Shared Decision Making and the Medical Treatment of Type 2 Diabetes

Speaker’s Disclosure There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Objectives Review the tenets of the Shared Decision Making Model Discuss the application of the Shared Decision Making model to diabetes care. Review the important clinical properties of the available medications for type 2 diabetes.

Clinical Decision Making in Diabetes: Competing Forces Evidence-Based Medicine Clinical Practice Guidelines “Quality” Patient-Centered Care

“Traditional” Paternalistic model of Doctor and Patient Physician Provider Proposes Treatment Patient expresses Resistance Provider presents Evidence Both experience Frustration

New Model: Shared Decision Making Physician Patient Support patient Self Determination Develop relational autonomy. Educate, Provide Options Elicit preferences based on value judgements

New Model: Shared Decision Making Physician Patient

There are now 12 CLASSES of FDA-Approved Antidiabetes Agents Insulin Biguanides (Metformin) Sulfonylureas (Glimepiride, Glipizide, Glyburide, etc.) Meglitinides (Repaglinide, etc.) Incretin Agonists (Exenatide, Liraglutide) Once-Weekly (Exenatide, Dulaglutide, Albiglutide) DPP-4 Inhibitors (Sitagliptin, Saxagliptin, etc.) SGLT2 inhibitors (Canagliflozin, Empagliflozin, etc.) Thiazolidinediones (Pioglitazone) A-Glucosidase Inhibitors (Acarbose, Miglitol) Bile Acid Sequestrant (Colesevalam) Amylin Mimetic (Pramlintide) Dopamine-2r Agonist (Bromocriptine)

Optimal Monotherapy of DM2: Metformin unless Contraindicated Recommended first-line therapy by all major clinical practice guidelines: ADA, ACP, AACE Metformin offers multiple secondary benefits: Stabilization in body weight, or modest weight loss. Improvement in serum lipid profile (LDLc, TG) Likely reduction in cardiovascular events (UKPDS 10-year extension) Mortality / Survival benefit in certain populations Lower Cancer Incidence, fewer cancer deaths ADA Standards of Medical Care in Diabetes, 2016

Beware: Metformin XR 1000mg tabs will cost your patients $$$$ Extended-release metformin 500mg tabs are generic. Cost $8-10 per month for 120 tabs at most pharmacies. Extended-release 1000mg tabs are brand-only (Glumetza). Current avg price: $1571

Revised FDA Guidance on Metformin: Safe in mild / mod CKD “We have concluded from the review of studies published in the medical literature that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.” All patients on metformin: annual eGFR GFR <60  hold metformin before radiocontrast GFR <45  do not start metformin. Pts already on metformin may continue if benefits outweigh risks. Expert advice: reduce dose to 500mg BID GFR <30  stop metformin FDA Drug Safety Communication, 4/8/2016

Choosing the Best “Second Line” Type 2 Diabetes Treatment Treatment is Individualized Cost? Efficacy? Burden of additional medications? Side effects? Effect on weight? Hypoglycemia risk? Secondary benefits?

Basal Insulin as “Second Line” Type 2 Diabetes Treatment Efficacy: High. Can be titrated accurately. Hypoglycemia risk: Very high Weight: Typical gain 2-4 kg/year

How Does Insulin Cause Weight Gain? Dose-Dependent Effects. Induces differentiation of new adipocytes from precursors. Cross-agonist of IGF-1 receptor leading to somatotropic changes, pseudo-acromegaloid features. High Doses Hypoglycemia  increased intake of rescue carbohydrates. Hypoglycemia induces surge in cortisol, HGH, ghrelin. Often, high CHO intake to prevent hypoglycemia. Induces Lipoprotein Lipase expression and glucose uptake. Stimulates de novo biosynthesis of fatty acids and TG. Increased uptake of carbs and fats into tissues. Physiologic Doses Suppresses glycosuria / polyuria. Low Doses Suppresses ketoacidosis. Blocks muscle catabolism. Allows anabolic effects of resistance training / exercise.

The “Vicious Cycle” of Insulin Therapy Weight Gain Worsening Insulin Resistance Worsening Glycemic Control Requiring more Insulin

Summary: Cost and the “Metformin Index” Drug Name Avg Retail Cost* per month “Metformin Index” Insulin Glargine (Lantus®) $178 / vial (33 units / d)  23 patients $267 / box of pens (50 units/d)  34 patients Insulin Detemir (Levemir®) $271 / vial (33 units / d) 35 patients $404 / box of pens (50 units/d) 52 patients Insulin NPH (Novolin® N) $24 / vial (33 units / d) 3 patients Ideal Patient: High Hemoglobin A1c (>10%). Longstanding “burned out” diabetes, or no response to sulfonylureas. Can tolerate weight gain. Regular / predictable diet and exercise regimen in order to minimize hypoglycemia risk. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/2017.

New Basal Insulins: Toujeo, Tresiba, Basaglar. All once-daily dosing Toujeo (Glargine u-300) Pens Dosed as daily or BID Avg retail $275 for 1 box containing 1350 units. Net cost approx. $0.20 per unit Tresiba (Degludec u-200) Pens Avg retail $463 for 1 box containing 1800 units. Net cost approx. $0.26 per unit Basaglar (Glargine u-100) Pens Avg retail $278 for 1 box containing 1500 units. Net cost approx. $0.15 per unit

Sulfonylureas as “Second Line” Type 2 Diabetes Treatments Glimepiride (Amaryl®), Glipizide (Glucotrol®), Glyburide (Micronase®) Efficacy: Very good. 1.0-1.5% A1c lowering Hypoglycemia risk: High Weight: Weight gain common Side Effects: Higher risk of progression to insulin requirement Secondary Benefits: convenient dosing

Sulfonylureas as “Second Line” Type 2 Diabetes Treatments Drug Name Avg Retail Cost* per month “Metformin Index” Glipizide (Glucotrol®) $8  1 patient Glyburide (Micronase®) Glimepiride (Amaryl®) $12  2 patients Ideal Patient: Desire to minimize cost of medications. Desire to avoid “injectables.” Lean. Can tolerate some weight gain. Regular / predictable diet and exercise regimen in order to minimize hypoglycemia risk. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/17.

Incretin Agents as “Second Line” Type 2 Diabetes Treatments Exenatide (Byetta®, Bydureon®), Liraglutide (Victoza®), Dulaglutide (Trulicity®), Albiglutide (Tanzeum®), Lixisenatide (Adlyxin®) Mechanism: Mimics the effects of anti-diabetic hormone GLP-1 Blocks release of hormone glucagon Stimulates growth and secretory activity of pancreatic beta cells. Slows emptying of stomach  reduced portion sizes. Stimulates NTS in brainstem  weight loss.

Incretin Agents as “Second Line” Type 2 Diabetes Treatments Exenatide (Byetta®, Bydureon®), Liraglutide (Victoza®), Dulaglutide (Trulicity®), Albiglutide (Tanzeum®), Lixisenatide (Adlyxin®) Efficacy: Intermediate. 0.8-1.2% A1c lowering Side Effects: Nausea, vomiting (particularly after large meal) Diarrhea, headache Rare: hemorrhagic pancreatitis Potential: c-cell hyperplasia (rodent model) Hypoglycemia risk: Minimal. Weight: Sustained modest weight loss.

Once-Weekly Incretin Agents: Exenatide Weekly (Bydureon®) Exenatide in lipid microsphere emulsion. Rapid release of surface-bound exenatide. Slow release of embedded exenatide over 10 weeks (peaks at week 2 and weeks 6-7). Standard dosing: 2mg SQ, weekly. Supplied as single dose pens. Protocol for administration is time consuming, requires multiple steps. Bydureon® prescribing information, Amylin Pharmaceuticals, 2012

Once-Weekly Incretin Agents: Albiglutide (Tanzeum®) Modified Human GLP-1 hormone, linked to albumin. Serum T1/2= 4-7 days. Supplied as single dose pens. Protocol for administration is complex, multiple steps, taking at least 15 minutes. Pancreatitis was observed in RCTs. Tanzeum® prescribing information, 2014

Once-Weekly Incretin Agents: Dulaglutide (Trulicity®) Modified Human GLP-1 hormone, linked to Fc fragment of immunoglobulin. Serum T1/2= 5 days. Efficacy is inferior to liraglutide Supplied as single dose pens. Administration protocol is simpler. Pancreatitis was observed in RCTs. Trulicity® prescribing information, 2014

Incretin Agents as “Second Line” Type 2 Diabetes Treatments Drug Name Avg Retail Cost* per month “Metformin Index” Exenatide (Byetta®) $692  89 patients Exenatide (Bydureon®) $645  83 patients Liraglutide (Victoza®) $833  107 patients Albiglutide (Tanzeum®) $542  70 patients Dulaglutide (Trulicity®) $685  88 patients Lixisenatide (Adlyxin®) $578 (new) 74 patients Ideal Patient: Obese. Desire for weight loss. Desire to avoid hypoglycemia Suitable insurance. Willing to pay more for medications. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/17.

DPP4 Inhibitors as “Second Line” Type 2 Diabetes Treatments Sitagliptin (Januvia®), Saxagliptin (Onglyza®), Linagliptin (Tradjenta®), Alogliptin (Nesina®) Mechanism: Blocks the degradation of the anti-diabetic hormone GLP-1 Blocks release of hormone glucagon Stimulates growth and secretory activity of pancreatic beta cells.

DPP-4 Inhibitors as “Second Line” Type 2 Diabetes Treatments Sitagliptin (Januvia®), Saxagliptin (Onglyza®), Linagliptin (Tradjenta®), Alogliptin (Nesina®) Efficacy: 0.8-1.1% lowering of HgbA1c Side Effects: generally well tolerated. Nausea is generally mild Hypoglycemia risk: minimal. Weight: Neutral. No significant gain or loss. Secondary Benefits: Once Daily Dosing

DPP-4 Inhibitors as “Second Line” Type 2 Diabetes Treatments Drug Name Avg Retail Cost* per month “Metformin Index” Sitagliptin (Januvia®) $416  53 patients Linagliptin (Tradjenta®) $330  42 patients Alogliptin (Nesina®) $146  19 patients Saxagliptin (Onglyza®) $372 48 patients Ideal Patient: Desires convenience of once-daily pill dosing. Desires a very mild side-effect profile. Desires to avoid weight gain. Desires oral medications over “injectables.” Willing to pay more for medications. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/17.

Pioglitazone as “Second Line” Type 2 Diabetes Treatment Efficacy: Modest. 0.5-0.8% lowering of HgbA1c Side Effects: Fluid Retention Contraindicated in heart failure. Avoid in heart disease Weight: Typical gain 2-4 kg/year. Hypoglycemia risk: minimal. Secondary Benefit: Once Daily Dosing, treats Non-Alcoholic Fatty Liver Disease

Pioglitazone as “Second Line” Type 2 Diabetes Treatment Drug Name Avg Retail Cost* per month “Metformin Index” Pioglitazone (Actos®) $13 2 patients Ideal Patient: No heart disease. Desire to minimize cost of medications. Desire convenience of once-daily pill dosing. Desire oral medications over “injectables.” Willing to tolerate weight gain. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/17.

Acarbose / Miglitol as “Second Line” Type 2 Diabetes Treatments Acarbose (Precose®), Miglitol (Glycet®) Mechanism: Blocks intestinal alpha-glucosidase  impairs digestion of disaccharides / polysaccharides Reduces postprandial glucose. Unabsorbed carbohydrates are fermented into gas by intestinal flora.

Acarbose / Miglitol as “Second Line” Type 2 Diabetes Treatments Efficacy: Decent. 0.8-1% lowering of HgbA1c Side Effects: Flatulence (esp after high-carb meal), can cause uncomfortable abdominal cramps / colicky pain. Weight: Neutral. Hypoglycemia risk: Minimal. Secondary Benefits: Fewer MIs observed in STOP-NIDDM trial. Also FDA-approved for prevention of diabetes.

Acarbose / Miglitol as “Second Line” Type 2 Diabetes Treatments Drug Name Avg Retail Cost* per month “Metformin Index” Acarbose (Precose®) $32  4 patients Ideal Patient: Desire oral medications over “injectables.” Desire modest weight loss. Desire to reduce medication costs. Willing / able to significantly reduce carb intake, or tolerate significant gas & flatulence. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/17.

Newest Drug Class: SGLT2 Inhibitors Canagliflozin (Invokana®): approved by FDA in 2013 Dapagliflozin (Farxiga®): approved by FDA in 2014 Empagliflozin (Jardiance®): approved by FDA in 2014 Works by blocking the SGLT2 glucose symporter in the proximal tubule of the nephron. Effect: far greater excretion of glucose in urine. Glucose pulls salt/water into urine by osmosis  osmotic diuresis  dehydration / thirst.

Newest Drug Class: SGLT2 Inhibitors Adverse effects: Dehydration can potentially injure kidneys Risk of UTIs & genitourinary infections Especially, Females Dapagliflozin: Increased Bladder Cancer in RCTs Canagliflozin: increased amputations in RCTs New Medication class: unknown potential risks.

SGLT2 Inhibitors as “Second Line” Type 2 Diabetes Treatments Efficacy: Decent. A1c reduction 0.7-1.0% Side Effects: Polyuria, hypovolemia (even kidney Injury). Glycosuria  UTIs & genitourinary infections. Dapagliflozin: increased bladder Ca in RCTs. Canagliflozin: increased amputations in RCTs Hypoglycemia risk: Intermediate. Slightly higher risk vs. placebo. Weight: Modest weight reduction 2-4% Canagliflozin (Invokana) Prescribing Information

Potential Benefit in Patients with Heart Disease: ? Diuretic Effect ? 7020 patients with diabetes and CAD, GFR >30, BMI <45. 4-year double-blind RCT of Empagliflozin vs. placebo 38% RRR in cardiovascular death. 35% RRR in hospitalization for heart failure. No difference in MI or CVA. N Engl J Med. 2016 Mar 17;374(11):1094

SGLT2 Inhibitors as “Second Line” Type 2 Diabetes Treatments Drug Name Avg Retail Cost* per month “Metformin Index” Canagliflozin (Invokana®) $447  57 patients Dapagliflozin (Farxiga®) $449  58 patients Empagliflozin (Jardiance®) $415  53 patients Ideal Patient: Desires convenience of once-daily pill dosing. Desires modest weight loss. Patient with coronary artery disease (in need of diuretic ???). Desires oral medications over “injectables.” Willing to pay more for medications. * Data are average of 1-month retail price from two lowest cost local pharmacies. Generics used when possible. Source: www.goodrx.com, accessed on 9/7/17.

Summary: Shared Decision Making in busy clinic setting Support patient Self Determination Develop relational autonomy. Educate, Provide Options Elicit preferences based on value judgements www.diabetesdecisionaid.mayoclinic.org

Summary Question #1 A 57 y/o woman presents for diabetes follow-up. Meds: Metformin 1000mg BID , simvastatin 10mg daily. BMI 33. A1c is 8.2%. Creat 1.1. What is the ideal next medication for this patient? (A) Glipizide (B) Basaglar insulin (C) Lixisenatide (D) Acarbose (E) Any of the above could be reasonable choices based on her goals and preferences.

Summary Question #2 A 60 y/o man with type 2 diabetes and moderate CKD returns after suffering an NSTEMI, and developing CHF with LVEF 40%. Meds: atorvastatin, metformin 1000mg BID, metoprolol, lisinopril, ASA BMI 32. Exam: 1+ bilateral pitting edema A1c: 8.2%. Creat 1.5 (eGFR 46) What is the ideal (least worst) treatment decision? (A) Stop metformin and change to Lantus insulin. (B) Add empagliflozin (C) Add pioglitazone (D) Add glyburide (E) Transition to insulin pump therapy.