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