2000

by Japanese Society of Hypertension (JSH, 2000)

Based on the higher mortality of cerebrovascular disease

than that of coronary artery disease in Japanese, the JSH

made their own guidelines for the management of hyper-

tension (JSH, 2000) in June 2000. Hypertensives were

stratified into three risk groups, i.e., low, middle, and high

risk, according to the blood pressure levels and the presence

or absence of risk factors such as diabetes mellitus, dysli-

pidemia, smoking, aging, and/or the presence of familial

history of cardiovascular disease at a younger age (Table 1).

Initiation of treatment is also tailored according to the risk

group (Fig. 2). The target blood pressure of less than 130/85

was recommended not only in diabetics but also in the

younger and middle-aged hypertensives without diabetes

mellitus. For elderly hypertensives of more than 65 years,

target blood pressure is less than 140–160/90 mmHg. Six

classes of hypotensive drugs are regarded as the first-line

drugs, since there was no evidence to show one class is

superior to the other class. However, compelling indications

for hypertensives with various complications are listed. For

example, Ca-antagonists are recommended for subjects with

cerebrovascular disease, angina pectoris, or diabetes melli-

tus, and the elderly. ACEIs are regarded to be suitable for

hypertensives with diabetes mellitus, congestive heart fail-

ure, postmyocardial infarction, left ventricular hypertrophy,

mild renal function impairment, cerebrovascular disease,

and the elderly.

5. Treatment of hypertension in diabetics (JSH, 2000)

Diabetics are stratified into the high-risk group irrespec-

tive of their blood pressure levels. As illustrated in Fig. 3,

hypotensive agents will be initiated if their blood pressure is

Table 1

Stratification of risk to quantify prognosis (JSH, 2000)

Mild hypertension

(140–159/90–99 mmHg)

Moderate hypertension

(160–179/100–109 mmHg)

Severe hypertension

(R 180/110 mmHg)

No risk factors Low risk Moderate risk High risk

At least one risk factor except

diabetes mellitus

Moderate risk Moderate risk High risk

TOD/CCD and/or DM High risk High risk High risk

TOD/CCD: Target organ damage/clinical cardiac disease, DM: Diabetes mellitus.

Fig. 2. Algorithm for the treatment of hypertension (JSH, 2000).

S. Katayama, M. Inaba / Journal of Diabetes and Its Complications 16 (2002) 87–91 89

more than 140/90 mmHg along with glycemic control and

lifestyle modification. When their blood pressure is within

the high normal (130–139/85–89 mmHg), lifestyle modi-

fication as well as glycemic control will be initiated. If their

blood pressure is not lowered to less than 130/85 mmHg

during the next 3–6 months, hypotensive agents will be

started. The target blood pressure is less than 130/85 mmHg.

ACEIs, Ca-antagonists, and a-blockers will be the first-linehypotensive agents, since these hypotensive agents improve

insulin sensitivity and do not worsen lipid metabolism.

6. Effects of hypotensive agents on insulin sensitivity

A Swedish group extensively investigated effects of

various hypotensive agents on insulin sensitivity, indicating

that ACEIs and a-blockers improve insulin sensitivity,

while thiazide diuretics and b-blockers deteriorate insulin

sensitivity (Pollare, Lithell, & Berne, 1989). We have also

demonstrated that captopril improves insulin sensitivity by

augmenting a diminished postprandial forearm blood flow

(Kodama et al., 1990). Importance of skeletal muscle blood

flow was proven by Baron et al. (1991), who demonstrated a

positive relationship of glucose disposal rate with leg blood

flow. We recently demonstrated that a long-acting dihydro-

pyridine Ca-antagonist, such as barnidipine, and a vaso-

dilatory b-blocker, such as nipradilol, which contains a

nitro-ester residue, improve insulin sensitivity (Kosegawa

et al., 1998).

Such an effect of ACEIs or Ca-antagonists on insulin

sensitivity was proven by the observation that ACEIs or

Ca-antagonists decrease the new incidence of Type 2 dia-

betes mellitus among patients with essential hypertension

without glucose intolerance. In the Captopril Prevention

Project (CAPPP) and Heart Outcomes Prevention Evaluation

(HOPE) study, ACEIs lowered the incidence of diabetes by

20–30% when compared with diuretics/b-blockers or pla-

cebo (Hansson et al., 1999; The HOPE Study Investigators,

2000). The INSIGHT study showed that the Ca-antagonist

nifedipine GITS lowered the new development of diabetes

by 23% (Brown et al., 2000).

7. Renoprotective effects of hypotensive agents

ACEIs are recommended to subjects with diabetic

nephropathy based on the Captopril Collaborative study

(Lewis et al., 1993). Recent evidences suggest that ACEIs

are effective to diminish urinary albumin excretion event at

the range of normo- to microalbuminuria not only in

hypertensives but also in normotensives (Ravid et al.,

1998; The EUCLID Study Group, 1997). Of interest are

the observations that ACEIs are more effective in delaying

the progression of diabetic nephropathy in diabetics with

elevated serum creatinine levels. In fact, subjects with the

serum creatinine levels up to 2.5 mg/dl were enrolled into

the Captopril Collaborative study. However, caution should

be paid to reducing the dosage of ACEIs for patients with

Fig. 3. Algorithm for the treatment of hypertension in diabetics (JSH, 2000).

S. Katayama, M. Inaba / Journal of Diabetes and Its Complications 16 (2002) 87–9190

impaired renal function because most ACEIs are cleared by

the kidneys. There are a few studies to demonstrate the

ameliorating effect of Ca-antagonists on renal function.

Since Ca-antagonists dilate the glomerular afferent artery,

they may increase the intraglomerular capillary pressure,

resulting in the glomerular hypertension. However, because

of their potent systemic hypotensive action, they may be

effective in delaying the progression of diabetic nephro-

pathy. This was partly supported by the result of the ABCD

study in which blood pressure was lowered to 138/86 in the

moderate control group and 132/78 in the intensive group

and no difference was observed between intensive versus

moderate blood pressure control and those randomized to

nisoldipine versus enalapril (Estacio et al., 2000). Lewis

et al. (1999) reported that target blood pressure in diabetics

with proteinuria of more than 1 g/day may be less than

125/75 mmHg (mean arterial blood pressure: 92 mmHg).

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