**9. Circulatory changes**

We recognize hypertension and DM as common disorders, but there is much evidence to suggest that the two occur together more frequently than by chance. Development of hyper‐ tension greatly worsens the prognosis of diabetic patients. Raised BP accelerates the progress of diabetic nephropathy, and possibly retinopathy, while the harmful cardiovascular effects of the two disorders are at least additional. There are a number of reasons why hypertension and diabetes may be associated, and these are discussed in this contribution.

Life expectancy is reduced in diabetic patients, both insulin-dependent (IDDM) and noninsulin dependent (NIDDM), and the leading causes of death are cardiovascular complica‐ tions. The excess mortality cannot be explained by the diabetic state *per se*. Based on the Whitehall study of more than 17.000 civil servants followed for 15 years, Jarrett and Shipley suggested that diabetes and cardiovascular disease may not be causally linked at all but might rather share a common, possibly genetic antecedent. Among the known risk factors for cardiovascular disease in diabetes, hypertension has attracted much interest. The prevalence of hypertension is increased in diabetic patients, IDDM and NIDDM, and hypertension is known to be a powerful risk factor for cardiovascular disease in diabetes, insulin treated or not.

It's well known that hypertension has also a consistent relation to coronary heart disease and other risk factors which are not only found by the presence of proteinuria. Furthermore, the clinical significance of hypertension as an important risk factor was recently strongly sup‐ ported by two independent studies on IDDM patients, demonstrating an improved survival rate in the decade following the introduction of efficient antihypertensive drugs.

**8.1. Diabetic retinopathy**

136 Treatment of Type 2 Diabetes

**8.2. Renal disease**

**9. Circulatory changes**

not.

proliferans (scar) and retinal detachment.

Is a relevant cause of blindness; however a high number of diabetic patients never lose the vision. When the occlusion of retinal capillaries occurs, it results in a subsequent formation of saccular and fusiform aneurysm and arteriovenous shunt. Hemorrhages into the inner retinal surface are dot-shaped; conversely, bleeding into the superficial larger nerve fiber produces flame-shaped, blot-shaped or linear lesions. Cotton-wool spots can be observed by angiogra‐ phy, and sudden increase of the number of these lesions has an ominous prognostic sign and is the beginning of rapid progress of retinopathy. Hard exudates are common findings and are probably related to leakage of protein and lipids from damaged capillaries. The lesions must be summarized into two categories: *simple* (microaneurysms, dilated veins, hard exudates, arteriovenous shunts, hemorrhage, cotton-wool spots, increased capillary permeability and capillary closure, and dilation) and *proliferative*: new vessels, vitreous hemorrhage, retinitis

Despite the worldwide importance of diabetic nephropathy as a cause of mortality and morbidity, many questions still remain about treatment aimed at delaying its harmful effects [22, 23]. So far, there is little scientific evidence to support strict glycemic control at this stage, although common sense dictates that wild swings of control should be avoided. Protein

We recognize hypertension and DM as common disorders, but there is much evidence to suggest that the two occur together more frequently than by chance. Development of hyper‐ tension greatly worsens the prognosis of diabetic patients. Raised BP accelerates the progress of diabetic nephropathy, and possibly retinopathy, while the harmful cardiovascular effects of the two disorders are at least additional. There are a number of reasons why hypertension

Life expectancy is reduced in diabetic patients, both insulin-dependent (IDDM) and noninsulin dependent (NIDDM), and the leading causes of death are cardiovascular complica‐ tions. The excess mortality cannot be explained by the diabetic state *per se*. Based on the Whitehall study of more than 17.000 civil servants followed for 15 years, Jarrett and Shipley suggested that diabetes and cardiovascular disease may not be causally linked at all but might rather share a common, possibly genetic antecedent. Among the known risk factors for cardiovascular disease in diabetes, hypertension has attracted much interest. The prevalence of hypertension is increased in diabetic patients, IDDM and NIDDM, and hypertension is known to be a powerful risk factor for cardiovascular disease in diabetes, insulin treated or

It's well known that hypertension has also a consistent relation to coronary heart disease and other risk factors which are not only found by the presence of proteinuria. Furthermore, the

restriction may have a role but the studies to support this have not been forthcoming.

and diabetes may be associated, and these are discussed in this contribution.

Hypertension is a community problem everywhere with hazardous solution. It is the major risk factor for development and progression of the disease in non-diabetic and diabetic chronic kidney disease. About one billion people worldwide have high BP (defined as > 140/90 mmHg), but the number is higher considering the present criteria of >130/80 mmHg, and it is expected to increase up to 1.56 billion patients by 2025. The predicted prevalence of hypertension will increase by 24 per cent in developed countries.

Hypertension control rate, defined as BP level < 130/80 mmHg, is substantially lower in patients with CKD, particularly in those with diabetes and chronic renal failure. This is illustrated by the National Kidney Foundation's (USA) Kidney Early Evaluation Program (KEEP), a US-based health screening program for individuals at a high risk for kidney disease.

Hypertension is the most prevalent cardiovascular disease in the world and a major public health issue. Cardiovascular disease is the leading cause of mortality worldwide and is expected to increase with the general ageing of the world's population. The goal of antihypertensive therapy is to reduce the incidence of blood pressure-related morbid events and cardiovascular mortality.

It is well established that heart is an important target organ in hypertension. Continuous high BP level is associated with myocardial problems, such as left ventricular hypertrophy and increases the burden of coronary artery disease (CAD). These forms of damage may result in congestive heart failure, CAD manifestations, arrhythmias and sudden cardiac death. The event rates of cardiovascular disease in Japan, for example, differ from those in Europe and the United States. Mortality from CAD in the Japanese country is one-third that of the United States, and mortality from cerebrovascular disease is 1.5 times higher in Japan than that reported in the United States. Hypertension is the most common cause of disease and is even more prevalent in the Japanese population than in the Western countries. The percentage of cerebral bleeding is two or three times greater than in Caucasian people from Europe and the United States, and cerebral infarction is mostly caused by lacunar type ischemic stroke owing to hypertensive small vessel disease. The incidence of athero-thrombotic infarction or cardioembolic infarction is currently increasing in Japan, and the dominant pathogenetic factor for stroke is changing from small arterial disease to large arterial disease in Japanese hypertensive patients. These differences may be partly explained by differences in the lifestyle of Japanese and Western populations, which are reflected in body mass index (mean BMI: 23.25 and 28-30 kg/m2 , respectively). However, most of mortality-morbidity trials have been carried out in the Western countries, in which none or only a minority of East Asian patients were included. Owing to the scarcity of large-scale trials in East Asian people, it remains to be determined whether the results from similar clinical trials in Western societies are internationally appli‐ cable to East Asian races or the Japanese population, or whether genetic background can cause different pharmacokinetic and pharmacodynamic responses to the same drug.

There is a clear and substantial evidence in juvenile onset IDDM that strict BP control by reducing and maintaining levels under 130/80 mmHg or a mean arterial pressure of 105 mmHg remains the only effective treatment for the physician to try to slow the development of end stage renal failure and the need for renal support. In practical terms, the use of a combination of drugs including diuretics will be often required. The newer classes of drugs such as ACE inhibitor or calcium channel blockers have a clear advantage in their side-effect profile over betablockers in diabetics, because they are safer and better tolerated. The primary goal remains effective in BP control and often beta-blockers may need to be added to the regime to achieve this.

In patients with IDDM aged older than sixty and in diabetics with nephropathy who are noninsulin dependent, there is no definitive scientific evidence that prognosis is improved and that the progression to end stage disease is slowed after antihypertensive treatment. It is reasonable for the physician to assume that aggressive treatment of BP in this group is justified from data of several studies in younger patients. A crucial question remains about the degree of BP reduction required and in particular whether it is necessary or indeed harmful to aggressively reduce systolic BP in this group. Accurate long-term clinical trials with measure‐ ment of cardiovascular end points as well as the slowing of GFR decline and reduction of proteinuria need to be carried out. Indeed, it is important to reach normal BP levels especially on the stage of incipient nephropathy in order to obtain better therapeutic results in patients.

Large scale, long-term multicenter studies in both IDDM and NIDDM patients with protei‐ nuria will be required to give a clear answer to the question of whether there is a selective benefit of the ACE inhibitor group over a suitable hypotensive agent such as a calcium channel blockers. So far, there is some evidence that ACE inhibitors used in the evolution of nephrop‐ athy or when employed later in combination with diuretics are effective in reducing protein excretion which may be separate from their BP lowering capacities. These data, make them a reasonable choice in the antihypertensive regime of diabetics with nephropathy. This property to reduce proteinuria without reducing BP has not been shown with any other antihyperten‐ sive agents and until and unless such evidence is forthcoming, the careful use of ACE inhibitors in combination with diuretics can be recommended in diabetic nephropathy. As many of these patients will have occult or manifest cardiovascular dysfunction, this approach may be beneficial also in improving cardiac performance. Future studies, especially in non insulindependent patients should evaluate the potential benefit of reducing morbidity and mortality from cardiovascular disease with the newer antihypertensive drugs, such as ARA II.

Coexisting hypertension and diabetes act as additive risk factors to accelerate vascular complications. The incidence of coronary and cerebral vascular diseases is much higher in hypertensive than in normotensive diabetic patients. Mortality rates in diabetic patients with systolic BP exceeding 160 mmHg is four times higher than that of other diabetic individuals. Whereas antihypertensive therapy has been clearly shown to retard deterioration of renal function and urinary albumin excretion, evidence that pharmacological control of BP reduces overall mortality in the diabetic population without overt nephropathy is strikingly lacking. Thus, current recommendations for drug intervention in diabetics with hypertension rely on data derived from the general hypertensive population. Specific adjustments in drug selection and dosage need to be made for drug effects which might be of particular significance in the diabetic patient. Nevertheless, a recent alarming retrospective study from the Joslin Clinic demonstrated that antihypertensive treatment is associated with a marked increase in cardiovascular mortality in diabetic hypertensive patients. The most obvious implication of this finding is the need for large scale prospective studies in diabetic hypertensive individuals to assess the risks and benefits in treating hypertension in this population. Some of the newest strategies for BP control must be examined and compared with these retrospective findings. Until further information becomes available, much attention should be given to careful drug selection, therapy monitoring, and judicious and continuous assessment of coexisting risk factors in the course of treatment of high BP in diabetes.
