Treatment Issues of Diabetes, Hypertension, and Lipids in the Elderly Patient

Treatment Issues of Diabetes, Hypertension, and Lipids in the Elderly Patient 17 th Primary Care Conference March 26, 2013 L. Brian Cross, PharmD, BCACP, CDE Chad K. Gentry, PharmD, BCACP, CDE

Objectives At 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.

Patient Case 76 yo male with history of type 2 DM for 17 years, HTN for 25 years, hyperlipidemia for 12 years. He has had 3 MI s, 1 CVA (with minimal residual deficits), and PTCA with stents X4 (5 years ago).

What is your suggested goal for this patient s A1c? 1. < 6 % 2. < 6.5 % 3. < 7 % 4. < 8 % 5. < 9 %

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.

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.

PT CENTERED APPROACH!!! TREAT THE PT NOT THE TARGET Diabetes Care. 2012;35:1364-79.

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.

TIER 1 Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea Lifestyle + Metformin + Intensive insulin Step 1 Step 2 Step 3 Lifestyle + Metformin + Pioglitazone No hypoglycemia Edema, CHF, Bone loss Lifestyle + Metformin + Pioglitazone + Sulfonylurea TIER 2 Diabetes Care 2009;32:193-203. Lifestyle + Metformin + GLP-1 agonist b No hypoglycemia; Weight loss, Nausea/vomiting Lifestyle + Metformin + Basal insulin

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

Proposed Recommendations egfr level (ml/min per 1.73 m 2 ) Action 60 No renal contraindication to metformin Monitor renal function annually < 60 and 45 Continue use Increase monitoring of renal fxn (q3-6 months) < 45 and 30 Prescribe metformin with caution Use lower dose (e.g., 50%, or halfmaximal dose) Closely monitor renal fxn (q 3 months) Do not start new patients on metformin < 30 STOP METFORMIN

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

Beer s List for DM DM Sliding scale insulin SU (glyburide) JAGS 2012

HTN ISSUES IN THE ELDERLY

Patient Case - Revisited 76 yo male with history of type 2 DM for 17 years, HTN for 25 years, hyperlipidemia for 12 years. He has had 3 MI s, 1 CVA (with minimal residual deficits), and PTCA with stents X4 (5 years ago).

What is your suggested goal for this patient s BP? 1. < 115 / 75 2. < 120 / 80 3. < 130 / 80 4. < 130 / 85 5. < 140 / 80 6. < 140 / 90

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 Blood Pressure Goals: < 130/80 mm Hg for CKD & DM < 125/75 mm Hg for pts with > 1 gm of proteinuria Am J Kidney Dis 2002;39:S1-S266. Hypertension. 2003;42:1206-12-52

Prevalence of Hypertension in the United States by Age Group * Hypertension Prevalence Age *Based on data from the 1999 2000 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.

Lifetime Risk of Developing Hypertension Among Adults at 65 Years of Age * Risk of Hypertension (%) Men Women *Residual lifetime risk of developing hypertension among adults at 65 years of age with a blood pressure <140/90 mm Hg. Vasan RS, et al. JAMA. 2002;287:1003-1010. Years

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 Events per 1000 patient yrs P=0.005 P=0.02 Tight (n=758) mean achieved BP 144/82 mmhg Less tight (n=390) mean achieved BP 154/87 mmhg P=0.01 P=0.009 Any diabetesrelated endpoint Diabetesrelated death Stroke Microvascular complications BMJ 1998;317:703-13.

HOT Outcomes by Target Blood Pressure Group* 90 85 80 Number of events Major cardiovascular events All myocardial infarction All stroke Cardiovascular Mortality Total Mortality *The outcomes for different blood pressure groups were not statistically significant Lancet 1998;351:1755-62.

Antihypertensive Treatment Can Reduce Cardiovascular Events in Diabetic Patients Hypertension Optimal Treatment (HOT) Study Target DBP (mm Hg) Achieved SBP* (mm Hg) Achieved DBP * (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 pressure SBP = systolic blood pressure Events Per 1000 Patient-Years P = 0.005 Events include all myocardial infarctions, all strokes, and all other cardiovascular deaths. 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.

Mean SBP at each visit NEJM 2010;362:1575-1585.

Outcomes NEJM 2010;362:1575-1585.

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?

INVEST Trial JACC 2009;54(20):1827-34.

INVEST Trial JACC 2009;54(20):1827-34.

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

ACCOMPLISH BP EFFECTS NEJM 2008;359:2417-2428

ACCOMPLISH: TIME TO PRIMARY EVENT NEJM 2008;359:2417-2428

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 & NEJM 2008;358:1547-59 Novartis press release 12/20/2011 hyperkalemia

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 1 st line Consider Chlorthalidone or Indapamide instead Wait for JNC-8 soon (maybe) Consider loop diuretic if GFR < 30 ml/min NEJM 2009; 361:2153-64. J Am Coll Cardiol 2011; 57:590-600.

Context SHEP antihypertenisive therapy with chlorthalidone resulted in lower rate of CV events than placebo but mortality not significant Objective study gain in life expectancy of participants randomized to active therapy at the 22-year f/u Results for each month of active treatment added 1 day extension in life expectancy

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 4 th line therapy for HTN Question of Atenolol vs. other B- blockers JACC 2007; 50:563-72. Cochrane Database Syst Rev 2007; 1:CD002003. Lancet 2005; 366:1545-53.

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

Beer s List for HTN HTN Central alpha-agonists Alpha blockers Sprinolactone > 25mg/day Vasodilators JAGS 2012

What will JNC 8 look like????

JACC 2011; 57:1-12. BMJ 2011; 25:1105-87. Journal of Hypertension 2007; 25:1105-87. Journal of Hypertension 2009; 27:1-38.

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

Patient Case - Revisited 76 yo male with history of type 2 DM for 17 years, HTN for 25 years, hyperlipidemia for 12 years. He has had 3 MI s, 1 CVA (with minimal residual deficits), and PTCA with stents X4 (5 years ago).

What is your suggested goal for this patient s LDL / HDL / TG? 1. 130 / 35 / 150 2. 100 / 40 / 150 3. 100 / 50 / 150 4. 70 / 45 / 250 5. 70 / 40 / 250 6. 70 / 40 / 150

JUPITER: Primary and individual end points in patients >70 years old 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) Glynn R. European Society of Cardiology 2009 Congress; August 30-September 2, 2009; Barcelona, Spain.

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease : Results of the Study Assessing Goals in the Elderly (SAGE) Prakash Deedwania, Peter H. Stone, C. Noel Bairey Merz, Juan Cosin-Aguilar, Nevres Koylan, Don Luo, Pamela Ouyang, Ryszard Piotrowicz, Karin Schenck-Gustafsson, Philippe Sellier, James H. Stein, Peter L. Thompson and Dan Tzivoni Circulation. 2007;115:700-707; originally published online February 5, 2007; doi: 10.1161/CIRCULATIONAHA.106.654756

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

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

Parting Thoughts.. Treat patients NOT numbers Use therapy to treat to a patient s level of risk Individualize therapy choices based on patient & medication properties

Blood Pressure (mm Hg) in SHEP and Syst-Eur Trials SHEP Syst-Eur Entry Goal (SBP) Baseline Achieved: Rx Achieved: Placebo 160-219/<90 160-219/<95 <160 <150 170/77 174/86 143/68 151/79 155/72 161/84 90

Treatment of Hypertension in the Elderly MRC Trial Diuretics B-Blockers Placebo Rate* Rate* Rate* Strokes 7.3 9.0 10.8 Coronary Events 7.7 12.8 12.7 All CV events 17.4 24.6 25.2 *Rate/1000 patient years BMJ, Feb 1992 91

Diuretics or B-Blockers as Initial Therapy in 8 Randomized Controlled Hypertension Treatment Trials in Older Persons Risk Reduction (%) 0-10 -20-30 -40-50 CHD Stroke CHF Death Diuretics B-blockers All reductions significant (p <.05) except CHD and death with B-blockers Cutler JA, et al. In Laragh JH, Brenner BM, eds, Hypertension 1995 92

REDUCTION OF STROKES WITH BP LOWERING - SHEP TRIAL No. of Patients: 4736 Follow-up: 4.5 years 37% in ischemic strokes 47% in lacunar infarcts 54% in hemorrhagic strokes Lower BPs - fewer strokes Am J Hypertension 2000;13:724-733 93