Katherine S. O Neal Pharm.D., MBA, BCACP, CDE, BC-ADM, AE-C Associate Professor The University of Oklahoma Health Sciences Center College of Pharmacy Department of Internal Medicine Oklahoma City, OK Member, Harold Hamm Diabetes Center Disclosure to Participants Notice of Requirements For Successful Completion Please refer to learning goals and objectives Learners must attend the full activity and complete the evaluation in order to claim continuing education credit/hours Conflict of Interest (COI) and Financial Relationship Disclosures: Presenter: Katherine S. O Neal, PharmD, MBA, BCACP, CDE, BC-ADM, AE-C Nothing to disclose Non-Endorsement of Products: Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity Off-Label Use: Participants will be notified by speakers to any product used for a purpose other than for which it was approved by the Food and Drug Administration. Review of FDA Guidance on Cardiovascular Outcomes for Diabetes Medication Trials and Application to Clinical Management Objectives Explain pathophysiologic defects associated with type 2 diabetes and explain the role of GLP-1 agonists and SGLT2 inhibitors in addressing these defects Detail outcomes of recent clinical studies pertaining to cardiovascular safety of GLP-1 agonists and SGLT2 inhibitors Overview of the Diabetes Landscape and CV Risks Translate clinical trial results and apply this information to individualized drug therapy 6 1
The Trend The Current Diabetes Landscape 295 million people do not have diabetes 86 million with prediabetes (26%) 29 million with diabetes (9.3%) 21 million diagnosed 8 million undiagnosed CDC.gov; American Diabetes Association, Statistics about Diabetes 8 Census.gov; American Diabetes Association, Statistics about Diabetes 9 2050 Projections Underlying Pathophysiology Ominous Octet 40 20 21% 33% 29% Low Incidence; High Mortality Same Trend; Low Mortality Boyle JP, et al. Projection of the year 2050 Popul Health Metr; 2010 0 Year 2050 Moderate Incidence; Moderate Mortality 9 Adapted From DeFronzo RA. Diabetes. 2009;58(4):773-795; Schwartz S. Diabetes Care 2016;39:179-186 Egregious Eleven 10 Natural Progression of Type 2 CV Complications β-cell failure Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Me. 2002;347:1342-1349; UKPDS 11 Adapted from American Diabetes Association. Diabetes Care. 2003;26:3160-3167; Tsao PS,et al. Arterioscler Thromb Vasc Biol. 1998;18:947-953; Hsueh WA, et al. Am J Med. 1998; 105(1A):4S-14S; American Diabetes Association. Diabetes Care. 1998;21:310-314 12 2
Age and Gender Risk CV Risk Statistics CV disease death rates 1.7x higher than those without diabetes Hospitalization rates for heart attack 1.8x higher Hospitalization rates for stroke 1.5x higher 71% of patients with diabetes are on hypertensive medication or have uncontrolled blood pressure Booth GL, et al. Relation between age and CV disease in men and women with diabetes Lancet. 2006;368:29-36 13 American Diabetes Association, Statistics about Diabetes; CDC National Diabetes Statistics Report, 2014 14 Meta-Analysis: A1c vs. CV Outcomes For every 1% increase in A1c. 15% increase in all-cause mortality 25% increase in CVD mortality 17% increase in CVD (18% in 2004) 15% increase in CHD (13% in 2004) 17% increase in fatal CHD (16% in 2004) 11% increase in heart failure 11% increase in stroke (17% in 2004) 29% increase in PAD (28% in 2004) Causes of Mortality in Patients with Diabetes Diabetes 13% Malignant Neoplasms 13% Other 9% Heart Disease and Cerebrovascular Disease 65% Zhang Y, et al. Glycosylated Hemoglobin in Relationship to CV Outcomes. PLOS One. 2012;7(8):e42551; Selvin E, et al. Metal-analysis glycosylated hemoglobin and CV disease in diabetes. Ann Intern Med. 2004;141:421-31; CVD: cardiovascular disease; CHD: coronary heart disease; PAD: Peripheral artery disease 15 Geiss LS, et al. Diabetes in America, 2 nd ed. 1995 17 Causes of Mortality in Patients with Diabetes Diabetes 11% Malignant Neoplasms 22% Other 21% Heart Disease and Cerebrovascular Disease 46% FDA Diabetes Drug Approval Process: Background and Current Focus Tancredi M, et al. Excess Mortality among Persons with Type 2. N Engl J Med, 2015 18 3
Glycemic Control for CV Outcomes CV Effects of Older Drugs ACCORD, ADVANCE, and VADT trials demonstrated that there was no benefit of intensive glucose control on primary CV endpoints in type 2 diabetes 1970 - UGDP trial concluded sulfonylureas may impair ischemic preconditioning; however, in 1998 the UKPDS refuted finding concluding no difference in rates of MI or CV death ACCORD found unexpected 22% increased relative risk of CV death with aggressive glucose lowering and trial stopped UKPDS and DCCT/EDIC demonstrated that earlier glycemic control is important for reducing long-term macrovascular complications: MI (15%, p=0.01) and all cause mortality (13%, p=0.007) 2011 - Thiazolidinedione (TZD), rosiglitazone, withdrawn due to increased risk of MI (43%, CI 1.03-1.98, P=0.03) and CV death (64%, CI 0.98-2.74, P=0.06) demonstrated in 2007 meta-analysis Das B, et al. Glycemic control and CV outcomes in diabetes. J Diabetes Metab. 2014;5(2); Coch RW, et al. Current CVOT in T2. Nutrition, Metabolism, and CV Disease. 2016;26:767-72; Nissen SE, et al. Effect of rosiglitazone. N Engl J Med. 2007;356(24):2457-71; Home PD, e tal. RECORD. Lancet. 2009. 373:2125-35; Selvin E,,et al. CVOT or oral diabetics. Arch Intern Med. 2008. 168:2070-80 Das B, et al. Glycemic control and CV outcomes in diabetes. J Diabetes Metab. 2014;5(2); Coch RW, et al. Current CVOT in T2. Nutrition, Metabolism, and CV Disease. 2016;26:767-72 19 20 Primary Endpoint - RECORD Rosiglitazone Update Significant increase in hospitalization or death due to heart failure Rosiglitazone no different to comparator (metformin + sulfonylurea or each with TZD) for primary endpoints CV death, MI, and stroke 2013 FDA removed prescribing restrictions 2015 FDA removed REMS restriction Home PD, e tal. RECORD. Lancet. 2009. 373:2125-35; Selvin E,,et al. CVOT or oral diabetics. Arch Intern Med. 2008. 168:2070-80 21 Home PD, e tal. RECORD. Lancet. 2009. 373:2125-35; Selvin E,,et al. CVOT or oral diabetics. Arch Intern Med. 2008. 168:2070-80 22 FDA Guidance for CV Risk - Overview FDA Guidance for CV Risk Risk Categories All new drugs must demonstrate that the drug will not cause an unacceptable increase in major adverse CV events (MACE) Cardiovascular endpoints include: CV mortality, MI, stroke, and can include hospitalization for acute coronary syndrome and urgent revascularization procedures Must include high risk patients: advanced disease, elderly, and some degree of renal impairment Upper bound of two-sided 95% confidence interval for estimated CV risk ratio (drug vs. control) >1.8 Approval denied. Additional single, large safety trial should be conducted that alone, or added to other trials, would satisfy this upper bound 1.3-1.8 Overall risk-benefit analysis supports approval. Single, postmarketing trial that is adequately powered or by combining results from a premarketing safety trial with a similarly designed postmarketing safety trial will be needed to definitively show the risk ratio is <1.3 <1.3 Overall risk-benefit analysis supports approval. Postmarketing trial generally not needed FDA Guidance for Industry, Dec 2008 23 FDA Guidance for Industry, Dec 2008 24 4
Timeline Overview of Drug Classes and Key Trials SAVOR- TIMI 53 EXAMINE 2013 2014 2015 2016 2017 2018 2019 2020 2021 TECOS ELIXA EMPA-REG LEADER SUSTAIN-6 GEMIGLIPTIN CVOT ITCA CVOT EXSCEL CAROLINA REWIND CARMELINA CREDENCE CANVAS DECLARE TIMI 58 CANVAS-R HARMONY VERTIS Johansen OE. Interpretation of CVOT in T2DM. World J Diabetes. 2015;6(9):1092-96 GLP-1 DPP4 SGLT-2 27 DPP4 Mechanism of Action Dipeptidyl Peptidase-4 Inhibitors (DPP4s) Suppresses glucagon secretion resulting in decreased liver glucose production Enhances insulin and amylin secretion 28 DPP4 Drug Class Overview Drugs Saxagliptin Alogliptin Sitagliptin Linagliptin DPP4 Trials Efficacy 0.6-0.8% A1c lowering CV Effects Decreased inflammation Decreased oxidative stress Decreased blood pressure Decreased lipids Decreased endothelial dysfunction Increased endothelial progenitors Antiplatelet effects Decrease vascular smooth muscle proliferation Lexi-Comp; Fadini G, et al. CV effects of DPp4 Inhibition. Vascular Pharm 2011 29 N Engl J Med 2013;369:1317-1326; Green JB, et al. N Engl J Med. 2015;373:233-42; White WB, et al. EXAMINE. N Engl J Med. 2013.369(14):1327-1335 30 5
Trial/Drug SAVOR TIMI-53 / Saxagliptin Trial Designs EXAMINE / Alogliptin TECOS / Sitagliptin DPP4 Baseline Patient Characteristics Design 16,492 patients 532 sites 7 countries Primary Endpoint CV death, MI, Unstable angina, or stroke 5,380 patients 904 sites 7 countries 14,671 patients 673 sites 38 countries CV death, MI, or stroke CV death, MI, unstable angina, or stroke Duration 2.9 years 3.3 years 3 years Population T2DM Age 40 with previous CVD or M>55, W>50 with at least 1 risk factor (dyslipidemia, smoking or hypertension) A1c 6.5-12% T2DM T2DM Age 18 Age 50 Diagnosis of acute Established CVD coronary syndrome 15-90 A1c 6.5-8% days prior to randomization A1c 6.5-11% SAVOR TIMI-53 EXAMINE TECOS Mean age 65 61 66 Mean duration of diabetes 10.3 7.3 10.0 Mean baseline A1c 8.0% 8.0% 7.2% Hypertension % 82 83 86 Dyslipidemia % 71 --- 77 Current smoker % --- 14 11 Previous HF % 13 28 18 Published 2013 2013 2015 N Engl J Med 2013;369:1317-1326 31 N Engl J Med 2013;369:1317-1326; Zannad F, et al. Lancet 2015. 385:2067-76; Green JB, et al. N Engl J Med. 2015;373:233-42 32 DPP4 Primary Endpoint DPP4 Hospitalization for Heart Failure Drug Hazard Ratio EXAMINE 11.8% 11.3% 0.96 (NA, 1.16) p<0.001 SAVOR-TIMI 53 7.4% 7.3% 1.00 (0.89-1.12) p<0.001 noninferiority p=0.99 superiority TECOS 11.6% 11.4% 0.98 (0.88-1.09) p<0.001 noninferiority Coch RW,,et al. Current CVOT in T2. Nutrition, Metabolism, and Cardiovascular Disease. 2016;26:767-772 Figure2 33 Coch RW,,et al. Current CVOT in T2. Nutrition, Metabolism, and Cardiovascular Disease. 2016;26:767-772-Figure3 34 DPP4 Summary Drugs are noninferior to placebo Adding a DPP4 does not increase risk of major adverse cardiovascular events nor does it provide CV benefit Would a longer trial reflect a benefit (<3 years)? April 2016 FDA added warning to labels for alogliptin and saxagliptin for increased risk of heart failure Risk factors include history of heart failure and kidney impairment Glucagon-Like Peptide-1 Agonist (GLP-1) FDA.gov; Lexi-Comp 35 6
GLP-1 Mechanism of Action GLP-1 CV Effects Improved weight, SBP, lipids Improved endothelial function Increased vasorelaxation Increased peripheral and coronary flow Increased ventricular function Decreased microvascular permeability 37 38 GLP-1 Drug Class Overview Drugs Liraglutide Exenatide Dulaglutide Lixisenatide Semaglutide (not FDA approved yet) Mechanism of Action Bind to GLP-1 receptors stimulating glucose dependent insulin synthesis and release, suppresses glucagon secretion, slows gastric emptying, decreases appetite Efficacy 1% A1c lowering Key Trials ELIXA (The Evaluation of Lixisenatide in Acute Coronary Syndrome) LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results) SUSTAIN-6 (Trial to Evaluate Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) Lexi-Comp Adverse Effects GI upset, pancreatitis, thyroid c-cell tumors, tachycardia, retinopathy (semaglutide) 39 40 ELIXA ELIXA Design Drug Lixisenatide vs. placebo Design 6,068 patients 49 countries Primary CV death, MI, Unstable angina, or stroke Endpoint Duration 2.9 years Population T2DM Age 30 A1c 6-10% Acute coronary syndrome even within past 180 days Published 2015 Pfeffer MA, et al. N Engl J Med. 2015;373:2247-57 41 Pfeffer MA, et al. N Engl J Med. 2015;373:2247-57 42 7
ELIXA Baseline Patient Characteristics (n=3034) Mean age 60.6 59.9 Mean duration of diabetes 9.4 9.2 Mean BMI 30.2 30.1 Mean A1c 7.6% 7.7% Hx of MI before ACS 22.1% 22.1% ACS Event: Unstable angina 17.4% 16.9% ACS Event: NSTEMI 39% 38.4% ACS Event: STEMI 43.4% 44.% Lixisenatide (n=3034) CV death, MI, stroke ELIXA Primary Endpoint (n=3034) Lixisenatide (n=3034) 13.2% 13.4% 1.02 (0.89-1.17) p=0.81 (S) p<0.001 (N) Pfeffer MA, et al. N Engl J Med. 2015;373:2247-57 43 Pfeffer MA, et al. N Engl J Med. 2015;373:2247-57 44 ELIXA Nonsignificant Findings LEADER (n=3034) Lixisenatide (n=3034) Hospital -ization for Heart Failure 4.2% 4.0% 0.96 (0.75-1.23) Death 7.4% 7.0% 0.94 from any (0.78-1.13) Cause p=0.75 p=0.50 Pfeffer MA, et al. N Engl J Med. 2015;373:2247-57 45 Marso SP, et al. N Engl J Med. 2016. 375(4):311-322 46 LEADER Design Drug Liraglutide vs. placebo Design 9,340 patients 410 sites 32 countries Primary CV death, MI, or stroke Endpoint Duration 3.8 years Population T2DM Age 50 with CVD or 60 with CVD risk factors A1c 7% Published 2016 LEADER Baseline Patient Characteristics (n=4672) Liraglutide (n=4668) Mean age 64 64.5 Mean BMI 32.5 32.5 Diabetes duration 12.9 12.8 Mean A1c 8.7% 8.7% Systolic Blood Pressure 135.9 135.9 Diastolic Blood Pressure 77.0 77.2 Established CVD 80.6% 82.1% CVD Risk Factors 19.4% 17.9% Marso SP, et al. N Engl J Med. 2016. 375(4):311-322 47 Marso SP, et al. N Engl J Med. 2016. 375(4):311-322 48 8
LEADER Primary Endpoint (n=4673) Liraglutide (n=4668) CV death, 14.9% 13.0% 0.87 MI, stroke (0.78-0.97) p<0.001(n) p=0.01 (S) NNT 66 LEADER CV Death (n=4673) Liraglutide (n=4668) CV Death 6.0% 4.7% 0.78 (0.66-0.93) p=0.007 Marso SP, et al. N Engl J Med. 2016. 375(4):311-322 49 Marso SP, et al. N Engl J Med. 2016. 375(4):311-322 50 Nonfatal MI Nonfatal Stroke LEADER Nonsignificant Findings (n=4673) Liraglutide (n=4668) 6.8% 6.0% 0.88 (0.75-1.03) 3.8% 3.4% 0.89 (0.72-1.11) p=0.11 p=0.30 SUSTAIN 6 Marso SP, et al. N Engl J Med. 2016. 375(4):311-322 51 Marso SP, et al. SUSTAIN-6. N Engl J Med. 2016. 52 SUSTAIN 6 Design Drug Semaglutide vs. placebo Design 3,297 patients 230 sites 20 countries Primary CV death, MI, or stroke Endpoint Duration 2.1 years Population T2DM Age 50 with CVD or 60 with CVD risk factors A1c 7% Published 2016 SUSTAIN 6 Baseline Patient Characteristics Semaglutide 0.5mg (n=826) Semaglutide 1mg (n=822) 0.5 mg (n=824) 1mg (n=825) Mean age 64.6 64.7 64.8 64.4 Duration* 14.3 14.1 14.0 13.2 Mean A1c 8.7% 8.7% 8.7% 8.7% Hx MI 32.2% 32.1% 32.4% 33.3% Hx Stroke 10.8% 10.8% 11.7% 13.2% Hx IHD 59.7% 60.2% 61.9% 60.1% SBP 136.1 135.8 135.8 134.8 DBP 77.1 76.9 77.5 76.7 Marso SP, et al. SUSTAIN-6. N Engl J Med. 2016. 53 Type 2 Duration; IHD: Ischemic Heart Disease; Marso SP, et al. SUSTAIN-6. N Engl J Med. 2016. 54 9
SUSTAIN 6 Primary Endpoint SUSTAIN 6 Nonfatal Stroke (n=1649) Semaglutide (n=1648) CV death, 8.9% 6.6% 0.74 MI, stroke (0.58-0.95) p<0.001(n) p=0.02 (S) NNT 45 Nonfatal Stroke (n=1649) Semaglutide (n=1648) 2.7% 1.6% 0.61 (0.38-0.99) p=0.04 Marso SP, et al. SUSTAIN-6. N Engl J Med. 2016. 55 Marso SP, et al. SUSTAIN-6. N Engl J Med. 2016. 56 Nonfatal MI CV Death SUSTAIN 6 Nonsignificant Findings (n=1649) Semaglutide (n=1648) 3.9% 2.9% 0.74 (0.51-1.08) 2.8% 2.7% 0.98 (0.65-1.48) p=0.12 p=0.92 GLP1 Summary Drugs are noninferior to placebo Patients with high CV risk: composite endpoint of rate of CV death, nonfatal MI, and nonfatal stroke significantly lower than placebo with superiority for liraglutide and semaglutide CV benefit theorized to be due to the modification of the atherosclerotic process Marso SP, et al. SUSTAIN-6. N Engl J Med. 2016. 57 58 SGLT-2 Mechanism of Action Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2) 60 10
SGLT-2 CV Effects Decreased blood pressure Decreased body weight Decreased arterial stiffness Decreased oxidative stress Decreased inflammation Increased glucagon secretion Increased cardiac function Decreased cardiac oxygen demand Lack of sympathetic nerve activation Sodium redistribution Increased uric acid excretion SGLT-2 Drug Class Overview Drugs Empagliflozin Canagliflozin Dapagliflozin Ertugliflozin (not FDA approved yet) Efficacy 0.5-1% A1c lowering Adverse Effects Urinary tract infections Acute kidney injury Acute renal failure Diabetic ketoacidosis Male and female genital infections Increased serum potassium Increased risk of bone fractures Marx N, et al. SGLT2 Inhibition for the Reduction of CV events in High Risk Patients. Eur Heart J. 2016 61 Lexi Comp 62 Key Trials EMPA-REG EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) CANVAS (Canagliflozin Cardiovascular Assessment Study) 63 64 EMPA-REG Design Drug Empagliflozin vs. placebo Design 7,020 patients 590 sites 42 countries Primary Endpoint CV death, MI, or stroke Secondary included primary + hospitalization for unstable angina Duration 3.1 years Population T2DM BMI 45 kg/m 2 A1c 7-10% Established CVD Published 2015 EMPA-REG Baseline Patient Characteristics 10mg (n=2345) 25mg (n=2342) (n=2333) Mean age 63 63.2 63.2 Mean duration of 57.7% 56.3% 57.4% diabetes, >10yrs Mean baseline A1c 8.07% 8.06% 8.08% History of MI 47.2% 46.2% 46.4% BMI 30.6 30.6 30.7 LDL Cholesterol 86.3 85.5 84.9 On STATIN therapy 77.9% 77.0% 76.0% Systolic Blood Pressure 134.9 135.6 135.8 Diastolic Blood Pressure 76.6 76.6 76.8 65 66 11
EMPA-REG Outcomes EMPA-REG Primary Endpoint (n=2333) Empagliflozin (n=4687) p- value NNT Primary Outcome 282 (12.1%) 490 (10.5%) 0.86 (0.74-0.99) Noninferiority <0.001 62.5 HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* Superiority 14% Superiority 0.04 Secondary Outcome 333 (14.3) 599 (12.8) 0.89 (0.78-1.01) 56.7 Noninferiority <0.001 Superiority <0.08 Death From any cause 194 (8.3) 269 (5.7) 0.68 (0.57-0.82) <0.001 38.5 From CV cause 137 (5.9) 172 (3.7) 0.62 (0.49-0.77) <0.001 45.5 67 68 EMPA-REG CV Death EMPA-REG All-Cause Mortality 38% 32% 69 70 EMPA-REG Heart Failure EMPA-REG Nonsignificant Findings 35% (n=2333) Empagliflozin (n=4687) Hazard Ratio Nonfatal MI 5.2% 4.5% 0.87 (0.70-1.09) p=0.22 Nonfatal stroke 2.6% 3.2% 1.24 (0.92-1.67) p=0.16 71 72 12
EMPA-REG - Other Findings CANVAS and CANVAS-R Reduction in A1c with no increase in hypoglycemia (0.24-0.6% drop) Reductions in weight (2kg) Reductions in blood pressure (4/2 mmhg) Small increase in LDL and HDL cholesterol Similar findings in both doses of drugs used (10 mg and 25 mg) 46% risk reduction in composite doubling of serum creatinine, initiation of renal replacement therapy, or death caused by renal disease (p=0.0002) ; Mudalair S, et al. Diabetes Care 2016; 39:1115 73 Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 74 Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med CANVAS Design Drug Canagliflozin vs. placebo Design 10,142 patients 667 sites 30 countries Primary Endpoint CV death, MI, or stroke CANVAS-R to assess effects on albuminuria Duration Followed for a mean of 188.2 weeks (8 yrs total from study start) Population T2DM A1c 7-10.5% Age 30 with symptomatic ASCVD or 50 with at least 2 CV risk factors Published 2017 75 CANVAS Baseline Patient Characteristics Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med canagliflozin (n=5795) (n=4347) Mean age 63.3 63.4 Mean duration of diabetes 13.5 years 13.7 years Mean baseline A1c 8.2% 8.2% History of CVD 64.8% 66.7% BMI 31.9 32.0 egfr 76.7 76.2 Microalbuminuria 23% 22% Macroalbuminuria 7.1% 8.2% Systolic blood pressure 136.4 136.9 Diastolic blood pressure 77.6 77.8 76 CANVAS Outcomes canagliflozin (n=5795) (n=4347) Primary Outcome 26.9% 31.5% 0.86 (0.75-0.97) Noninferiority Superiority Secondary Outcomes p<0.001 p=0.02 CANVAS Primary Endpoint HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* 14% Superiority Death from any cause 17.3 participants/1000 patient-years 19.5 0.87 (0.74-1.01) p=0.24 Death from CV cause 11.6 12.8 0.87 (0.72-1.06) p=0.24 Hospitalization for HF 5.5 8.7 0.67 (0.52-0.87) p>0.05 Progression of albuminuria 89.4 128.7 0.73 (0.67-0.79) p>0.05 Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 77 Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 78 13
CANVAS All-Cause Mortality CANVAS Heart Failure 32% 35% Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 79 Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 80 Beneficial Mechanisms? Effect Hemodynamic Osmotic diuresis Decreased blood pressure Decreased arterial stiffness Direct effect on myocardium Decreased sympathetic tone Metabolic Glycemic control Increased fatty acid oxidation Increased ketones Increased uric acid excretion Increased glucagon Weight loss Changes in sodium level Theory For: Reduces extracellular volume and vascular pressure, lowering ventricular preload and afterload Against: CV benefits seen within 3 months, these effects take much longer to have an impact For: Specifically, increased ketone bodies improve myocardial and renal fuel metabolism and is rapid in onset Against: CV benefits seen within 3 months, these effects take much longer to have an impact or causal association not established SGLT2 Summary Unclear as to the exact mechanism Upcoming trials should help clarify Class effect Mechanism Effect on slowing atherosclerosis FDA voted in a 12-11 vote 6/28/16 in favor of changing the drug label of empagliflozin to reflect a reduction in death from heart related disease Adapted from: Abdul-Ghani M, et al. SGLT2 inhibitors and CV risk. Diabetes Care. 2016;39:717-725; Mudaliar S, et al. Diabetes Care. 2016;39:1115 81 82 Summary Study SAVOR TIMI 53 EXAMINE TECOS CAROLINA CARMELIN A DPP4 Saxagliptin Alogliptin Sitagliptin Linagliptin Linagliptin Comparator Sulfonylurea N 16492 5380 14671 6000 8300 Results 2013 2013 2015 2018 2018 Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND GLP1 Liraglutide Lixisenatide Semaglutide Exenatide LR Dulaglutide Comparator N 9340 6068 3297 9500 9600 Results 2015 2015 2016 2018 2019 Study EMPA-REG CANVAS DECLARE VERTIS SLGT2 Empagliflozin Canagliflozin Dapagliflozi n Ertugliflozin Comparator N 7020 10,142 17276 3900 Results 2015 2017 2019 2021 84 14
ADA/EASD T2D Algorithm Summary - Clinical Implications In patients at high CV risk, drug classes with proven benefit could serve as preferential options GLP1, DPP4 and SGLT2 have demonstrated CV safety (noninferior to placebo) Benefits noted in high risk populations may not be translatable to lower risk patients The long-term effects of medications are not known Trials were designed to assess CV safety Trials do not clarify or change the optimal sequence medications that are used in type 2 diabetes Consider patient specific factors when choosing drug therapy Diabetes Care 2017;40(Suppl. 1):S64 S74 85 86 Case Studies Stay Tuned Case 1 Patient: 60 yo female PMH: Type 2 DM (5 yrs), CHF (2 yrs), HTN (9 yrs), osteoporosis (1 yr), MI (5 yrs ago) SH: Running, tennis, denies smoking and alcohol Weight: 198 lbs, BMI 29 kg/m 2 Labs: A1c 8.1%, egfr 55 ml/min/1.73m 2, T- score (-) 2.7, FRAX Major 23%, Hip 6% DM Medication: Metformin 1000mg twice daily Case 2 Patient: 67 yo male PMH: Type 2 DM (2 yrs), CAD, pancreatitis Labs: A1c 8.1% DM Medication: Metformin 1000mg twice daily Which medication would be appropriate to add on for her diabetes? A. alogliptin C. empagliflozin B. glyburide D. liraglutide Which medication would be appropriate to add on for his diabetes? A. alogliptin C. empagliflozin B. glyburide D. liraglutide 89 90 15
References 1. CDC.gov; American Diabetes Association, Statistics about Diabetes 2. Census.gov; American Diabetes Association, Statistics about Diabetes 3. Boyle JP, et al. Projection of the year 2050 and burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr; 2010 4. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm. Diabetes. 2009;58(4):773-795 5. Ramlo-Halsted BA, Edelman SV. The natural history of diabetes. Implications for clinical practice. Prim Care. 1999;26:771-789 6. Nathan DM. Medical management of hyperglycemia in type 2 diabetes. N Engl J Me. 2002;347:1342-1349 7. Follow up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160-3167 8. Tsao PS,et al. Interaction of Diabetes and Hypertension on Determinants of Endothelial Adhesiveness. Arterioscler Thromb Vasc Biol. 1998;18:947-953 9. Hsueh WA, et al. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am J Med. 1998; 105(1A):4S-14S 10. Booth GL, et al. Relation between age and CV disease in men and women with diabetes Lancet. 2006;368:29-36 11. Zhang Y, et al. Glycosylated Hemoglobin in Relationship to CV Outcomes. PLOS One. 2012;7(8):e42551 12. Selvin E, et al. Metal-analysis glycosylated hemoglobin and CV disease in diabetes. Ann Intern Med. 2004;141:421-31 13. Geiss LS, et al. Diabetes in America, 2nd ed. 1995 14. Tancredi M, et al. Excess Mortality among Persons with Type 2. N Engl J Med, 2015 15. Das B, et al. Glycemic control and CV outcomes in diabetes. J Diabetes Metab. 2014;5(2) 16. Coch RW, et al. Current cardiovascular outcomes trials in type 2 diabetes. Nutrition, Metabolism, and CV Disease. 2016;26:767 17. Nissen SE, et al. Effect of rosiglitazone on the risk of myocardial infarction and death. N Engl J Med. 2007;356(24):2457-71 18. Home PD, e tal. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009. 373:2125-35 19. Selvin E,,et al. Cardiovascular outcomes in trials of oral diabetics. Arch Intern Med. 2008. 168:2070-80 20. FDA Guidance for Industry, Dec 2008 21. Clinicaltrials.gov 22. Scirica BM, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-1326 23. Green JB, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:233-42 24. White WB, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013.369(14):1327-1335 25. Pfeffer MA, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-57 26. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016. 375(4):311-322 27. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117 28. Neal B, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 16