Critical Issues on Full-Length Articles
The following excerpt discusses the advantages of Valsartan for type II diabetic patients.  These patients
display elevated Urine Albumin Excretion (UAER), a modifiable risk factor for renal and cardiovascular disease
in type 2 diabetes that is effectively lowered by Valsartan but not Amlodipine.  Since both are blood pressure
medications, the results rule out hypertension reduction as an explanation for Valsartan's actions.  Outline the
essay by choosing the Topic Sentences in each paragraph.  Assemble these into a paragraph.  These sentences
should form a crude paragraph that flows logicically and reaches a conclusion.

Outlining Exercise

This study demonstrates that UAER was significantly reduced by valsartan in type 2 diabetic patients with
microalbuminuria. Amlodipine had no significant effects on UAER over the time period of this trial. Valsartan
also induced regression to normoalbuminuria in a significantly greater proportion of patients than amlodipine.
Importantly, BP was reduced to a nearly identical extent by both drugs. Specific analysis of the relation
between changes in BP and UAER confirmed that the differences in UAER reduction between treatment
groups were not related to differences in BP reduction. This conclusion is strengthened further by the
observation that in the normotensive subgroup valsartan but not amlodipine significantly lowered UAER despite
similar minimal and nonsignificant changes in arterial pressure. We believe the results to be of importance
because they suggest that blockade of the AT1 receptor might be used to prevent progression of albuminuria in
the absence of arterial hypertension. Even in the subgroup that achieved BP targets, the between-treatment
group differences in the reduction of UAER persisted (data not shown). These results strongly support the
notion that the albuminuria-lowering effects of valsartan are in addition to and, to a large extent, divorced from
its antihypertensive action.

Our data add new information to previous studies suggesting that lowering of BP in diabetic patients by ACE
inhibition or AT1 receptor antagonism results in greater reduction of albuminuria than that obtained with other
antihypertensive agents.  In virtually all these trials, however, the reduction in BP obtained by ACE inhibitor or
AllA was greater than that of the comparator group, and this confounded interpretation. Our findings leave little
doubt that AT1 receptor antagonism affects albuminuria also by mechanisms separate from systemic BP
changes. These may involve distinct renal effects relating to microcirculation changes, glomerular capillary wall
permeability properties, and tissue remodeling.  Angiotensin II receptor blockade also prevents the loss of
nephrin in the glomeruli of the diabetic animal, and recent data suggest that AIIAs may reduce levels of
TGF-beta in type 2 diabetic patients with microalbuminuria. There are possible alternative interpretations of our
results. Amlodipine per se, independent of its BP effect, could promote albuminuria, as suggested for other
CCBs. If this was the case, one could still argue that because of the properties of the comparator, the effect of
valsartan on proteinuria was entirely attributable to BP lowering. This interpretation, however, is unlikely.
Several publications suggest that CCBs lower UAER through a systemic BP dependent mechanism, especially
at BP reductions of the magnitude achieved in this study, though their effects may be delayed. There is no
consistent evidence that dihydropyridine CCBs have an independent proteinuria-enhancing action.  Thus, our
conclusion that the prompt and profound effect of valsartan on UAER was independent of its antihypertensive

Sixty-five percent of the whole group was found to be hypertensive at entry into the study. The observation that
valsartan reduced microalbuminuria by >40% both in the hypertensive and particularly the normotensive
subgroups is very important. Microalbuminuria in this patient population is an independent risk factor for both
renal disease and cardiovascular disease. Our study was short-term and cannot establish whether the
correction of microalbuminuria by valsartan will be translated into clinical benefit. Several studies, however, in
patients with more advanced proteinuria, with and without diabetes, have shown a clear relation between
proteinuria reduction and slowing of renal disease progression. Moreover, it is the type 2 diabetic subgroup
with microalbuminuria that appears to benefit most from ACE inhibition in terms of cardioprotection. A recent
trial in type 2 diabetic patients with microalbuminuria, all of whom had hypertension, has shown that 300 mg/d
(but not 150 mg/d) irbesartan significantly reduced UAER by 46% and lowered the risk of progression to
persistent albuminuria by 70% over a 2-year period, compared with conventional antihypertensive therapy that
excluded ACE inhibitors and dihydropyridine CCBs. These results were obtained in the face of similar average
reductions in DBP, but mean SBP, throughout the trial, was highly significantly lower by ~3 mm Hg in the 300
mg/d irbesartan group compared with placebo. This further underscores the importance of our findings in the
normotensive subgroup in which the administration of valsartan was BP neutral but highly effective in lowering

Two other trials in type 2 diabetic patients with overt nephropathy have also recently shown a renoprotective
effect of angiotensin receptor antagonism with losartan and irbesartan that appears largely though not entirely
independent of BP reduction, underscoring the therapeutic relevance of other mechanisms of action, of which
proteinuria lowering is likely to be an important one, of this class of compounds.

In conclusion, valsartan significantly reduces microalbuminuria in type 2 diabetic patients, an effect that appears
to be independent of its BP-lowering action.
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