2016 Georgia Society of Health-System Pharmacists Summer Meeting CV Risk Factors: Emerging Data on Management of Type 2 Diabetes and Hypertension

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1 2016 Georgia Society of Health-System Pharmacists Summer Meeting CV Risk Factors: Emerging Data on Management of Type 2 Diabetes and Hypertension Jeff Langford, PharmD BCPS Clinical Pharmacy Specialist, Cardiology University Health Care System Augusta, GA

2 Disclosure No relationships to disclose.

3 Learning Objectives 1. Describe cardiovascular (CV) outcome data for dipeptidyl peptidase 4 (DPP 4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors. 2. Optimize a treatment plan for type 2 diabetes (DM2) based on current evidence and patient specific factors. 3. Identify blood pressure (BP) treatment goals based on current clinical practice guidelines and recent evidence. 4. Select an evidence based blood pressure treatment goal based upon patient specific factors.

4 Select Abbreviations A1C = hemoglobin A1C HF = heart failure ACS = acute coronary syndrome HTN = hypertension AE = adverse events HPL = hyperlipidemia ASA = aspirin LFT = liver function test ASCVD = atherosclerotic cardiovascular disease MACE = major adverse cardiac event CAD = coronary artery disease MI = myocardial infarction CV = cardiovascular NNT = number needed to treat CVD = cardiovascular disease NS= non significant DM2 = type 2 diabetes PAD = peripheral arterial disease DPP 4 I = dipeptidyl peptidase 4 inhibitor RR = relative risk EF = ejection fraction RRR = relative risk reduction ESRD = end stage renal disease SAE = serious adverse events GFR = glomerular filtration rate SGLT2 I = sodium glucose cotransporter 2 inhibitor GIP = glucose dependent insulinotropic polypeptide TZD = thiazolidinedione GLP 1 = glucagon like peptide 1 TIA = transient ischemic attack HD = hemodialysis ULN = upper limit of normal

5 Obesity Inactivity Smoking CV Risk Factors Modifiable DM Non modifiable Risk Factors Age Gender Heredity Other contributing factors: Stress Alcohol Diet, nutrition HPL HTN Your Risk of Heart Attack_UCM_002040_Article.jsp#.V1slltIrK7A

6 Diabetes Mellitus: Epidemiology & Impact %20Sean/Documents/Fast_Facts_ a.pdf basics/statistics/cdc infographic.html

Diabetes Mellitus: Epidemiology & Impact 2012 Economic Burden DM in US $245 Billion $176 Billion = direct costs 90 95% have DM2 $69 Billion = indirect costs

7 Diabetes Mellitus: Epidemiology & Impact 2012 Economic Burden DM in US $245 Billion $176 Billion = direct costs 90 95% have DM2 $69 Billion = indirect costs %20Sean/Documents/Fast_Facts_ a.pdf basics/statistics/cdc infographic.html

8 DM2 Hosp for MI & stroke 2 4 fold in CV Disease (CVD) Atherosclerotic CVD (ASCVD): ACS, hx of MI Stable/unstable angina Coronary/arterial revasc Stroke/TIA PAD Life expectancy 6 7 years Holman RR et al. Lancet 2014;383: Skyler JS et al. Circulation. 2009;119: American Diabetes Association. Diabetes Care 2016; 39 (Suppl. 1):S1 S112. ASCVD in DM2: Largest cause of morbidity and mortality Largest driver of direct and indirect costs of care

9 Heart Failure: Frequent, forgotten and often fatal complication of DM DM risk of HF 2 5 fold Not neatly microvascular or macrovascular HF mortality ~ 2 x that of non diabetic population Gilbert RE et al. Lancet 2015; 385:

10 Heart Failure: Frequent, forgotten and often fatal complication of DM DM risk of HF 2 5 fold Cardiotoxic Tetrad Not neatly microvascular or macrovascular HTN Diabetic Cardiomyopathy HF mortality ~ 2 x that of non diabetic population Gilbert RE et al. Lancet 2015; 385: CAD HF in DM Extracellular Fluid Expansion

11 DM2 management is challenged by questions about CV effects related to intensity of treatment & related to drug choice. UGDP 1970 Rosiglitazone 2007 FDA 2008 DPP 4 Inhibitor Studies EMPA REG 2015 UKPDS 1998 ACCORD ADVANCE VADT 2008 Hiatt WR et al. N Engl J Med 2013; 369:

12 Effect of Intensive Glucose Lowering in DM2 UKPDS ACCORD ADVANCE VADT Microvascular Primary CV Endpoint Micro/ macrovascular events Primary CV Endpoint MI 16% (NS) At 10 year follow up: MI Mortality (NS) Mortality Macro (CV) events Mortality Mortality Skyler JS et al. Circulation. 2009; Holman RR et al. Lancet 2014;383:

13 UKPDS ACCORD ADVANCE VADT N ,251 11, Mean age, y Duration of DM, y < Sex M/F % 59/41 61/39 58/42 97/3 History of CVD % NS 35% 32% 40% Median Baseline A1C % A1C Goal < 6 vs vs local guidelines Median Followup, y A1C, % (Intensive vs Standard) < 6.0 vs planned separation of (term early) vs vs vs vs 8.5 Skyler JS et al. Circulation. 2009;

14 UKPDS ACCORD ADVANCE VADT Outcome (NF: nonfatal) Aggregate of DM related endpoint, DM related death, all cause mortality NF MI + NF stroke + CV death Microvascular + macrovascular (NF MI + NF stroke + CV death NF MI + NF stroke + CV death + Hosp HF + revascularization Primary Outcome HR (95% CI) 0.88 ( ) 0.90 ( ) 0.9 ( ) 0.88 ( ) macrovascular 0.94 ( ) Mortality HR (95% CI) 0.94 ( ) 1.22 ( ) 0.93( ) 1.07 ( ) Skyler JS et al. Circulation. 2009; Ray KK et al. Lancet 2009;373:

15 Cardiac Effects of DM2 Therapies Metformin Sulfonylureas TZDs DPP 4 Inhibitors SGLT2 Inhibitors GLP 1 Agonists α Glucosidase Inhibitors ASCVD 1 /? 2 / / 4 HF 3 / 1 ASCVD with 1 st generation agent (tolbutamide) 2 Conflicting results for rosiglitazone 3 HF with saxagliptin and trend to w/ alogliptin; sitagliptin 4 with liraglutide Data in yellow shaded boxes based on CV outcomes trials Gilbert RE et al. Lancet 2015; 385: Kumar R et al. Eur Heart J Cardiovasc Pharmacother. doi: /ehjcvp/pvv035

16 2015 AHA/ADA: Prevention of CV Disease in DM2 Statin BP < 140/90 ASA A1C 7% Fox CS et al. Diabetes Care. doi: /dci

17 2015 AHA/ADA: Prevention of CV Disease in DM2 Moderate intensity statin High intensity statin if ASCVD risk 7.5% Statin BP< 140/90 ASA A1C 7% Fox CS et al. Diabetes Care. doi: /dci

18 2015 AHA/ADA: Prevention of CV Disease in DM2 Moderate intensity statin High intensity statin if ASCVD risk 7.5% Statin BP< 140/90 Treatment to include ACEI/ARB Select patients, SBP < 130 mm Hg ASA A1C 7% Fox CS et al. Diabetes Care. doi: /dci

19 2015 AHA/ADA: Prevention of CV Disease in DM2 Moderate intensity statin High intensity statin if ASCVD risk 7.5% Statin BP< 140/90 Treatment to include ACEI/ARB Select patients, SBP < 130 mm Hg ASA A1C 7% For select patients, A1C: < 6.5% or < 8% Fox CS et al. Diabetes Care. doi: /dci

20 2015 AHA/ADA: Prevention of CV Disease in DM2 Moderate intensity statin High intensity statin if ASCVD risk 7.5% Statin BP< 140/90 Tx to include ACEI/ARB For select patients, SBP < 130 Low dose Aspirin for: CVD risk 10% & NO risk of bleed Consider w risk 5 10% ASA A1C 7% For select patients, A1C: < 6.5% or < 8% Fox CS et al. Diabetes Care. doi: /dci

21 CV Outcomes Studies in DM2 Therapies Rosiglitazone? CV Effects 2007 Rosiglitazone Meta analysis (Cochran s Q test, P > 0.10) 43% in risk of MI (p = 0.03) 64% in risk of CV death (p = 0.06) FDA 2008 FDA Guidance for Industry Pre/post approval studies for new DM2 therapies to rule out excess CV risk Emerging CV Outcome Studies DPP 4 inhibitors and SGLT2 inhibitors More data to come Nissen SE et al. N Engl J Med 2007;356: Food and Drug Administration. Published December Accessed June 20, 2016.

22 Question #1 The DPP 4 inhibitor and SGLT2 inhibitor classes for treatment of DM2 improve glycemic control and reduce CV risk. A. True B. False

23 Question #2 Which of the following DM2 medications are associated with an increased risk of HF? A. Sitagliptin B. Empagliflozin C. Saxagliptin D. All of the above

24 DPP 4 Inhibitors Agents Alogliptin Linagliptin Saxagliptin Sitagliptin

25 DPP 4 Inhibitors Agents Profile Alogliptin Linagliptin Saxagliptin Sitagliptin AIC ~ % Weight Hypoglycemia

26 DPP 4 Inhibitors Agents Alogliptin Linagliptin Saxagliptin Sitagliptin Profile AIC ~ % Weight Hypoglycemia? Pancreatitis Arthralgia Hypersensitivity AE: Adverse Effects

27 DPP 4 Inhibitors: Mechanism of Action Incretin Hormones (GLP 1 & GIP) Brain Gut Pancreas Satiety Slows Gastric emptying Insulin Glucagon Muscle Liver GLP 1: glucagon like peptide 1 GIP: glucose dependent insulinotropic polypeptide Glucose Uptake Glucose Production Jose T et al. Diab Vasc Dis Res. 2012; 9(2):

28 DPP 4 Inhibitors: Mechanism of Action Incretin Hormones (GLP 1 & GIP) Brain Gut Pancreas Satiety Slows Gastric emptying Insulin Glucagon DPP 4 Inhibitors half life & bioavailability of GLP 1 and GIP Muscle Liver Glucose Uptake Glucose Production Jose T et al. Diab Vasc Dis Res. 2012; 9(2):

29 Vascular Repair Slow atherosclerosis CV Effects of DPP 4 Inhibition Prevent LV dysfunction Inflammation Jose T et al. Diab Vasc Dis Res 2012; 9(2):

30 SAVOR TIMI 53 (saxagliptin) Design Subjects Exclusion Criteria Primary Endpoint Dose Randomized, double blind Saxagliptin or placebo Median follow up 2.1 years N = 16,492 Patients with DM2 & CVD or multiple risk factors Currently using incretin therapy (or within prior 6 months) ESRD/HD, renal transplant, or SCr > 6mg/dl MACE (CV death + nonfatal MI + nonfatal stroke) Saxagliptin 5mg daily (2.5mg daily if GFR 50ml/min) Scirica BM et al. N Engl J Med 2013;369: MACE: major adverse cardiac event

31 SAVOR TIMI 53: Patient Population at Baseline Mean age 65 years Male 67% Duration of DM years Mean A1C 8% Mean GFR 73 ml/min ASCVD 78% Prior HF 12.8% Scirica BM et al. N Engl J Med 2013;369:

32 % Patients w/ End Point HR % CI SAVOR TIMI 53: Results HR % CI HR % CI HR % CI Placebo Saxagliptin HR % CI MACE CV Death MI Stroke HF Hosp Scirica BM et al. N Engl J Med 2013;369:

33 SAVOR TIMI 53: Additional Considerations CV Risk Factor Management (Baseline) Glycemic Control Saxagliptin: Pancreatic Saxagliptin: Hypoglycemia Saxagliptin: Renal Saxaglipitin: ASA 75% Statin 78% ACEI 54% ARB 28% A1C 0.2% More patients with A1C < 7% Acute, chronic or pancreatic cancer Major 2.1% vs 1.7% Minor 14.2 vs 12.5% More likely to have improved albumin/ creatinine ratio Scirica BM et al. N Engl J Med 2013;369:

34 EXAMINE (alogliptin) Randomized, double blind, non inferiority (margin 1.3) Design Alogliptin or placebo Subjects Exclusion Criteria Median follow up 18 months N = 5380 Very high CV risk patients: DM2 w/ ACS in last days DM1, unstable cardiac disorder 1, HD within 14 days before screening Primary Endpoint Dose White WB et al. N Engl J Med. 2013;369: MACE (CV death + nonfatal MI + nonfatal stroke) 25mg daily (GFR 60ml/min) 12.5mg daily (GFR ml/min) 6.25mg daily (GFR < 30ml/min) 1 NYHA Class IV HF, refractory angina, uncontrolled arrhythmia, critical valvular heart disease or,severe uncontrolled HTN

35 EXAMINE: Patient Population at Baseline Median age 61 years Male 68% Median Duration of DM2 7.3 years Mean A1C 8% Median GFR 71 ml/min MI 88% HF 28% White WB et al. N Engl J Med. 2013;369:

36 % Patients with Endpoint EXAMINE: Results HR % CI 1.16 HR % CI HR % CI HR % CI Placebo Alogliptin HR % CI MACE CV Death MI Stroke HF Hosp White WB et al. N Engl J Med. 2013;369: Zannad F et al. Lancet. 2015;385:

37 EXAMINE: Additional Considerations CV Risk Factor Management (Baseline): ASA 90% Statin 90% RAAS Blocker 82% Beta Blocker 82% Glycemic Control Alogliptin: A1C 0.33% Hypoglycemia Any or serious hypoglycemia Pancreatic Acute, chronic pancreatitis No report of pancreatic cancer White WB et al. N Engl J Med. 2013;369:

38 TECOS (sitagliptin) Randomized, double blind, non inferiority (margin 1.3) Design Subjects Sitagliptin or placebo Median follow up 3.0 years N = 14,671 Patients w DM2 and established CV disease History of CAD, ischemic cerebrovascular dx or PAD Exclusion Criteria DPP 4 Inhibitor, GLP 1 agonist or TZD 1 during prior 3 months 2 episodes of hypoglycemia during previous 12 months GFR < 30ml/min Primary Endpoint Dose Green JB et al. N Engl J Med. 2015;373: MACE (CV death + nonfatal MI + nonfatal stroke + hospitalization unstable angina) Sitagliptin 100mg daily Sitagliptin 50mg daily for GFR 30ml/min and < 50ml/min 1 Other than pioglitazone

39 TECOS: Patient Population at Baseline Mean age 65.5 years Male 70% Mean Duration of DM years Mean A1C 7.2% Mean GFR 75 ml/min CVD 74% (MI 43%) HF 18% Green JB et a. N Engl J Med. 2015;373:

40 12 HR % CI TECOS: Results Placebo Sitagliptin % Patients with Endpoint HR % CI HR % CI HR % CI: HR % CI MACE (3pt) CV Death MI (All) Stroke (All) HF Hospitalization Green JB et al. N Engl J Med. 2015;373: doi: /nejmoa

41 TECOS: Additional Considerations CV Risk Factor Management (Baseline): ASA 78% Statin 79% ACE or ARB 78% Glycemic Control Sitagliptin: A1C 0.29% Hypoglycemia: severe Pancreatic Sitagliptin: Acute pancreatitis (NS) Pancrea c cancer (NS) Renal Sitagliptin: GFR slightly in sitagliptin group (Δ = 1.34 ml/min) Green JB et al. N Engl J Med. 2015;373:

42 DPP 4 Inhibitors: CV Perspective HF Risk 1 Disadvantages Advantages 1 FDA warning for HF risk w saxagliptin & alogliptin CV Neutral

43 DPP 4 Inhibitors: Individualizing Treatment Choices in DM2 ADR 2 HF Risk 1 Cost Disadvantages Advantages 1 FDA warning for HF risk w saxagliptin & alogliptin 2 ADR include? pancreatitis & hypersensitivity CV Neutral Modest A1C Low risk Hypoglycemia

44 SGLT2 Inhibitors Agents Canagliflozin Dapagliflozin Empagliflozin

45 SGLT2 Inhibitors Agents Profile Canagliflozin A1C ~ 0.5 1% Dapagliflozin Weight Empagliflozin Hypoglycemia

46 SGLT2 Inhibitors Agents Canagliflozin Profile A1C ~ 0.5 1% Bone fractures Hypotension, volume depletion Ketoacidosis Dapagliflozin Empagliflozin Weight Hypoglycemia Renal effects UTI, Genital Infections

47 SGLT2 Inhibitors Mechanism of Action Kidney Filters ~ g glucose/day Proximal Tubule Marx N et al. [Published online May 5, 2016]. Eur Heart J. SGLT1 SGLT2 10% Glucose Reabsorption 90% Glucose Reabsorption SGLT2 Inhibitors Glucose Excre on (60 100g/day) Plasma Glucose Plasma Volume Natriuresis

48 LDL 3-7 mg/dl HDL 2-5 mg/dl CV Effects of SGLT2 Inhibition Body Weight 2-3kg Uric Acid Arterial Stiffness/ Vascular Resistance SBP 3 5mmHg DPB 2mmHg Inzucchi SE et al. Diab Vasc Dis Res 2015;12(2):

49 EMPA REG OUTCOME (empagliflozin) Design Randomized, double blind, non inferiority (margin 1.3) Empagliflozin versus placebo Median follow up 3.1 years Subjects N = 7020 patients DM2, high CV risk Exclusion Criteria Exclusions: GFR < 30 ml/min, LFT > 3 x ULN, ACS, stroke or TIA within 2 months prior to consent Primary Endpoint MACE (CV death + nonfatal MI + nonfatal stroke) Dose Empagliflozin 10 or 25mg vs placebo Zinman B et al. N Engl J Med. 2015;373:

50 EMPA REG OUTCOME: Patient Population at Baseline Mean age 63 years Male 71% Duration of DM2 > 10 years for ~ 57% Mean A1C 8 % Mean GFR 74 ml/min CAD 76% (MI 47%) HF 10 % Zinman B et al. N Engl J Med. 2015;373:

51 % Patients with Endpoint HR % CI HR % CI EMPA REG OUTCOME: Results HR % CI HR % CI Placebo Empagliflozin HR % CI MACE CV Death MI Stroke HF Hosp Zinman B et al. N Engl J Med. 2015;373:

52 EMPA REG OUTCOME: Results Absolute Risk Reduction Relative Risk Reduction Number Needed to Treat (3.1 years) Primary Outcome 1.6% 14% 63 CV Death % 45 Any Death % 39 HF % 71 Zinman B et al. N Engl J Med. 2015;373:

53 EMPA REG OUTCOME: Additional Considerations CV Risk Factor Management (Baseline): ASA 83% Statin 76% ACE/ARB 80% Glycemic Control Empagliflozin: A1C 0.24% (10mg) A1C 0.36% (25mg) AE Empagliflozin: Genital infection Urosepsis AE Empagliflozin: UTI Pyelonephritis AKI DKA Fracture Volume depletion CV Weight Waist circumference Uric acid SBP& DBP HR LDL and HDL Zinman B et al. N Engl J Med. 2015;373:

54 Empagliflozin: CV Perspective Disadvantages Advantages HF Hosp CV Death All cause Death Improve CV risk factors

55 Empagliflozin: Individualizing Treatment Choices in DM2 AE 1 Cost Disadvantages Advantages 1 Possible AE include: Genital Infections, UTI, Fractures, Renal effects, Hypotension, Volume depletion, Ketoacidosis HF Hosp CV Death All cause Death Improve CV risk factors A1C

56 Factors in Individualizing DM2 Therapy Efficacy Quality of life Safety Cost ADR Outcomes Fox CS et al. Diabetes Care. doi: /dci

57 Hypertension Epidemiology Hypertension Prevalence US Hypertension Control Overall Age % Uncontrolled 51.8 % Controlled Race Hispanic Asian Black White

58 Impact Heart Disease & Stroke > 1000 deaths/day in US $48.6Billion / year

59 Question # 3 Based on current evidence or clinical practice guidelines which of the following BP goals would be appropriate for a 65 year old male with a medical history significant for HTN, HPL, and MI? A. < 150/90 mm Hg B. < 140/90 mm Hg C. < 120/90 mm Hg D. Any of the above may be supported by current evidence or clinical practice guidelines.

60 HTN Goals (mm Hg): Comparison of Guideline Recommendations Uncomplicated HTN Diabetes CV Disease Chronic Kidney Disease Older Adults JNC 7 (2003) < 140/90 <130/80 <140/90 <130/80 Not specified JNC 8 (2014) < 140/90 <140/90 <140/90 <150/90, age 60 yr ASH/ISH (2013) <140/90 <140/90 <140/90 <140/90 <150/90, age 80 yr CHEP (2016) <140/90 1 < 130/80 <140/90 1 <140/90 1 <150/90, age 80 yr ESH/ESC (2013) <140/90 <140/85 <140/90 <140/90 <150/90, age 80 yr JNC: Joint National Committee ASH/ISH: American Society of Hypertension, International Society of Hypertension CHEP: Canadian Hypertension Education Program ESH/ESC: European Society of Hypertension, European Society of Cardiology McConnnell KJ et al. Pharmacotherapy Self Assessment Program, 2016 Book 1. Cardiology. 2016:7 27. Leung et al. Can J Cardiol. 2016;32: For high risk patients, age 50 years, with SBP 130, consider target SBP 120. Patient selection recommended; caution for certain high risk groups.

61 HTN Goals (mm Hg): Comparison of Disease Specific Guideline Recommendations Uncomplicated HTN Diabetes CV Disease Chronic Kidney Disease ADA (2016) <140/90 < 130/80 for select patients ACC/AHA (2015) <140/90 <150/90 for age 80 yr KDIGO (2012) <140/90 <130/80 w/ proteinuria Older Adults ADA: American Diabetes Association ACC/AHA: American College of Cardiology/American Heart Association KDIGO: Kidney Disease: Improving Global Outocmes American Diabetes Association. Standards of Medical Care in Diabetes Diabetes Care 2016; 39 (Suppl. 1):S1 S112. McConnnell KJ et al. Pharmacotherapy Self Assessment Program, 2016 Book 1. Cardiology. 2016:7 27.

62 SPRINT: Intensive vs Standard BP Control Randomized, controlled, open label Design Subjects Exclusion Criteria SBP target < 120 mm Hg (intensive) vs < 140 mm Hg (standard) Median follow up: 3.26 years (terminated early) N = 9361 Pa ents with CV Risk but without DM At least 50 yo, SBP mm Hg DM, prior stroke, GFR < 20 ml/min or ESRD, EF <35% Primary Endpoint Treatment. Wright JT et al. N Engl J Med. 2015;373: MI + ACS + Stroke +HF + CV Death HTN meds: All major classes included Encouraged use of drug classes w/ strongest evidence for CV outcomes

63 SPRINT: Patient Population at Baseline Mean age 68 years Male 64% BP 140/78 mm HG GFR 72 ml/min 10 yr CV Risk Score 20% # of BP Meds 1.8 Wright JT et al. N Engl J Med. 2015;373:

64 SPRINT: Treatment Algorithms INTENSTIVE STANDARD Start with 2 3 drug regimen If SBP 160 (or 140 last 2 visits): Titrate or add therapy If SBP 120: Titrate or add therapy and see monthly If DBP 100 (or 90 last 2 visits): Titrate or add therapy Follow up: Monthly x 3 months, then every 3 months; adjust meds monthly for SBP < 120 If DBP 100 (or 90 last 2 visits): Titrate or add therapy If SBP < 130 (or < 135 last 2 visits): Step down Follow up: Monthly x 3 months, then every 3 months; Follow in 1 month if SBP 160 Wright JT et al. N Engl J Med. 2015;373:

65 SPRINT: Antihypertensive Utilization Number of Agents Intensive (%) Standard (%) Class Intensive (%) Standard (%) ACEI/ARB Thiazide diuretic Calcium channel blocker DHP Beta blocker Alpha 1 blocker Average (#) Wright JT et al. N Engl J Med. 2015;373: Aldosterone receptor blocker DHP: Dihydropyridine

66 SPRINT: Antihypertensive Utilization Number of Agents Intensive (%) Standard (%) Class Intensive (%) Standard (%) ACEI/ARB Thiazide diuretic Calcium channel blocker DHP Beta blocker Alpha 1 blocker Average (#) Wright JT et al. N Engl J Med. 2015;373: Aldosterone receptor blocker DHP: Dihydropyridine

67 SPRINT: Antihypertensive Utilization Number of Agents Intensive (%) Standard (%) Class Intensive (%) Standard (%) ACEI/ARB Thiazide diuretic Calcium channel blocker DHP Beta blocker Alpha 1 blocker Average (#) Wright JT et al. N Engl J Med. 2015;373: Aldosterone receptor blocker DHP: Dihydropyridine

68 % Patients with Endpoint HR % CI HR % CI SPRINT: Results HR % CI Standard Intensive HR % CI HR % CI Primary CV Outcome CV Death MI Stroke HF Wright JT et al. N Engl J Med. 2015;373:

69 SPRINT: Results Absolute Risk Reduction Relative Risk Reduction Number Needed to Treat (3.26 years) Primary CV 1.6% 25% 63 Outcome CV Death 0.6% 43% 167 Any Death 1.2% 27% 83 HF 0.8% 38% 125 Wright JT et al. N Engl J Med. 2015;373:

70 SPRINT: Subgroup Analysis Primary Outcome Age 75 Male Non black No Prior CV Disease SBP 132 Age < 75 Female Black Prior CV Disease SBP > 132 Intensive Better No Difference Standard Better Wright JT et al. N Engl J Med. 2015;373:

71 SPRINT: Additional Considerations CV Risk Factor Management (Baseline): ASA ~ 50% Statin 43% Δin BP at Year 1: SBP 14.8 mm Hg DBP 7.6 mm Hg AE Intensive: Injurious falls Bradycardia Orthostatic hypotension AE Intensive: Hypotension Syncope Electrolyte abnormalities AKI Patient Perceived Health Status Wright JT et al. N Engl J Med. 2015;373: Berlowitz D et al. J Am Soc Hypertens. 2016;10(4):e4 e5.

72 SPRINT Analysis Outcome Age 75 CV Event Mortality HF AE AE results show trenddifferences not statistically significant Syncope AKI Hypotension Falls Williamson JD et al. JAMA. [Published online May 19, 2016]. doi: /jama

73 % Patients with Endpoint/year HR % CI HR % CI SPRINT Age 75 Years: Results HR % CI HR % CI Standard Intensive HR % CI Primary CV Outcome CV Death MI Stroke HF Williamson JD et al. JAMA. [Published online May 19, 2016]. doi: /jama

74 Intensive Blood Pressure Control: Individualizing Treatment Targets in HTN AE 1 Monitoring Pill Burden & Cost Populations excluded from SPRINT 2 Disadvantages Advantages 1 AE include: AKI, Hypotension, Syncope, Electrolyte Abnormalities 2 DM, Stroke, GFR < 20, EF < 35%, Recent MI 3 Benefits maintained in age 75 Primary CV Outcome 3 CV Death All cause Death 3 HF 3

75 Factors in Selecting Appropriate BP Target Age Access for follow up Comorbidity Compliance Risk of ADR

CV Risk Factors: Emerging Data on Management of DM2

risk Modest A1C Empagliflozin (SGLT2 Inhibitor)

careful patient selection Intensive BP Control

in patients 75 yo Careful patient selection

76 CV Risk Factors: Emerging Data on Management of DM2 & HTN DPP 4 Inhibitors CV Neutral Some agents HF risk Modest A1C Empagliflozin (SGLT2 Inhibitor) MACE, CV death, HF Modest A1C Potential AEs require careful patient selection Intensive BP Control Primary CV Outcome, Mortality, HF Benefit similar in patients 75 yo Careful patient selection required (AE, compliance, monitoring, certain populations excluded)

77 Question #1 The DPP 4 inhibitor and SGLT2 inhibitor classes for treatment of DM2 improve glycemic control and reduce CV risk. A. True B. False

78 Question #2 Which of the following DM2 medications are associated with an increased risk of HF? A. Sitagliptin B. Empagliflozin C. Saxagliptin D. All of the above

79 Question # 3 Based on current evidence or clinical practice guidelines which of the following BP goals would be appropriate for a 65 yo male with a medical history significant for HTN, HPL, and MI? A. < 150/90 mm Hg B. < 140/90 mm Hg C. < 120/90 mm Hg D. Any of the above may be supported by current evidence or clinical practice guidelines.

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