**10. Etiology of chronic diabetes complications**

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

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

this.

138 Treatment of Type 2 Diabetes

The cause of diabetic complications is still unknown and probably multifactorial. Chronic complications of DM affect many organ systems and are responsible for the majority of morbidity and mortality. Special attention must be given to the metabolic conversion of glucose to sorbitol. This one is implicated in the pathogenesis of neuropathy, retinopathy, aortic disease, nephropathy and lens damage (cataracts). Another mechanism of possible pathoge‐ netic relevance is glycation of proteins. The effect of glycation on hemoglobin is well known; in addition, other proteins are altered by the same mechanism such as plasma albumin, fibrin, collagen, lipoproteins, and low protein. Retinopathy, nephropathy and neuropathy are considered common disorders of microvascular complications; and stroke, gangrene, and myocardial infarction for macrovascular complications [table 4].
