Treatment of HTN in Adult DM

1
Treatment of HTN in Adult DM

• ? ? ? ? ?
• ???????????
• Reference DM Care 25134-147, 2002

2
Outline

• INTRODUCTION
• SECTION I DEFINITION, PREVALENCE, AND
  PATHOPHYSIOLOGY
• SECTION 2 MANAGEMENT OF HTN IN DM
• SECTION 3 REVIEW OF PHARMACOLOGICAL AGENTS IN
  THE MANAGEMENT OF HTN IN DM
• COST-EFFECTIVENESS
• CONCLUSIONS
• SUGGESTIONS FOR FUTURE RESEARCH

3
INTRODUCTION

• HTN extremely common comorbidity of DM,
  affecting 2060 of DM a major risk factor for
  CV events and microvascular complications.
• CV disease the most costly complication of DM ,
  cause 86 of deaths in DM.
• Recent studies support aggressive approach to
  diagnosis and treatment of HTN with DM in order
  to substantially reduce incidence of both
  macrovascular and microvascular complications.

4
Definition of HTN in DM populations (1)

• Studies in general population indicate increase
  DBP or SBP 5 mmHg is associated with increase CV
  disease 2030.
• Studies in DM populations markedly higher
  frequency of progression of DM retinopathy when
  DBP excess 70 mmHg .

5
Definition of HTN in DMpopulations (2)

• 1997, the JNC VI recommended a lower target for
  DM (130/85 mmHg) than general population (140/90
  mmHg). Standard definition of HTN is BP 140/90
  mmHg . Evidence clinical trials in DM suggests a
  continuum of risk and significant benefit in
  outcomes with BP below 140/80 mmHg.
• For elderly populations with systolic HTN,
  benefits when BP below 140 mmHg .
• Epidemiological studies benefit to reduce SBP
  130 mmHg or below.
• Goal for BP 130/80 mmHg.

6
Prevalence (1)

• Prevalence of HTN in DM population is 1.53 times
  higher than that of non DM age-matched groups.
• In type 1 DM, HTN develops after several years
  and usually reflects development of DM
  nephropathy. It ultimately affects 30 of
  individuals with type 1 DM.
• In type 2 DM, HTN may be present at the time of
  diagnosis or even before the development of
  hyperglycemia.

7
Prevalence (2)

• Type 2 DM pts are older and have a greater
  degree of adiposity than nondiabetic.
• Prevalence of HTN in Western populations
  increases with age and degree of obesity.
  Elevated BP in these individuals may represent
  the aging or obesity.
• After adjusting for age and weight, prevalence of
  HTN is still 1.5 times higher in DM groups.
• 2060 of type 2 DM will develop HTN, depending
  on age, ethnicity, and obesity.

8
Pathophysiology (1)

• In presence of nephropathy, extracellular fluid
  volume and total body Na levels are increased.
  The activity of the renin-angiotensin-aldosterone
  system (RAAS) is reduced, and HTN is
  volume-dependent, similar to other nephropathies
  .
• In absence of DM nephropathy, other factors must
  play a role in development of HTN. These factors
  are both genetic and acquired. Elevated total
  body Na with low or normal activity of the RAAS
  has been reported .

9
Pathophysiology (2)

• Studies have found hyperinsulinemia secondary to
  insulin resistance and decreased insulin
  clearance .
• Hyperinsulinemia may be associated with increased
  renal Na resorption and SNS overactivity, leading
  to HTN in obese individuals and other
  insulin-resistant states, such as type 2 DM.
• Insulin resistance is also associated with a
  decreased vasodilatory response to insulin in
  skeletal muscle and an increased vasoconstrictor
  response to various vasopressors.

10
Screening and initial evaluation (1)

• All DM should have BP measured when diagnosis or
  initial office evaluation and at each scheduled
  DM visit.
• Because high CV risk with BP 130/80 mmHg in DM,
  130/80 mmHg is considered to the cut point for
  defining HTN, rather than 140/90 mmHg, as in the
  general population.
• Initial assessment should include a complete
  medical history with special emphasis on CV risk
  factors and DM complications and other CV
  complications.

11
Screening and initial evaluation (2)

• Measurement of BP in supine and standing
  position.
• Two or more determinations in each position
  should be obtained using an appropriately sized
  cuff obese require a large arm cuff and
  sometimes a thigh cuff to ensure accuracy.
• CV autonomic neuropathy with significant
  orthostatic changes is common in DM can cause
  falsely low or high readings, depending on the
  position when the BP is taken and should be
  considered when treating pts.

12
Screening and initial evaluation (3)

• Dx should be reserved for those individuals whose
  BP levels exceed 130/80 mmHg on at least two
  separate occasions separated by at least 1 week.
• P.E. should include height, weight, funduscopic
  examination, and careful evaluation of arterial
  circulation.
• Lab. examination should include serum Cr,
  electrolytes, A1C test, fasting lipid profile,
  and UAE.

13
Behavioral treatments of HTN (1)

• Dietary management with moderate Na restriction
  is effective in reducing BP in individuals with
  essential HTN.
• Controlled studies have looked at the
  relationship between weight loss and BP
  reduction. Weight reduction can reduce BP
  independent of Na intake and improve blood
  glucose and lipid levels.
• Loss 1 kg BW decreases in mean arterial BP 1
  mmHg.

14
Behavioral treatments of HTN (2)

• Some appetite suppressants, both prescription and
  over-the-counter, may increase BP and be careful.
  
• Phenylpropanolamine, increased risk of
  hemorrhagic stroke in women and has been taken
  off the market however, pts may still have
  supplies of this drug.
• Weight reduction an effective measure in
  initial management of mild-to-moderate HTN, and
  results could most likely be extrapolated to DM
  hypertensive population.

15
Behavioral treatments of HTN (3)

• Na restriction has not been tested in DM
  population in controlled clinical trials.
• Controlled trials in essential HTN have shown a
  reduction of 5 mmHg for SBP and 23 mmHg for
  DBP, with moderate Na restriction ( 200 mmol
  4,600 mg to 100 mmol 2,300 mg of Na per day).
  
• A dose-response effect has been observed with Na
  restriction. Reductions in daily Na intake to
  1020 mmol (230460 mg) per day have resulted in
  decreases in SBP of 1012 mmHg .

16
Behavioral treatments of HTN (4)

• Moderately intense physical activity, such as
  3045 min of brisk walking most days of the week,
  and smoking cessation and moderation of alcohol
  intake can lower BP and is recommended in JNC VI
  .
• Several trials analyze effects of Ca
  supplementation on BP levels. A meta-analysis
  published in 1990 reported a very small BP change
  ( mean reduction in SBP 1.8 mmHg and DBP 0.7
  mmHg).
• No randomized clinical trials on Mg
  supplementation in DM subjects with HTN.

17
Drug therapy

• All available agents produce similar reduction in
  BP at the doses available for clinical use (1015
  mmHg in SBP and 510 mmHg in DBP).
• The differences are usually small.
• Many studies published various antihypertensive
  agents effect on metabolic parameters, including
  lipids, glucose levels, and insulin resistance.

18
REVIEW OF PHARMACOLOGICAL AGENTS IN THE
MANAGEMENT OF HTN IN DM

• The most commonly antihypertensive agents
  available in the U.S. and their classification
  are presented in Table 1.
• At the doses available for clinical use, most
  antihypertensives will produce a reduction in SBP
  or DBP of 510 in mild or moderate HTN.

19
Thiazide diuretics (1)

• Reduce total body Na through natriuretic action
  and have vasodilatory effects.
• 2550 mg hydrochlorothiazide associated
  hypokalemia, hyponatremia, volume depletion,
  hypercalcemia, and hyperuricemia.
• K supplementation as clinically indicated.
• Efficacy in reducing risk of stroke and CHF in
  large randomized clinical trials including
  mild-to-severe HTN.
• In elderly isolated systolic HTN, thiazides
  decreased CV morbidity.

20
Thiazide diuretics (2)

• Evidence suggests increased CV mortality in DM
  receiving diuretics, not randomized, and
  significant baseline differences between
  diuretics and not receiving them may have
  existed. These studies were based on data
  collected in 1970s, when high-dose diuretic
  treatment was the norm.
• SHEP study showed low-dose thiazide for systolic
  HTN in older DM subjects had a significant
  reduction in CV events.
• Thiazides may not be effective when significantly
  decreased renal function (i.e., GFR lt 60 ml
  min-1 1.73 m-2).
• The effects on early or advanced DM nephropathy
  have not been studied in large randomized
  clinical trials.

21
Thiazide diuretics (3)

• Insulin sensitivity has been measured in DM pts
  receiving thiazides. Hydrochlorothiazide 25 mg/d
  or bendrofluazide 1.25 mg/d does not
  significantly decrease insulin sensitivity.
• Bendrofluazide 5 mg/d caused a significant
  reduction of in vivo insulin sensitivity.
• Low-dose chlorthalidone combined atenolol had low
  insulin sensitivity and increased TG, clinical
  significance unknown.
• In diuretic-based therapy, low-dose thiazide
  reduced CV event rate 34 compared with placebo
  the absolute risk reduction was twice for DM
  versus non-diabetic.

22
Loop diuretics

• Mechanism of loop diuretics is related to
  significant decrease in total body Na although
  acutely, these agents also act as vasodilators.
• Furosemide combined ß- blockers was mainstay
  regime in a study reported by Parving et al. in
  DM nephropathy------significant reduction in
  deterioration of GFR in type 1 DM treated with an
  aggressive antihypertensive regimen.
• Loop diuretics can induce hypokalemia,
  hyponatremia, and volume depletion. Use when GFR
  lt60 ml min-1 1.73 m-2, usually combined with
  other agents.

23
Adrenergic blockers - Centrally acting agents

• Effectively lower BP by decreasing central
  sympathetic outflow.
• Effects on microvascular complications or CV
  disease have not been studied in detail.
• Associated with orthostatic hypotension, and use
  with caution in CV autonomic neuropathy.
• Common side effects drowsiness, impotence, and
  dry mouth. Less common effects depression and
  Coombs-positive anemia (with ?-methyldopa).

24
Adrenergic blockers - ß-Blockers (1)

• Nonselective ß-blockers inhibit B1- and
  B2-receptors.
• Selective ß-blockers predominantly inhibit
  B1-receptors .
• Reduction of deterioration of GFR in type 1 DM
  nephropathy used ß-blockers and diuretics,
  frequently with other drugs .
• In three randomized studies in DM hypertensive
  pts in which proteinuria was examined , atenolol
  (a selective ß-blocker) produced similar
  reductions in proteinuria compared with ACEI.
• In a long-term study (43 pts followed for 3.5
  yrs), atenolol and lisinopril produced similar
  reductions in the decline of GFR in type 2 DM
  nephropathy.

25
Adrenergic blockers - ß-Blockers (2)

• In UKPDS-HDS, atenolol and captopril were
  equally effective in decreasing risk of
  DM-related end points (pooling of microvascular
  and CV complications) and microvascular events in
  type 2 DM.
• In some pts, atenolol was associated with modest
  weight gain, the development of side effects
  (e.g., cold extremities, intermittent
  claudication, bronchospasm) and a slightly lower
  compliance rate.
• ß-Blockers have efficacy in MI with relative
  reductions in mortality of 25.

26
Adrenergic blockers - ß-Blockers (3)

• Because DM with MI have a much higher mortality
  than non DM, the absolute benefit of a given
  relative reduction may be greater in DM pts.
• A long-standing concern about effect of
  ß-blockers on the perception of and recovery from
  hypoglycemia, which may be blunted or prolonged
  by these agents.
• Nonselective ß-blockers decreased
  counter-regulatory responses to hypoglycemia,
  particularly in pts taking insulin .

27
Adrenergic blockers - ß-Blockers (4)

• It is unknown this effect is clinically
  important UKPDS study did not show increased
  incidence of hypoglycemic episodes with
  ß-blockers.
• Avoid ß-blockers in insulin-using pts who have a
  history of severe hypoglycemia.
• In other pts with DM, especially with a recent
  MI where the benefits are clearly proven,
  benefits of ß-blockers outweigh the potential
  risks.

28
Adrenergic blockers - a-blockers (1)

• Inhibitors of a-postsympathetic adrenergic
  receptors.
• Antihypertensive effects are similar to other
  groups.
• No long-term randomized clinical trials examining
  renal or CV outcomes have been published.
• Improved insulin sensitivity in insulin
  resistance associated with essential HTN .
• A slight decrease in LDL in small short-term
  clinical studies, all involving lt25 pts per
  group . Clinical significance of these findings
  is unclear.

29
Adrenergic blockers - a-blockers (2)

• Initial doses of these agents, particularly
  prazosin, associated with orthostatic
  hypotension, caution in DM autonomic neuropathy.
• The Antihypertensive and Lipid-Lowering Treatment
  to Prevent Heart Attack Trial (ALLHAT) study had
  an arm comparing ?-blocker (doxazosin) with
  ß-blocker, Ca-blocker, and ACEI versus diuretic.
• Recently, this part of the study was terminated
  because increased incidence of CV events,
  specifically CHF, in pts receiving ?-blocker.
  Separate results for DM pts were not reported .

30
Ca channel blockers (1)

• Inhibit Ca influx through membrane-bound
  voltage-dependent Ca channels, decrease
  intracellular Ca levels and vasodilation three
  subclasses with significant differences in
  hemodynamic effects.
• The dihydropyridine group (DCCBs) has mainly
  vasodilatory effects and relatively small effects
  on cardiac inotropism or AV conduction. Reflex
  tachycardia can be seen, and edema is the most
  common side effect.
• Many drugs in this group and pharmacokinetic
  differences between agents and pharmacological
  preparations of a single agent exist. Difficult
  to assess and generalize results of clinical
  studies with DCCB agents.

31
Ca channel blockers (2)

• The second group, the benzothiazepines, have
  moderate vasodilatory effects and moderate
  negative inotropic and chronotropic effects.
  Diltiazem is the only agent available, and
  several preparations with different
  pharmacokinetic profiles exist.
• The third group, the phenylalkylamines, has
  similar vascular and cardiac effects as
  diltiazem. Verapamil is the only agent available
  in U.S. , in slow- and rapid-release forms with
  different pharmacokinetics.
• Diltiazem and verapamil are referred to as
  NDCCBs.

32
DCCBs (1)

• Effective antihypertensive agents.
• Conflicting evidence exists regarding safety and
  efficacy in reducing CV end points. Benefit in
  decreasing CV events in hypertensive DM p'ts has
  been shown in Syst-Eur and HOT trials. However,
  in both trials most p'ts were also receiving a
  ß-blocker or an ACEI to achieve the goals.
• It is difficult to judge effectiveness of
  monotherapy with these drugs in reducing CV end
  points.
• ABCD and FACET studies suggest a greater benefit
  of ACEIs over DCCBs with respect to CV events.

33
DCCBs (2)

• A retrospective analysis of short-acting
  nifedipine, not approved for HTN tx in U.S.,
  suggested an increase in CV mortality.
  Short-acting dihydropyridines are not approved or
  labeled for treating HTN and should not be
  prescribed for that purpose.
• A recent meta-analysis suggests that Ca-blockers
  may be equivalent in protecting against stroke
  but less effective in reducing MI and combined
  major coronary events than ACEIs, ß-blockers, or
  diuretics.
• All-cause mortality was found to be equivalent
  among all classes of drugs given equivalent
  control of BP, not affected by the presence of
  DM.

34
DCCBs (3)

• One study with nifedipine has shown an increase
  in proteinuria in DM nephropathy , but long-term
  effects of this agent on renal function are
  unknown.
• Whereas other studies have not found significant
  differences between DCCBs and other agents, a
  recent study by Lewis et al. found amlodipine to
  be no different from placebo regarding the
  progression of nephropathy and inferior to
  irbesartan, an ARB.
• In general, DCCBs seem to have a neutral effect
  on metabolic parameters.

35
NDCCBs (benzothiazipines and phenylalkylamines)

• Small studies of short duration using diltiazem
  and verapamil have been associated with decreased
  proteinuria in p'ts with overt DM nephropathy.
• But long-term studies showing a reduction in the
  rate of fall of GFR have not been carried out.

36
ACE inhibitors (1)

• Useful in management of HTN in DM p'ts with or
  without DM nephropathy.
• UKPDS-HDS showed similar beneficial effects of
  captopril and atenolol on DM-related mortality
  and microvascular and CV complications in type 2
  DM.
• Effective in decreasing CV mortality and
  morbidity in CHF and postMI. ACEIs have been
  extensively studied in DM nephropathy and
  effective in preventing progression of
  retinopathy.

37
ACE inhibitors (2)

• Recent HOPE trial documented decreased CV end
  points despite quite minor changes in BP raises
  the possibility that ACEIs have benefits
  independent of antihypertensive effect. Whether
  this is a class effect or an effect specific to
  ramipril is unknown.
• Postulated mechanisms include effects on
  endothelium as a result of decreased vascular
  smooth muscle growth, decreased release of
  endothelin, increased fibrinolysis, and release
  of vasodilating substances nitric oxide and
  prostacyclin mediated by bradykinin.

38
ACE inhibitors (3)

• The most common side effects cough and,
  occasionally, acute decreases in renal function.
• Hyperkalemia can be seen, especially in p'ts with
  renal insufficiency, bilateral renal artery
  stenosis, hyporeninemic hypoaldosteronism.

39
ARBs

• Angiotensin receptor blockers (ARBs) have been
  shown to retard progression of albuminuria and
  development and progression of nephropathy.
• Losartan, ibesartan, telmesartan, candesartan,
  eprosartan, and valsartan are effective
  antihypertensive agents.
• Decrease proteinuria and have renoprotective
  effect independent of any BP-lowering effect.
• Long-term data on CV outcomes are limited.

40
Combinations of antihypertensive agents (1)

• Diuretic agents combined with adrenergic blockers
  have been used in several nephropathy studies and
  in the UKPDS-HDS and SHEP study.
• ACEIs have been used in combination with
  diuretics and Ca-blockers.
• In a small study, dual blockade of
  renin-angiotensin system using cardesartan and
  lisinopril (Candesartan and Lisinopril
  Microalbuminuria CALM study) reduced BP and
  urinary albumin levels to a greater extent than
  either medication alone.

41
Combinations of antihypertensive agents (2)

• Combination therapy may improve compliance, as
  one drug may antagonize adverse effects of
  another.
• Fixed-dose combinations are available and
  appropriate when requires more than one drug, the
  dosages are appropriate for pt, and the costs
  are not greatly increased.
• Superiority of one combination regime over
  another has not been documented.
• Intensive treatment of HTN, with goals similar to
  those recommended by the ADAs new target of
  lt130/80 mmHg, will require more than one drug in
  most p'ts and three or more in many.

42
BP goals in DM p'ts (1)

• UKPDS and HOT study both demonstrate improved
  outcomes, especially in preventing stroke, in
  p'ts assigned to tighter control (HOT, DBP 80
  mmHg, achieved 81 mmHg UKPDS, lt150/85 mmHg,
  achieved 144/82 mmHg) and less tight control
  (HOT, 90 mmHg UKPDS, lt180/105 mmHg).
• Optimal outcomes in HOT study were achieved at a
  mean DBP of 82.6 mmHg.
• ABCD trial, the primary outcome measure was
  decreased Ccr, showed a decrease in all-cause
  mortality in the group treated to a goal DBP of
  75 mmHg (achieved 132/78) vs. 8089 (achieved
  138/86) .

43
BP goals in DM p'ts (2)

• There is support from these randomized clinical
  trials for reducing SBP to 140 mmHg and for
  reducing DBP to 80 mmHg.
• Epidemiological evidence demonstrates BPs
  120/80 mmHg increased CV event rates and
  mortality in DM.
• A target BP goal of 130/80 mmHg is reasonable,
  if it can be safely achieved.
• A similar target has recently been advocated by
  the National Kidney Foundation.

44
BP goals in DM p'ts (3)

• Whether even more aggressive treatment would
  reduce the risk still is an unanswered question.
• There is no threshold value for BP, and risk
  continues to decrease well into the normal range.
• Achieving lower levels would increase the cost of
  care as well as drug side effects and is
  difficult in practice.
• BP goals are outlined in Table 2.

45
COST-EFFECTIVENESS (1)

• The higher the risk, the more cost-effective
  treatment is, so that elderly p'ts and those with
  severe HTN can be treated at lower cost per
  quality-adjusted life-year.
• In 1998, UKPDS investigators published a
  cost-effectiveness analysis of p'ts with DM
  enrolled in the HTN arm of that study and found
  that the incremental cost of tight control
  (lt150/85) versus less tight control (lt200/105
  initially, modified to lt180/105 in 1992) was well
  within the range of interventions generally
  considered to be effective.
• Differences in health care systems make the
  direct extrapolation to the U.S. health care
  system somewhat questionable.

46
COST-EFFECTIVENESS (2)

• Another recent study, using a computer model
  populated with cost assumptions based on the U.S.
  health care system and using data from HOT and
  UKPDS studies, showed that more intensive
  treatment of HTN is potentially cost-saving in
  persons 60 years of age and over, as long as the
  incremental treatment cost is less than
  414.00/year (U.S. dollars, 1996).
• HTN treatment in DM is a relatively good value
  from the standpoint of cost-effectiveness, given
  the cost-effectiveness of HTN treatment in the
  general population and the larger absolute risk
  reduction seen in DM.
• Special emphasis on African-Americans and other
  groups with very high rates of ESRD in the U.S.
  would also likely be highly cost-effective .

47
CONCLUSIONS (1)

• All p'ts with DM should have routine BP
  measurements at each scheduled DM follow-up
  visit.
• DM with SBP gt130 mmHg or DBP gt80 mmHg are
  candidates for antihypertensive treatment aimed
  at lowering BP to lt130/80 mmHg.
• Before beginning treatment, p'ts with elevated
  BPs should have their BP reexamined within 1
  month to confirm the presence of HTN.

48
CONCLUSIONS (2)

• BPs between 130/80 and 140/90 mmHg, behavioral
  approach for at least 3 months, consist of
  moderate Na restriction, calorie and alcohol
  restriction, and increased physical activity.
• Weight reduction should be the goal in obese
  p'ts.
• After behavioral treatment, SBP remains gt130 mmHg
  or DBP gt80 mmHg, pharmacological treatment should
  be added.

49
CONCLUSIONS (3)

• BPs of 140/90 mmHg are candidates for immediate
  pharmacological treatment in addition to
  behavioral treatment. Initial drugs include
  ACEIs, ARBs, low-dose thiazide diuretics, and
  ß-blockers.
• Because large number studies in DM demonstrating
  improvement in a range of outcomes, including
  progression of nephropathy, CV events, mortality
  it is now an established practice to begin
  hypertensive p'ts with DM and without
  microalbuminuria on an ACEI.

50
CONCLUSIONS (4)

• When microalbuminuria or more advanced stages of
  nephropathy is present, ACEIs (type 1 DM) and
  ARBs (type 2 DM) have been found to be effective
  in preventing progression of nephropathy.
• CV data are limited with ARBs.
• Initial therapy with ß-blocker, unless
  contraindicated, because UKPDS study showed
  ß-blockers to be roughly equivalent to ACEIs in
  improving multiple DM-related end points.

51
CONCLUSIONS (5)

• If the target BP goal is not obtained with the
  initial doses of first-line drugs, increases in
  doses or the addition of a second drug from a
  different group should be considered.
• Most p'ts will require more than one drug to
  achieve the recommended target of 130/80 mmHg,
  and many will require three or more.
• Achieve target BP may be more important than the
  particular drug regimen used.

52
CONCLUSIONS (6)

• Thiazide diuretics can improve CV outcomes and
  may address the volume or salt-sensitive
  components of HTN, complementing the mechanisms
  of action of other drugs, are appropriate choices
  for a second or third drug and can be initial
  therapy in p'ts without additional CV risk
  factors or proteinuria.
• Effect of thiazide diuretics on progression of DM
  nephropathy compared with other drugs is unknown.

53
CONCLUSIONS (7)

• NDCCBs can be used when ACEIs, ARBs, or
  ß-blockers are not tolerated or contraindicated
  or when a second or third drug is required.
• NDCCBs are not as effective in preventing
  complications, particularly MI, heart failure,
  and nephropathy.
• In studies achieving low-targeted BPs with
  substantial improvements in outcomes, such as HOT
  study and UKPDS, DCCBs were commonly part of an
  effective multi-drug regimen that also included
  ACEI or ß-blocker, diuretic.

54
CONCLUSIONS (8)

• In DM p'ts gt65 Y/O with isolated systolic HTN
  (i.e., SBP gt140 and DBP lt80 mmHg),
  pharmacological treatment should be initiated.
  Earlier recommendations to treat SBP lt160 have
  been reduced in order to be consistent with JNC
  VI and are based on increased CV risk of these
  p'ts and results of SHEP study, in which a SBP of
  144 was achieved.
• Combinations are often required. When drug
  therapy is intensified, monitor carefully for
  adverse effects, such as orthostatic hypotension.
• In DM p'ts, the greatest reduction in CV
  mortality occurs at a DBP of 80 mmHg.

55
CONCLUSIONS (9)

• Aggressive BP control in all DM p'ts.
• Treatment decisions should be individualized
  based on clinical characteristics, including
  comorbidities as well as tolerability, personal
  preference, and cost, especially for p'ts who
  must pay out of pocket for medications.
• Fixed-dose combinations are available,
  compliance, less expensive for p'ts with a
  per-prescription co-payment.

56
SUGGESTIONS FOR FUTURE RESEARCH (1)

• Limited data regarding entire classes of
  antihypertensive agents, such as ?-blockers, in
  tx of HTN with DM.
• Class effects of drugs cannot be differentiated
  from particular drug effects because no studies
  available.
• Studies should include cost comparisons and
  quality of life as well as CV and microvascular
  end points.
• Studies of effects on metabolic parameters may be
  useful in determining safety but may be
  misleading if used as a surrogate for clinically
  significant end points.

57
SUGGESTIONS FOR FUTURE RESEARCH (2)

• The ALLHAT, a large National Heart, Lung, and
  Blood Institute (NHLBI)-sponsored study,designed
  to compare diuretic-based treatment with
  Ca-blockers, ACEI, and ?-blocker as well as to
  investigate whether lipid-lowering therapy is of
  value in moderate hypercholesterolemia.
• As previously noted, the ?-blocker arm of the
  study has been terminated because of excess CV
  events, especially CHF, in p'ts taking an
  ?-blocker versus a diuretic. Approximately
  one-third of the 40,000 p'ts randomized has DM.
  Final results of this study will not be available
  until March of 2002.