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Treatment Issues of Diabetes, Treatment Issues of Diabetes, Hypertension, and Lipids in the Hypertension, and Lipids in the Elderly PatientElderly Patient
L. Brian Cross, PharmD, BCACP, CDEChad K. Gentry, PharmD, BCACP, CDEMarch 26, 2013
17th Primary Care Conference
ObjectivesAt the completion of this presentation the participant will be able to:
• Design an individualized pharmacotherapy regimen for the treatment of diabetes in a geriatric patient.
• Design an individualized pharmacotherapy regimen for the treatment of hypertension in a geriatric patient.
• Design an individualized pharmacotherapy regimen for the treatment of hyperlipidemia in a geriatric patient.
DM ISSUES IN THE ELDERLY
DM Disease Related Issues
• Intensive A1C lowering in trials offers modest benefit, mostly microvascular over 5+ yrs. There is some evidence for macrovascular benefit over the long‐term (>10‐20yrs).
• Intensive A1C lowering may increase risk of harm including major hypoglycemia & increased all‐cause death in some.
Cochrane Database Syst Rev. 2011 Jun 15;(6):CD008143.9
N EnglJ Med. 2008 Jun 12;358(24):2545‐59.
Diabetes Care. 2008;31:1913-19.
ACCORDADVANCE
VADT
Recent DM Outcomes Trial Results
• ACCORD – ↑ CV events with intensive DM management
• ADVANCE – no improvement in events with intensive DM management
• VADT – no improvement in events with
intensive DM management
DM Disease Related Issues• In studies with A1Cs as high as 7.9% and 8.4%
in the less intensive Tx arms, there were only marginal clinical outcome differences, but much less hypoglycemia in the less intensive Tx arms. Since frail elderly patients are even more likely to experience potential harms, these A1Cs provide some insight as to potentially reasonable A1C targets/ranges.
IS THERE A J-CURVE IN BLOOD GLUCOSE?
GPRD Retrospective Cohort Analysis
Lancet. 2010;375:481-9.
DM Disease Related Issues• The cohort study in aging found that the mortality
risk is a U‐ shaped curve which increases for A1Cs <6% and >9%. Risk of any complication increased with A1Cs >8%. A similar study of patients with diabetes and CKD found a similar U‐curve where mortality was increased with A1C <6.5% and >8.0%.
• Some guidelines have provided specific recommendations on how to individualize glycemic control in the elderly.
Diabetes Care. 2011Jun;34(6):1329‐36.Arch Intern Med. 2011 Nov 28;171(21):1920‐7
Endocrine Practice. 2011;17(suppl2):1-53.
Diabetes Care. 2012;35:1364-79.
PT CENTERED APPROACH!!!
TREAT THE PT NOT THE TARGET
Less stringent A1C goals (such as <8% or even slightly higher) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive comorbid conditions and for those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self‐management education, appropriate glucose monitoring, and effective doses of multiple glucose‐lowering agents including insulin.
Diabetes Care. 2012;35:1364-79.
Diabetes Care. 2012;35:1364-79.
Diabetes Care. 2009;32:193-203.
Lifestyle+
MetforminLifestyle + Metformin
+Sulfonylurea
Lifestyle + Metformin+
Intensive insulin
Lifestyle + Metformin+
PioglitazoneNo hypoglycemia
Edema, CHF, Bone loss
Lifestyle + Metformin+
GLP-1 agonistb
No hypoglycemia; Weight loss, Nausea/vomiting
Lifestyle + Metformin+
Pioglitazone+
Sulfonylurea
Lifestyle + Metformin+
Basal insulin
Step 1 Step 2 Step 3
TIER 1
Diabetes Care 2009;32:193-203.
Lifestyle + Metformin+
Basal insulin
TIER 2
T2B (Time to Benefit)
• > 6yrs for microvascular• > 10yrs for macrovascular (+/-)• therefore, individualize tx & consider
patient values/preferences
VA/DOD INDIVIDUALIZED APPROACH TO A1C GOALS
DM Medication Related Issues• Metformin – still foundational therapy, more
debate on dose adjustments with renal function (GFR < 30 = D/C; 30 = <850mg/day; 60 = <1700mg/day), GI issues & elderly may be more difficult in some, lactic acidosis risk unclear
• SU’s – ↑hypoglycemia, esp with decreased renal function, ? CV events, repaglinide (Prandin®) might be useful for pts with varying appetites
• TZD’s – less useful due to concerns (HF, edema, weight gain, fractures), cost
• DPP-4’s/GLP-1’s – limited beta-cell function?, cost, less hypoglycemia vs. SU’s & insulin
DM Medication Related Issues• Insulin – basal & premix sometimes helpful
if mealtimes / activity times are predictable, MDI OK in some but need to assess pt & caregiver ability, glargine & detemir may have less hypos, AVOID sliding scales,
• FIX LOW’s FIRST, THEN HIGH’S• SMBG – growing controversial data on utility
HTN ISSUES IN THE ELDERLY
Hypertension Guidelines
• 2003 - The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, & Treatment of High Blood Pressure (JNC VII)
• 2007 - American Heart Association Scientific Statement (AHA)
• 2002 - National Kidney Foundation (NKF)
JNC VIII (to be released in 2010, 11, 12) Hypertension. 2003;42:1206-52.Circulation. 2007;115:2761-2788.Am J Kidney Dis 2002;39:S1-S266.
2003 – JNC VII
• Primary Goal:– Decrease morbidity and mortality
• Blood Pressure Goals:– < 140/90 mm Hg for most patients– < 130/80 mm Hg for DM and CKD
Hypertension. 2003;42:1206-52.
2007 – AHA
• Blood Pressure Goals:– < 140/90 mm Hg for most patients– < 130/80 mm Hg for
•CKD•CAD•CAD risk equivalents (Framingham
>10%)
– < 120/80 mm Hg for•CHF
Circulation. 2007;115:2761-2788
2002 – NKF
Hypertension. 2003;42:1206-12-52Am J Kidney Dis 2002;39:S1-S266.
• Blood Pressure Goals:– < 130/80 mm Hg for CKD & DM
– < 125/75 mm Hg for pts with > 1 gm of proteinuria
†
Hyp
ert
en
sio
nP
revale
nce
Age
Prevalence of Hypertensionin the United States by Age Group*
*Based on data from the 19992000 National Health and Nutrition Examination Survey. Hypertension is defined as blood pressure 140/90 mm Hg or as receiving antihypertensive treatment.
†Low reliability due to large relative error.Fields LE, et al. Hypertension. 2004;44:398-404.
*Residual lifetime risk of developing hypertension among adults at 65 years of age with a blood pressure <140/90 mm Hg.
Lifetime Risk of Developing HypertensionAmong Adults at 65 Years of Age*
Vasan RS, et al. JAMA. 2002;287:1003-1010.
Ris
k o
f H
yp
ert
en
sio
n (
%)
Years
Men Women
Older population
• Often isolated systolic HTN• SHEP and Syst-Eur trials demonstrated
benefits– > 80 years old underrepresented in these
• HYVET in 2008– Stopped early due to incidence of death
21% higher in placebo treated patients
• How aggressive?– HYVET over 80 < 150/80 mm Hg
Treatment choices in older population
• At risk for volume depletion• Centrally acting agents should be
avoided or used with caution• Diuretics, ACE, ARB are all valid
choices– Use small initial doses and titrate over
longer periods
Risk of Orthostatic Hypotension
• Significant drop in BP when standing• Defined as > 20 mm Hg SBP or > 10
mm Hg DBP when changing supine to standing
• Older patients, DM, severe volume depletion, baroreflex dysfunction, autonomic insufficiency, and use of dilators
UKPDS Event Rates for Select Endpoints With Tight vs Less Tight Blood Pressure Control
Any diabetes-related endpoint
Diabetes-related death
Stroke Microvascular complications
Eve
nts
per
100
0 p
atie
nt
yrs P=0.005
P=0.02
P=0.01P=0.009
Less tight (n=390) mean achieved BP 154/87 mmHg
Tight (n=758) mean achieved BP 144/82 mmHg
BMJ 1998;317:703-13.
HOT Outcomes by Target Blood Pressure Group*
Major cardiovascular
events
All myocardial infarction
All stroke
Cardiovascular Mortality
Total Mortality
*The outcomes for different blood pressure groups were not statistically significant
Nu
mb
er o
f ev
ents
90 85 80
Lancet 1998;351:1755-62.
Antihypertensive Treatment Can Reduce Cardiovascular Events in Diabetic PatientsHypertension Optimal Treatment (HOT) Study
Ev
en
ts†
Pe
r 1
00
0 P
ati
en
t-Y
ea
rs
P = 0.005
†Events include all myocardial infarctions, allstrokes, and all other cardiovascular deaths.
TargetDBP
(mm Hg)
AchievedSBP*
(mm Hg)
AchievedDBP*
(mm Hg)
Patients with
Diabetes
90 143.7 85.2 501
85 141.4 83.2 501
80 139.7 81.1 499
*Mean of all blood pressures for all study patients in the blood pressure subgroups from 6 months of follow-up to the end of the study.
DBP = diastolic blood pressureSBP = systolic blood pressure
Lancet 1998;351:1755-62.
Controversy is Brewing
• 2009 Cochrane review– 7 trials (n = 22,089) comparing
different DBP targets – Did not demonstrate more
aggressive lowering of BP reduced mortality or morbidity better than the standard < 140/90 mm Hg
JAMA 2009;302(10):1047-8.
• 4733 patients with type 2 diabetes • Intensive BP control – SBP < 120 mm Hg• Standard BP control – SBP < 140 mm Hg
•Primary endpoint• nonfatal MI, nonfatal stroke, or death from CVD
NEJM 2010;362:1575-1585.
NEJM 2010;362:1575-1585.
Mean SBP at each visit
NEJM 2010;362:1575-1585.
Outcomes
BP Targets in CKD & Proteinuria as an Effect Modifier“Available evidence is INCONCLUSIVE but DOES NOT PROVE that a lower blood pressure target of less than 130/80 mm Hg improves clinical outcomes more than a target less than 140/90 mm Hg in adults with CKD. A lower target MAY BE BENEFICIAL in patients with proteinuria greater than 300 to 1000 mg/d.”
Ann Int Med 2011;154:541-8.
IS THERE A J-CURVE IN BLOOD PRESSURE?
JACC 2009;54(20):1827-34.
INVEST Trial
JACC 2009;54(20):1827-34.
INVEST Trial
Combination Regimens
• # of antihypertensive agents needed:– ≥ 2 if goal is < 140/90 mm Hg– ≥ 3 if goal is < 130/80 mm Hg
• Diuretic is usually additive• Numerous fixed dose
combinations• Fixed-dose combinations may be
beneficial
• Randomized, double-blind, controlled trial
• 11,506 patients with HTN and:•Age ≥ 60 years; 55-59 years eligible if ≥ 2 CV disease or target organ damage•SBP ≥ 160 mm Hg or on antihypertensive•Evidence of CVD, renal damage, or target organ damage
• Primary endpoint: CV morbidity or mortality
NEJM 2008;359:2417-2428
NEJM 2008;359:2417-2428
ACCOMPLISH BP EFFECTS
NEJM 2008;359:2417-2428
ACCOMPLISH: TIME TO PRIMARY EVENT
Combination Issues• Recent evidence from
ONTARGET/TRANSCEND trials suggests should NOT use ACE-I/ARB combination– Increased side effects without any improved
outcomes with the combination
• Recent evidence from ALTITUDE trial suggests should NOT add DRI to either ACE or ARB monotherapy– Increased nonfatal CVA, renal complications &
hyperkalemia
NEJM 2008;358:1547-59
Novartis press release 12/20/2011
Recent Meta-Analysis:HCTZ vs. Chlorthalidone• When used at 12.5 – 25 mg/day is
inferior to most other antihypertensives
• Should not be used as 1st line• Consider Chlorthalidone or
Indapamide instead• Wait for JNC-8 soon (maybe)• Consider loop diuretic if
GFR < 30 ml/min
J Am Coll Cardiol 2011; 57:590-600.
NEJM 2009; 361:2153-64.
Previous Meta-Analyses Question B-blockers as first-line
• Not as effective when compared to thiazides, CCBs, or renin-angiotensin system (RAS) inhibitors
• Suggested B-blockers should be considered 4th line therapy for HTN
• Question of Atenolol vs. other B-blockers
Lancet 2005; 366:1545-53.Cochrane Database Syst Rev 2007; 1:CD002003.JACC 2007; 50:563-72.
3845 HTN patients > 80 years of age and sustained SBP > 160 mm Hg•Indapamide or placebo (perindopril or placebo added if needed)•Goal < 150/80 mm Hg
What will JNC 8 look like????
Journal of Hypertension 2009; 27:1-38.Journal of Hypertension 2007; 25:1105-87.BMJ 2011; 25:1105-87.
JACC 2011; 57:1-12.
JNC HISTORY
• JNC 1 = 1976• JNC 2 = 1980• JNC 3 = 1984• JNC 4 = 1988• JNC 5 = 1992• JNC 6 = 1997• JNC 7 = 2003
JNC 8???
• Possible new focuses– Changes in recommended BP levels
for different patient types– Preferred medication classes (&
within classes) – don’t forget about aldosterone blockers
– Preferred medication combinations
JACC 2011; 57:2037-114.
• Older patients benefit equally to younger patients from antihypertensive treatment.
• Target blood pressures:– For octogenarians (>80 years) – a target BP of
<140–150/90 mm Hg should be applied to regardless of additional risk factors
• The ideal target BP is <140/90 mm Hg and should be attempted if BP control (SBP <150 mmHg) can be accomplished by the use of by one or two drugs.
• Alternatively, if a) more than three drugs are necessary, b) unacceptable side effects occur or c) treatment hypotension develops (DBP drops below 65 mmHg), a target BP of <150/90 mm Hg is acceptable.
• For septuagenarians (>70 years) and patients as young as 65 years – a target BP of <140/90 mm Hg is appropriate.
Drug Choices– There is some evidence for the greater efficacy of ACEI + Diuretic for combined systolic/diastolic HTN.– Diuretics should, whenever possible, be part of the therapy.– CCB and Diuretics should be used in patients with ISH.– Combination therapy, especially single-pill
combinations, should be considered as it is effective in reducing side effects and in increasing efficacy and patient adherence.
T2B – Time to Benefit
• 1+ years• strong evidence for decreased CVA &
proteinuria• Chlorthalidone, Amlodipine, ACE –
NOT beta-blockers unless post-MI or HF
LIPID ISSUES IN THE ELDERLY
LIPID Disease Related Issues
• T2B – 2+ yrs• No significant changes in
recommendations in general elderly• Lack of significant data in pts > 80-85
– suggested in this group to use moderate dose statins (Atorva 10mg; Prava 40mg; Simva 20mg); some question of cognitive SE’s
• Lack of evidence for ezetimibe• Less evidence for benefit > harm with
fibrates
End point Hazard ratio (95% CI)
Primary end point (nonfatal MI, nonfatal stroke, revascularization, unstable angina, cardiovascular death)
0.61 (0.46–0.82)
MI 0.55 (0.31–1.00)Stroke 0.55 (0.33–0.93)Revascularization or unstable angina 0.51 (0.33–0.80)MI, stroke, cardiovascular death 0.61 (0.43–0.86)Any death 0.80 (0.62–1.04)Venous thromboembolism (VTE) 0.59 (0.31–1.11)Primary end point and any death 0.69 (0.56–0.85)Primary end point and any death or VTE 0.69 (0.56–0.84)
JUPITER: Primary and individual end points in patients >70 years old
Glynn R. European Society of Cardiology 2009 Congress; August 30-September 2, 2009; Barcelona, Spain.
Figure 3. Least-squares mean percent changes in lipid parameters from baseline. *P<0.001 versus pravastatin; ‡P<0.001 versus atorvastatin; †P=0.009 versus atorvastatin.
Deedwania P et al. Circulation 2007;115:700-707
Copyright © American Heart Association
Figure 4. Kaplan-Meier plot for the time to the first MACE end point up to month 12. *At risk at month 12 plus 8 days.
Deedwania P et al. Circulation 2007;115:700-707
Copyright © American Heart Association
Figure 5. Kaplan-Meier estimates of time to all-cause death during the 12-month treatment period. *At risk at month 12 plus 8 days.
Deedwania P et al. Circulation 2007;115:700-707
Copyright © American Heart Association