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Disclosure No conflict of interest to disclose. New Drugs for Diabetes: Which Ones, Which Patients? Lisa Kroon, PharmD, CDE Chair and Professor of Clinical Pharmacy UCSF School of Pharmacy Diabetes: U.S. Impact Learning Objectives 1 in 7 Americans has Diabetes § Describe the 2018 American Diabetes Association’s pharmacologic approaches to glycemic treatment § Describe the mechanism of action(s) and unique characteristics of the various (new) classes of medications used in type 2 diabetes that are recommended as add-on therapy to metformin. § Discuss contraindications/warnings/precautions for use and side effect profiles of these medications. § Select among the classes of medications to develop appropriate and effective medication regimens to improve glycemic control for an individual patient. https://www.cdc.gov/nchs/data/databriefs/db319.pdf (Sept. 2018; NHANES 2013-2016) 1 | [footer text here]

Diabetes Prevalence by Race and Hispanic Diabetes Prevalence by Weight Origin https://www.cdc.gov/nchs/data/databriefs/db319.pdf https://www.cdc.gov/nchs/data/databriefs/db319.pdf (Sept. 2018; NHANES 2013-2016) (Sept. 2018; NHANES 2013-2016) DCCT: Cumulative Incidence of First Occurrence of Diabetes-Related Complications among U.S. Adults with and Nonfatal Myocardial Infarction, Stroke, or Death from without Diagnosed Diabetes (1990–2010) Cardiovascular Disease 57% ↓ r isk The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Gregg EW et al. N Engl J Med 2014;370:1514-1523 . Complications (DCCT/EDIC) Study Research Group. N Engl J Med 2005;353:2643-2653. 2 | [footer text here]

UKPDS-10 year Follow-Up: UKPDS-10 year Follow-Up: Glucose Control Clinical Outcomes 3,277 patients (of 4,209) entered post-trial monitoring; seen annually for 5 years Outcome SFU and Insulin Groups Metformin Group Relative Risk (p-value) Relative Risk (p-value) Mean A1C: Difference between Any DM-related endpoint ↓ 9% (0.04) ↓ 21% (0.01) conventional and MI ↓ 15% (0.01) ↓ 33% (0.005) control groups lost Microvascular disease ↓ 24% (0.001) ↓ 16% (0.31) within 1 year after study ended Death from any cause ↓ 13% (0.007) ↓ 27% (0.002) “Legacy Effect” Across studies to date, tight glycemic control consistently ↓ RR of nonfatal MI by 15%. Holman RR et al. NEJM 2008;359:1577 [UKPDS 80] Holman RR et al. NEJM 2008;359:1577 [UKPDS 80] Rodriguez-Gutierrez R, Montori RM. Circ Cardiovasc Qual Outcomes; 2016. 9(5):504-12. Medication Treatment Options Since 2005 Medication Treatment Options To 2000 § Amylin (pramlintide) § Insulin (human and analogs) § Glucagon-like peptide receptors agonists (GLP-1 RAs) § Sulfonylureas (1950’s) § Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) § Biguanides (metformin 12/94) § Bile acid sequestrants (colesevelam) § Alpha-glucosidase inhibitors (Acarbose 9/95) § Dopamine agonist (bromocriptine) § Meglitinides (Repaglinide 12/97; Nateglinide 12/00) § Sodium-glucose cotransporter- 2 inhibitors (SGLT-2 § Thiazolidinediones (Rosiglitazone 5/99; Pioglitazone 7/99) inhibitors) 3 | [footer text here]

Type 2 Diabetes Drug Utilization Glycemic Control Among T2DM Patients, 2006–2013 2006-2013 Brand medications $300-$450 + monthly § Recent price increases § - Glutmetza (metformin XL MOD) For 1000 mg pill: $133.60 § For generic metformin ER pill: $1.50 § For generic metformin IR pill: $0.08-$1.45 § - Insulins: Humulin U-500 vial $220 to $1,200 (6/2014) Generic availabilities ( $4 generics) § Lipska KJ et al. Diabetes Care 2017;40:468-475. Kasia J. Lipska et al. Diabetes Care 2017;40:468-475. STANDARDS OF MEDICAL CARE IN DIABETES American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 4 | [footer text here]

Recommendations: Pharmacologic Therapy For T2 Diabetes § Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for T2DM. A § Consider insulin therapy (with or without additional agents) in patients with newly dx’d T2DM who are markedly symptomatic* and/or have elevated blood glucose levels (>300 mg/dL) or A1C (>10%). E *Symptomatic: 3 P’s (polyuria, polydipsia, polyphagia), fatigue, and weight loss § Consider initiating dual therapy in patients with newly diagnosed T2DM who have A1C >9%. E American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 5 | [footer text here]

Pharmacologic Therapy For T2DM, cont’d Pharmacologic Therapy For T2DM, cont’d Long-term use of metformin may be associated with biochemical vitamin B12 In patients with T2DM and established ASCVD, antihyperglycemic therapy should § § deficiency, and periodic measurement of vitamin B12 levels should be considered in begin with lifestyle management and metformin and subsequently incorporate an metformin-treated patients, especially in those with anemia or peripheral neuropathy. B agent proven to reduce major adverse CV events and CV mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors In patients without atherosclerotic cardiovascular disease (ASCVD), if monotherapy or ( Table 8.1 ). A § dual therapy does not achieve or maintain the A1C goal over 3 months, add an additional antihyperglycemic agent based on drug-specific and patient factors (Table In patients with T2DM and established ASCVD, after lifestyle management and § 8.1). A metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse CV events , based on drug-specific and patient factors ( Table 8.1 ). C A patient-centered approach should be used to guide the choice of pharmacologic § agents. Considerations include efficacy, hypoglycemia risk, history of ASCVD, impact on weight, potential side effects, renal effects, delivery method, cost, and patient preferences. E American Diabetes Association Standards of Medical Care in Diabetes. American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Approaches to glycemic treatment. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Glycemic Goals Pharmacologic Therapy For T2DM, cont’d ü HbA1c < 7.0% (mean PG 154 mg/dl) ü Pre-prandial PG 80-130 mg/dl Continuous reevaluation of the medication regimen and adjustment as needed to § incorporate patient factors ( Table 8.1 ) and regimen complexity is recommended. E ü Post-prandial PG <180 mg/dl For patients with T2DM who are not achieving glycemic goals, drug intensification, § ü Individualization is key: including consideration of insulin therapy, should not be delayed . B Ø More stringent A1C goals (<6.5%) – short duration of Metformin should be continued when used in combination with other agents, § including insulin , if not contraindicated and if tolerated. A diabetes, long life expectancy, no significant CVD. Ø Less stringent A1C goals (<8.0%) – long-standing diabetes, limited life expectancy, advanced micro/macro complications, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia American Diabetes Association Standards of Medical Care in Diabetes. American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Glycemic Targets. Diabetes Care 2018; 41 (Suppl 1): S55-S64. 6 | [footer text here]

Why Metformin as 1 st Line? Tailored Approach to the Management of Hyperglycemia A1C more less Patient/Disease Features 7% § Demonstrated long-term impact on macrovasular stringent stringent complications Risk of hypoglycemia/drug adverse effects low high § Stimulates AMP-activated protein kinase, which ¯ hepatic Disease Duration glucose output newly diagnosed long-standing - Inhibits mitochondrial respiratory chain, causing shift towards Life expectancy anaerobic metabolism (lactate is by-product) resulting in ¯ short long energy for gluconeogenesis Important comorbidities absent Few/mild severe § +CV effects: ¯ TG, ¯ LDL-C, ­ HDL-C; improves endothelial function Established vascular complications § Other effects: anticancer properties? absent Few/mild severe § SE: GI (diarrhea, nausea, anorexia, metallic taste) Patient attitude & expected § No weight gain; no hypoglycemia (except when used in highly motivated, adherent, less motivated, nonadherent, treatment efforts combo therapy); affordable poor self-care capabilities excellent self-care capabilities Resources & support system readily available limited American Diabetes Association Standards of Medical Care in Diabetes. Glycemic Targets. Diabetes Care 2018; 41 (Suppl 1): S55-S64. Metformin in Renal Dysfunction FDA Revised Metformin Warnings for Patients with Reduced Kidney Function Incidence of lactic acidosis among metformin users is 3 to § ¨ Before initiation, check eGFR 10/100,000 person-years (almost indistinguishable from rate in ¨ Check eGFR annually; check more frequently in elderly people with diabetes not on metformin) eGFR Recommendation <30 ml/min Metformin is contraindicated 30-45 ml/min Starting metformin is not recommended After on metformin, if <45 ml/min Assess benefits and risks After on metformin, if <30 ml/min Discontinue FDA. 04.08.16 Inzucchi SE. JAMA, 2014;314:2668-75. 7 | [footer text here]