1. Shared Decision Making and the Medical Treatment of Type 2 Diabetes

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

3. 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.

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

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

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

7. New Model: Shared Decision Making
Physician
Patient

9. 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)

10. 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

11. 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

12. 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

13. 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?

14. 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

15. 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.

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

17. 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: accessed on 9/7/2017.

18. 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

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

20. 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: accessed on 9/7/17.

21. 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.

22. Incretin Agents as “Second Line” Type 2 Diabetes Treatments
Exenatide (Byetta®, Bydureon®), Liraglutide (Victoza®), Dulaglutide (Trulicity®), Albiglutide (Tanzeum®), Lixisenatide (Adlyxin®)
Efficacy: Intermediate % 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.

23. 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

24. 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

25. 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

26. 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: accessed on 9/7/17.

27. 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.

28. DPP-4 Inhibitors as “Second Line” Type 2 Diabetes Treatments
Sitagliptin (Januvia®), Saxagliptin (Onglyza®), Linagliptin (Tradjenta®), Alogliptin (Nesina®)
Efficacy: % 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

29. 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: accessed on 9/7/17.

30. Pioglitazone as “Second Line” Type 2 Diabetes Treatment
Efficacy: Modest % 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

31. 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: accessed on 9/7/17.

32. 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.

33. Acarbose / Miglitol as “Second Line” Type 2 Diabetes Treatments
Efficacy: Decent % 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.

34. 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: accessed on 9/7/17.

35. 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.

36. 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.

37. SGLT2 Inhibitors as “Second Line” Type 2 Diabetes Treatments
Efficacy: Decent. A1c reduction %
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

38. 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 Mar 17;374(11):1094

39. 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: accessed on 9/7/17.

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

42. 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.

43. 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.