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Table 2. How antihypertensive agents may be combined in diabetes b-Blockers ACE inhibition or angiotensin Yes (diuretics often required) Yes (diuretics Yes often required) Yes (theoretically interesting combination, results promising) receptor blockers Ca blockers1 Yes (diuretics often required) Diuretics Yes (rarely used) b-Blockers Yes (rarely used) b-Blockers + diretics Yes (often used; also with diuretics) ACE inhibition CarefulclinicalmetabolicandBPmonitoringalwaysrequired,includingcontrolofserumelectrolytesand serum creatinine of GFR index (combination therapy used in more than 50% of patients). 1 Some results suggest cardiovascular long-term eVect less favorable than with ACE inhibition in type 2 diabetes. ever, since these phenomena may not point clearly to specific modalities of treatment, they will not be further discussed. TreatmentofBPElevation Mechanisms of BP Elevation and Choice of Therapy in Nephropathy Based upon the known mechanisms operating in the genesis of hyperten- sion, some interesting concepts regarding selection of antihypertensive treat-ment are evolving in diabetes. The abnormalities in renal function, where hyperfusion, hyperfiltration and increased glomerular pressure may be impor-tant mediators, favor the use of ACE inhibitors, since these agents tend to reduce eVerent glomerular resistance. This eVect, operating by reducing glomerular pressure, may even to some extent be independent of systemic hypertension or systemic BP level. The sodium retention evident in both type 2 and type 1 diabetes supports the use of diuretics and sodium restriction in antihypertensive programs in diabetes. The early cardiac hyperfunction in microalbuminuric patients may suggest the use of cardioselective b-blockers to reduce this hyperfunction. Obviously, the generalized BP reduction seen with all these agents may be of prime importance, but these mechanisms could also favor the use of combined treatment: ACE inhibitors, diuretics and possibly b1-blockers (or other agents) in diabetic patients (table 2). Calcium blockers reduce BP, and may be important in therapy although some, but decreasing, controversy exists. Mogensen 162 Table 3. Diabetes-related side eVects and favorable eVects related to antihypertensive treatment in diabetics (mainly type 1 diabetes) Diuretics (thiazide Noncardio-or loop) selective b-blockers Cardioselective ACE inhibitors b-blockers Triple treatment: diuretic b1-blockers/ ACE inhibitors Calcium blockers Angiotensin receptor blockers Glucose intolerance Yes, type 2, but No problem No problem related strongly to hypokalemia) No side eVects Limited or no change No No Insulin sensitivity (with small dosages) not changed clinically Hypoglycemic No masking Yes, mainly in type 1 diabetes A problem, but Not seen limited, seen in few patients Limited or no change No No (with small dosages) Unfavorable lipid profits Yes, but not with Likely small doses Limited or No side eVects ? No No nonexisting Other unfavorable eVects May cause sodium depletion Less physical exercise capacity Less physical Coughing and Limited (with exercise capacity drug-related side small dosages) eVects (uncommon) Foot edema seen No in few patients Favorable eVects (apart from BP reduction) Elimination of edema Reduction of Reduction of cardiovascular cardiovascular morbidity/ morbidity/ mortality mortality Normalization Normalization of cardiac of cardiac arrhythmias? arrhythmias? Elimination Probably also sodium excess combination of and possibly favorable eVects restoration of (stable GFR?) glomerular pressure gradients No potentiation of peripheral ischemia? Under investigation EVect on abnormal albuminuria Not well documented Not well documented Yes, but relatively Very consistent few studies exist finding Addition of ACE Related to BP Yes inhibition reduces reduction abnormal albuminuria Reducing fall rate of GFR Not documented Not Yes Yes documented GFR stable on this program Not documented Ungoing studies Obviously, from a theoretical point of view, potential additional beneficial eVect should be considered (table 3). For example, ACE inhibitors may as suggested specifically reduce the localized increased pressures seen in these patients, as originally observed in animal studies. The presence of edema of course favors the use of diuretics. It is suggested that arrhythmias may play a role in the early mortality, especially in type 2 diabetic patients, and the observation that in trials in patients at risk b-blockers are especially eVective in diabetic patients points to additional beneficial eVects of b-blockers in the management of hypertension in diabetics where cardial disease and silent myocardial infarctions are not uncommon. Importantly, in heart failure b-blockers are increasingly being used according to new trials, e.g. the Merit HF Study. Clearly, side eVects are important and these are usually dose related. For example,thewell-knowndiabetogeniceVectofdiureticsmaybedosedependent with suYcient BP reduction with small doses that are not diabetogenic. Potas-sium loss is important but can readily be restored by potassium supplemen-tation or by the use of ACE inhibition. Also small doses of diuretics may Nephropathy and Hypertension in Diabetic Patients 163 not impair lipid parameters. A side eVect that has caused some concern is hypoglycemic unawareness. This was previously reported with unselective b-blockers but is only of minor importance with cardioselective b-blockers and thephenomenonisnotimportantin type2diabeticsthatmayespeciallybenefit from cardioprotection by b-blockers. Most ACE inhibitors do certainly not possess any diabetogenic eVects, rather they are neutral. Thus there is no negative eVect on glucose metabolism or lipid homeostasis; a positive eVect has in fact been observed in some studies. This positive or rather neutral pattern may therefore favor the use of ACE inhibitors in diabetic patients. Importantly,noincreasedfrequencyofhypoglycemiaisseeninclinicalpractice. Coughing as a side eVect is surprisingly rare in diabetic patients, possibly due to diabetic neuropathic changes. The new angiotensin II receptor antagonists could be considered in this situation, also with other side eVects caused by ACE inhibitors. Problems of Optimized Glycemic Control During Antihypertensive Treatment In recent years it has become increasingly clear that good glycemic control is of clear importance in the prevention and postponement of diabetic renal disease. As documented in the DCCT, good glycemic control can reduce the number of patients that develop advancing renal disease. Improved metabolic control seems also to protect against deterioration in renal function in patients with microalbuminuria. However, it is important to stress that it is quite often diYcult to obtain good metabolic control, especially in patients with incipient or overt renal disease. There are no formalized long-term trials with a suYcient number of patients on the eVect of optimized diabetes care in patients with overtrenaldisease.However,newstudiesstronglysuggestacorrelationbetween progression in renal disease, as measured by fall rate of GFR and level of HbA1c. If HbA1c is satisfactory, with values around 7–8% (reference value 5.5%),progressionisslow.Thisobservationwasrecentlyconfirmed.Inpatients with type 2 diabetes, progression can be reduced by early intervention. With overt nephropathy there is no correlation between progression and HbA1c. The UKPDS clearly documented the role of good glycemic control in preventing microvascular complications. Intervention Trials in Normoalbuminuria Even in type 1 diabetic patients with normal BP and normal albumin excretion, renal hemodynamics may be beneficially influenced by ACE inhibi-tion. This study was of experimental nature and treatment of such individuals cannot be recommended, although a trial should be conducted in high-risk normoalbuminuric patients (high normal UAE (?12 lg/min), high HbA1c Mogensen 164 (?9–10%)). However, the Euclid Study did not document any clear eVect in normoalbuminuria in a 2-year trial, but longer intervention is likely to be positive, according to unpublished studies from Denmark. MicroalbuminuriaandAntihypertensiveTreatment Severalinterventionstudieshavebeenpublished,somewithself-controlled or crossover design, some double-blinded without being long term and some long term and randomized without being blinded. All these trials generally showedareductionorastabilizationinmicroalbuminuria.Inarecentrandom-ized double-blind large-scale placebo-controlled study, the eVect of an ACE inhibitor was investigated with respect to progression to clinical nephropathy in normotensive type 1 diabetic patients with microalbuminuria. The major endpoint was the progression to persistent proteinuria (UAER ?200 lg/min). In this large study, treatment delayed the progression to overt renal disease in normotensive, type 1 diabetic patients with microalbuminuria. Interestingly, in all these studies confirmed from 1985 to 1999, patients were included purely on the basis of microalbuminuria and indeed in most studies patients should not be hypertensive (often an exclusion criterion for participation). Therefore, in most studies BP was close to normal, and in some of the patients BP was in the middle of the range as seen in healthy young individuals(meanarterialpressureB90 mm Hg).Thereseemstobeatendency towards a correlation between reduction in BP and reduction in albuminuria. The clinical consequence is that the indication for antihypertensive treat-ment should be microalbuminuria (as in the clinical trials) rather than some elevation of BP (fig. 2). Obviously any elevation of BP or any increasing BP would further strengthen the indication, because there is a correlation between rate of progression of microalbuminuria and BP; still the conclusion from these studies would mean that antihypertensive treatment should be initiated whenever microalbuminuriais consistentlyfound. Amore cautiousview would be to start antihypertensive treatment if microalbuminuria is clearly increasing (5–10% per year), but the variability in UAE makes this approach somewhat diYcult in the practical clinical setting. All studies document a reduction or stabilization in microalbuminuria, irrespective of the treatment used; however, most studies were conducted with ACE inhibitors as the principal agent with few or no side eVects. Diuretics were systematically added in one important study. Thus the scenario for the use of antihypertensive treatment, in particular ACE inhibitors, is moving from the indication of elevated BP to the indication of increased or increasing UAE as proposed in recently published guidelines. Combination therapy is also very useful in such patients. Nephropathy and Hypertension in Diabetic Patients 165 Fig. 2. Microalbuminuria (MA) in type 1 diabetic patients below 60 years of age. New studies suggest similar eVects in the relative young and lean type 2 diabetic patients. A/C>Albumin/creatinine ratio. Modified from Mogensen et al. In type 2 diabetic patients, microalbuminuria can be reduced by ACE inhibition and two long-term studies suggest a beneficial eVect on GFR. The fall rate of GFR correlates to BP. This important topic has recently been reviewed by Cooper and McNally, and ACE inhibition as early treatment seems equally important in type 1 and type 2 diabetes. Mogensen 166 ... - tailieumienphi.vn
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