Treatment of Type 2 Diabetes: One Size Does Not Fit All

Treatment of Type 2 Diabetes: One Size Does Not Fit All Lisa Kroon, PharmD, CDE, FCSHP Professor and Chair, Clinical Pharmacy School of Pharmacy, University of California San Francisco

Disclosure No conflict of interest to disclose

Learning Objectives 1. Summarize the key changes to the ADA Standards of Medical Care in Diabetes-2015. 2. Review the classes of medications used in type 2 diabetes and their place in therapy. 3. Discuss the ADA approaches to glycemic treatment for type 2 diabetes with emphasis on how to individualize therapy, taking into account evidence of particular therapies on their effect on reducing the risk of long-term diabetes complications.

Case Study MK, a 52 year old male, was diagnosed with type 2 diabetes by his primary care provider. [A1C 8.1%; LDL-C 66;TG 148;HDL-C 53; BMI 32; BP136/80]. Other medical problems include hypertension (on HCTZ 25 mg daily, benazepril 40 mg daily) and dyslipidemia (on atorvastatin 40 mg daily). He was started on metformin by his PCP. Over the next 2 months, the metformin is titrated to 1000 mg BID. His A1C is now 7.1%. What is your assessment of his glycemic control? Is he at goal? What are other strategies for his glycemic control and overall diabetes management? What other standards of care for diabetes should MK receive?

Diabetes Mellitus: U.S. Impact Source: ADA; released June 10, 2014 [12-14% in 2012] ~1-1.5 Million Type 1 (5%) Diabetes (A1C 6.5%) 29.1 Million (9.3%) 2/3 Diagnosed ~28 Million Type 2 1/3 Undiagnosed (8.1 Million) Pre-Diabetes (A1C 5.7-6.4%) 86 Million (37%; people age 20 and older) 50% of U.S. population has either prediabetes or diabetes

Age-Adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults Aged 18 Years or older Obesity (BMI 30 kg/m 2 ) 1994 2000 2010 No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Diabetes 1994 2000 2010 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

UKPDS 10-year Cohort Data: Reductions with Intensive Vs. Conventional Therapy A1C results: 7.0% vs 7.9% 0 HbA 1c All-Cause Mortality Diabetes-Related Death Any Diabetes- Related Complication Myocardial Infarction Microvascular Complication -10-20 -30-11% -6% -10% -12% (p=0.029) For every 1 % A1C, a 35% in risk of microvascular complications -16% (p=0.052) -25% (p=0.0099) UKPDS Group. Lancet. 1998;352:837-853.

UKPDS-10 year Follow-Up Glucose Control Holman RR et al. NEJM 2008;359:1577 [UKPDS 80] 3,277 patients (of 4,209) entered post-trial monitoring; seen annually for 5 years Mean Glycated Hemoglobin: Difference between conventional and control groups lost within 1 year after study ended

Outcome UKPDS-10 year Follow-Up Clinical Outcomes SFU and Insulin Groups Relative Risk (p-value) Metformin Group Relative Risk (pvalue) Any DM-related endpoint 9% (0.04) 21% (0.01) MI 15% (0.01) 33% (0.005) Microvascular disease 24% (0.001) 16% (0.31) Death from any cause 13% (0.007) 27% (0.002) Legacy Effect Holman RR et al. NEJM 2008;359:1577 [UKPDS 80]

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow-up * in T1DM

STANDARDS OF MEDICAL CARE IN DIABETES 2015

Antihyperglycemic Therapy in Type 2 Diabetes ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1; adapted with ADA. Standards of Medical Care-2015. permission Diabetes from Inzucchi Care SE, et 2015;38;Suppl al. Diabetes Care, 2015;38:140-149 1

Glycemic Goals HbA1c < 7.0% (mean PG 150-160 mg/dl) Pre-prandial PG 80-130 mg/dl Post-prandial PG <180 mg/dl Individualization is key: Tighter targets (<6.5%) - younger, healthier Looser targets (<8.0%) - older, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia PG=plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Approach to the Management of Hyperglycemia ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Lifestyle Modification Therapeutic options: Lifestyle - Weight optimization - Healthy diet ( nutrition therapy ) - Increased activity level Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

20 oz bottle 65 gm CHO (sugar) 75 mg sodium 240 calories

Why Metformin as 1 st Line? Only type 2 DM medication shown to have long-term impact on macrovasular complications Stimulates AMP-activated protein kinase, which hepatic glucose output Inhibits mitochondrial respiratory chain, causing shift towards anaerobic metabolism (lactate is by-product) resulting in energy for gluconeogenesis +CV effects: TG, LDL-C, HDL-C; improves endothelial function Other effects:? anticancer properties SE: GI (diarrhea, nausea, anorexia, metallic taste), lactic acidosis, vit B 12 deficiency No weight gain; no hypoglycemia (except when used in combo therapy) Inzucchi SE. JAMA, 2014;314:2668-75. Salpeter SR. Arch Intern Med. 2003;163:2550.

Metformin: CI/Precautions Jan 2009 Glucophage package insert Contraindications Renal disease or dysfunction scr 1.4 mg/dl in women and 1.5 mg/dl in men abnormal creatinine clearance; particularly cautious if 80 yrs of age Acute or chronic metabolic acidosis Precautions Active liver disease Excessive alcohol use or alcoholism Hypoxic states (HF-unstable/acute; acute MI) Other: radiologic studies using iodinated contrast materials (stop at time of/prior to and withhold 48 hr after)

Metformin in Renal Dysfunction Incidence of lactic acidosis among metformin users is 3 to 10/100,000 person-years (almost indistinguishable from rate in people with diabetes not on metformin) Suggested approach: Inzucchi SE. JAMA, 2014;314:2668-75.

Case Study MK, a 52 year old male, was diagnosed with type 2 diabetes by his primary care provider. [A1C 8.1%; LDL-C 66;TG 148;HDL-C 53; BMI 32; BP136/80]. Other medical problems include hypertension (on HCTZ 25 mg daily, benazepril 40 mg daily) and dyslipidemia (on atorvastatin 40 mg daily). He was started on metformin by his PCP. Over the next 2 months, the metformin is titrated to 1000 mg BID. His A1C is now 7.1%. What is your assessment of his glycemic control? Is he at goal? Yes, or close to What are other strategies for his glycemic control and overall diabetes management? Diet, physical activity, SMBG if not already What other standards of care for diabetes should MK receive? Immunizations (PCV13, PPSV23), albuminuria test, ophtho (annual; or q2-3 years if no retinopathy present), other CV risk reduction (BP, lipids)

Case Study, cont d It is now 2 years later and MK still is taking metformin 1000 mg po BID. Labs: A1C 8.3% (was as low as 6.5% 1 year after starting metformin); Cr 0.9;LFT s wnl; BMI 28. What is your assessment? What is his A1C goal? What do you recommend?

Advancing to Dual Therapy On meformin already: SFU (or glinide) DPP-4 inhibitor GLP-1 RA TZD SGLT-2 inhibitor Insulin (usually basal insulin)

Antihyperglycemic Therapy in Type 2 Diabetes Combination Therapy: Combine Agents with Different Mechanisms of Action ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

DPP-4 Inhibitors GLP-1 Rec. Agonists SFUs/Glinides GLP-1 Rec. Agonists Acarbose Miglitol TZDs Metformin http://professional.diabetes.org/imagebank.aspx

TZDs & CVD Risk: Rosiglitazone On 9/22/2010, rosiglitazone become available through restricted access only (meta-analysis in NEJM, 5/21/07 and redone in 2010 - significantly risk of MI by 28% [OR 1.28]) June 5-6, 2013, readjudicated results of RECORD were discussed by FDA; committee members voted to eliminate REMS or lessen restrictions. FDA announced (11/25/13) to remove restrictions on Avandia.

Pioglitazone & CVD risk and other ADEs Pioglitazone does not appear to have MI risk, however does increase risk for heart failure Observational study suggests rosi has HR for heart failure of 1.25 compared to pioglitazone in an elderly population (Graham DJ et al. JAMA 2010;304) On 8/4/11, FDA updated safety announcement indicated label changes to Actos to reflect that use of pioglitazone for more than one year may be associated with an increased risk of bladder cancer. TZDs use due to ADEs (e.g., increases risk HR, edema, reduced bone density) have reduced use overall

Incretin-Based Therapies Gut hormones released postprandially 2 main gut incretins Glucose-dependent insulinotropic polypeptide (GIP) Released by K cells in duodenum Glucagon-like peptide-1 (GLP-1) Released by L cells in small intestines Levels are diminished in type 2 DM post-meal; t 1/2 <2 minutes Rapidly degraded by dipeptidyl peptidase IV (DPP-IV) GLP-1 analogs (injectable) Exenatide (BID and weekly) Liraglutide (injected daily) Albiglutide (injected weekly) Dulaglutide (injected weekly) DPP-IV inhibitors (oral, daily): sitagliptin, saxagliptin, linagliptin, alogliptin

Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Incretin effect accounts for 50-70% of insulin response to oral glucose. Vilsboll T et al. Diabetologia. 2004;47:357-66 Plasma Glucose (mg/dl) 200 100 C-peptide (nmol/l) 2.0 * 1.5 * * 1.0 0.5 * Incretin Effect * * * 0 0.0 0 60 120 180 Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498 0 60 120 180 Time (min)

Actions of GLP-1 GLP-1: Secreted upon the ingestion of food Promotes satiety and inhibits appetite Alpha cells: Postprandial glucagon secretion Beta cells: -Enhances glucose-dependent insulin secretion - Beta cell mass - apoptosis Liver: Glucagon reduces hepatic glucose output Stomach: Slows gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

2-h Postprandial Plasma GLP-1 (pm) Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1 75 50 25 0 7.2 7.9 15.1 63.8 75 50 25 0 2-h Plasma Exenatide (pm) Baseline Exenatide Sitagliptin Plasma GLP-1 Plasma Exenatide Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE 2-wk post-treatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952

GLP-1 Agonists: Nausea While nausea declines after 3 weeks, it persists in some patients. Pratley R et al. Int J Clin Pract 2011;65:397-407

Comparison of GLP-1 RAs (A1C) DeVries JH et al. Diabetes Care. 2012

Comparison of GLP-1 RAs (A1C) DeVries JH et al. Diabetes Care. 2012

Liraglutide shows improved effect on weight compared to other therapies Niswender K et al. Diabetes Obes Metab. 2013

GLP-1 RAs + Insulin (basal) Balena R et al. Diabetes Obes Metab. 2012

Sequential intensification of therapy with liraglutide followed by basal insulin DeVries JH et al. Diabetes Care. 2012

GLP-1 RA can help counteract weight gain with insulin DeVries JH et al. Diabetes Care. 2012

GLP-RAs vs. DPP-4 Inhibitors (not head-to-head) Aroda VR et al. Clinical Therapeutics. 2012

DPP4-Inhibitors: head-to-head with other oral agents AJ Scheen. Diabetes & Metabolism. 2012

Incretin Agents: Safety Concerns Thyroid cancer and neoplasia Thyroid C-cell tumors in rodent models CI/not recommended for use in patients with personal or family history of MTC (medullary thyroid cancer) or MEN 2 Joint pain (08/28/15: FDA safety alert for DPP-4 inhibitors) Pancreatic cancer Butler et al. Diabetes 2013 Exocrine cell proliferation and dysplasia (panins) Pancreatitis

Incretin Therapy and Pancreatitis Pancreatitis 1 st noted with exenatide (0.33-5.7 cases per 1000 patient years) Risk of pancreatitis difficult to determine due to: Low event rate Type 2 diabetes associated with 3-fold increased risk FDA and EMA independent reviews of patient and animal data: no evidence of causal relationship, but recommend risk to be disclosed and further investigation (Egan et al, NEJM 2014) Avoid if history of pancreatitis, gallstones, alcoholism, hypertriglyceridemia Patient education: abdominal pain (persistent, severe, radiating to back, N/V, anorexia) to contact provider

Lack of increased risk of pancreatitis specific to incretin-based therapy use Thomsen RW et al. Diabetes Care. 2015

SGLT-2 inhibitors SGLT-2 inhibitor class: inhibit sodium glucose cotransporter-2 in proximal tubules, where ~90% of glucose filtered through nephron is reabsorbed Chao EC & Henry RR. Nat Rev Drug Disc. 2010

SGLT-2 Inhibitors, cont. Several options 3/29/13: canagliflozin (Ivokana): 09.10.15 FDA safety alert for bone fracture risk/decreased bone density 1/8/14: dapagliflozin (Farxiga): Previously rejected approval 1/2012 due to breast & bladder cancer concerns; Do no use in patients with bladder cancer 08/01/14: empagliflozin (Jardiance) ADEs Common side effects: genital fungal infections and UTIs (due to increased glucose in urine) Increased risk of dehydration, hypovolemia, hypotension, dizziness in 1 st few months (diuretic effect) egfr limits (<45, 60 GFR) Euglycemic DKA reports A1C lowering 0.5-0.8

Ongoing CV Risk Outcome Trials Drug Trial Name ClinicalTrials.gov identifier Dulaglutide REWIND NCT01394952 Exenatide EXSCEL NCT01144338 Liraglutide LEADER NCT01179048 Canagliflozin CANVAS NCT01032629 Dapagliflozin DECLARE-TIMI58 NCT01730534 Empagliflozin EMPA-REG OUTCOME* NCT01131676 Multiple oral agents BMS NCT01086280 TZDs vs. SFUs TOSCA-IT NCT00700856 Linagliptin vs. Glimepiride CAROLINA NCT01243424 Completed Insulin glargine (U-100) ORIGIN NCT00069784 Saxagliptin SAVOR-TIMI53 NCT01107886 Sitagliptin TECOS NCT00790205 *Promising data at EASD 2015

Saxagliptin & CV Outcomes Note: rate of hospitalization for HF increased Scirica BM et al. NEJM. 2013

Sitagliptin and CV Outcomes Green JB et al. NEJM. 2015

Case Study, cont d What 2 nd agent would you add? SFU ( or glinide) DPP-4 inhibitor GLP-1 RA SGLT-2 inhibitor Insulin

Advancing to Triple Therapy? Which One? (added to metformin & SFU) Gross JL. Ann Intern Med. 2011;154:672-79

Case Study, cont d How would you modify his therapy if he was obese? he developed renal dysfunction? he had severe liver dysfunction? this was a postmenopausal woman (or person with osteopenia/osteoporosis)? he was elderly with a history of an MI? his A1C was 10.4% on metformin only? Or on 2 (or 3) non-insulin therapies?

Individualizing Therapy: Examples Circumstance Avoid Consider Renal dysfunction Metformin, certain SFUs Glipizide, glinides, DPP-4 inhibitors (dose adjust) Severe liver dysfunction Most agents Insulin, metformin Overweight/obese TZD Metformin, GLP-1 agonist, DPP- 4 inhibitor Heart failure Reduced bone density or osteoporosis History of pancreatitis History of bladder cancer TZD, metformin (only unstable/severe) TZD, Canagliflozin GLP-1 agonist, DPP-4 inhibitor Pioglitazone, Dapagliflozin Most other agents Most other agents Most other agents Most other agents Pre-existing edema TZD Most other agents Joint pain DPP-4 inhbitors Most other agents

1. Set A1C target Patient factors Individualizing Care Provider considerations 2. Assess how close patient is to target Why or why not? Changes since last visit (improve/worsen/same) Assess adherence, medication SEs, lifestyle (exercise, meals); psychosocial factors 3. Create a patient-specific plan to reach target Is patient on submax/therapeutic dose of particular medication? Titrate Is patient on max/therapeutic dose of medication? Add-on? Insulin? Adapted from Anne Peters, MD. February 9, 2014

Individualizing Care, cont d 4. Goal setting http://guidelines.diabetes.ca/selfmanagementeducation/smetools

Individualizing Care, cont d 5. Summarize plans from visit Teach back Handouts 6. Follow-up Continual guidance/support http://guidelines.diabetes.ca/selfmanagementeducatio n/smeactionplan

Test Questions 1. A 70 year old male previously received the pneumococcal vaccination (PPSV23) when he was diagnosed with type 2 diabetes at age 50. According to the 2015 American Diabetes Association Standards of Medical Care, the following vaccine is now routinely recommended for him if he has not previously received it: a. Hepatitis B vaccination b. PCV13 vaccination c. Meningococcal vaccination d. Hepatitis A vaccination 2. A 78 year old male with a 20 year history of type 2 diabetes is taking metformin, sitagliptin, glipizide and insulin glargine. His medical problems include hypertension, dyslipidemia, background retinopathy, and a history of a myocardial infarction (10 years ago). His glipizide dose was recently reduced due to mild hypoglycemic episodes. What would be a reasonable A1C target for him according to the American Diabetes Association Guidelines? a. <6% b. <7% c. <8% d. <10% 3. A 52 year old female with type 2 diabetes is taking metformin and glimepiride. She is obese (BMI is 35). Her A1C is 8%. What class of agents would be a reasonable addition to help improve her glycemic control and lose weight? a. GLP-1 receptor agonist b. Thiazolidinedione c. Long-acting insulin d. DPP-4 inhibitor

Questions?

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