Jonathan Stoehr, MD PhD Endocrinology, Diabetes, Metabolism and Nutrition Virginia Mason Medical Center Seattle, WA
There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
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.
Physician Provider Proposes Treatment Patient expresses Resistance Provider presents Evidence Patient expresses Resistance Patient Both experience Frustration
Physician Patient Support patient Self Determination Develop relational autonomy. Educate, Provide Options Elicit preferences based on value judgements
Physician Patient
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, etc.) Thiazolidinediones (Pioglitazone) A Glucosidase Inhibitors (Acarbose, Miglitol) Bile Acid Sequestrant (Colesevalam) Amylin Mimetic (Pramlintide) Dopamine 2r Agonist (Bromocriptine)
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, 2014
Treatment is Individualized Cost? Efficacy? Side Effects? Effect on Weight? Hypoglycemia Risk? Secondary Benefits?
Efficacy: High. Can be titrated accurately. Hypoglycemia risk: Very high Weight: Typical gain 2 4 kg/year
High Doses 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. Physiologic Doses Induces Lipoprotein Lipase expression and glucose uptake. Stimulates de novo biosynthesis of fatty acids and TG. Increased uptake of carbs and fats into tissues. Low Doses Suppresses glycosuria / polyuria. Low Doses Suppresses ketoacidosis. Blocks muscle catabolism. Allows anabolic effects of resistance training / exercise.
Worsening Glycemic Control Requiring more Insulin Insulin Therapy Worsening Insulin Resistance Weight Gain
Drug Name Avg Retail Cost* per month Metformin Index Insulin Glargine (Lantus ) $397.36 / vial (33 units / d) 99 patients Insulin Detemir (Levemir ) $347.14 / vial (33 units / d) 87 patients Insulin NPH (Humulin N) $66.88 / vial (33 units / d) 17 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 Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
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
Drug Name Avg Retail Cost* per month Metformin Index Glipizide (Glucotrol ) $7.83 2 patients Glyburide (Micronase ) $6.00 1.5 patients Glimepiride (Amaryl ) $8.00 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 Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
Exenatide (Byetta, Bydureon ), Liraglutide (Victoza ), Dulaglutide (Trulicity ), Albiglutide (Tanzeum ) 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.
Exenatide (Byetta, Bydureon ), Liraglutide (Victoza ), Dulaglutide (Trulicity ), Albiglutide (Tanzeum ) 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.
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 complex, requires multiple steps. Bydureon prescribing information, Amylin Pharmaceuticals, 2012
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
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. Significantly more expensive. Pancreatitis was observed in RCTs. Trulicity prescribing information, 2014
Drug Name Avg Retail Cost* per month Metformin Index Exenatide (Byetta ) $442.74 110 patients Exenatide (Bydureon ) $455.92 114 patients Liraglutide (Victoza ) $607.02 152 patients Albiglutide (Tanzeum ) $339.86 85 patients Dulaglutide (Trulicity ) $1001.74 250 patients Ideal Patient: Obese. Desire for modest weight loss. Desire to avoid hypoglycemia Suitable insurance. Willing to pay more for medications. * Data are average of 1-month retail price from Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
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.
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
Drug Name Avg Retail Cost* per month Metformin Index Sitagliptin (Januvia ) $161.32 40 patients Linagliptin (Tradjenta ) $314.36 79 patients Alogliptin (Nesina ) $297.06 74 patients Saxagliptin (Onglyza ) $309.01 77 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 Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
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
Drug Name Avg Retail Cost* per month Metformin Index Pioglitazone (Actos ) $15.87 4 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 Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
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.
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 Heart attacks observed in clinical trials. Also indicated for prevention of diabetes.
Drug Name Avg Retail Cost* per month Metformin Index Acarbose (Precose ) $37.24 9 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 Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
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.
Adverse effects: Dehydration can potentially injure kidneys Risk of UTIs & genitourinary infections Especially, Females Dapagliflozin: Increased Bladder Cancer in RCTs New Medication class: unknown potential risks.
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. Hypoglycemia risk: Intermediate. Slightly higher risk vs. placebo. Weight: Modest weight reduction 2 4% Canagliflozin (Invokana) 2012 Virginia Prescribing Mason Medical Information Center
Drug Name Avg Retail Cost* per month Metformin Index Canagliflozin (Invokana ) $325.64 81 patients Dapagliflozin (Farxiga ) $325.64 81 patients Empagliflozin (Jardiance ) $314.36 78 patients Ideal Patient: Desires convenience of once daily pill dosing. Desires modest weight loss. Desires oral medications over injectables. Willing to pay more for medications. * Data are average of 1-month retail price from Walmart and Costco pharmacies. Generics used when possible. 2012 Source: Virginia Mason www.goodrx.com, Medical Center accessed on 12/3/2014.
Support patient Self Determination Develop relational autonomy. Educate, Provide Options Elicit preferences based on value judgements
FDA approved in 2009 Treatment of Type 2 DM In addition to Metformin, Sulfonylurea, or Insulin Unknown Mechanism of Action Efficacy: Modest Hgb A1c benefit: 0.5% Adverse Effects: Nausea, dizziness, rhinitis common. Pijl H, et al. 2012 Diabetes Virginia Mason Care Medical 23:1154 1161 Center
FDA approved in 2008 for Treatment of Diabetes: In addition to Metformin, SU, or Insulin Unknown Mechanism of Action GLOWS Trial Improved LDLc Modest Hgb A1c reduction (0.5%, greater in patients with higher starting A1c). ADVERSE EFFECTS: 9/29 (29.0%) subjects in colesevelam arm 3/34 (8.8%) subjects in placebo arm Gastrointestinal disorders 22.6% Constipation 19.4% Zieve FJ, et 2012 al. Virginia Clinical Mason Medical Therapeutics: Center 29(1): 74-83