Medication Titration Algorithm for Type 2 ¹ V2.1 updated 6/1/2017

Hemoglobin A1c AM SMBG³ Goals²: < 65 yrs <7% 70-130 ≥ 65 yrs <8% 100-160 Metformin + Lifestyle Modifications Basal Long Acting < 2% > 2% ⁴ Above Above Goal Goal 10 units SQ at hs ↑ 2 units q. 2 days until at target

Educate about Start Use optimal Contraindications: 500 mg: titration intervals - eGFR <30 to help patient - HF class 3-4 ½ tablet bid → 1 tablet bid → - LFTs>3xULN 2 tablets bid reach goal ASAP CAUTION: eGFR < 45 Titrate q. 1-2 weeks aiming →Use Alternate Agent for AM SMBG target³ Insulin therapy should not be Thiazoladinedione delayed () $

Not At At Goal After 3 Goal months $$

Maintain Dual Therapy A-glucosidase Risk of Severe Therapy yes Add Alternate Inhibitors Hypoglycemia Agent⁵ $$ no

Add ⁴ Contraindications: DPP-4 Inhibitor Severe sulfa allergy $$$$ →Use 5 mg: ½ tablet bid → Meglintinides 1 tablet bid → 2 tablets bid Titrate q. 2 weeks until at target SGLT-2 Inhibitor $$$$ Add Basal Long After 3 Acting Insulin At Goal A1c ≥ 1% no months of Goal or Alternate Agent⁵ GLP-1 Receptor Agonist yes $$$$

Add Basal Long Acting Insulin Maintain 10 units SQ at hs Therapy ↑ 2 units q. 2 days until at target

⁴ Carries increased risk of Hypoglycemia. Severe hypoglycemia = resulting or ¹ Excluding – for pregnant women and women intending pregnancy, use CDAPP likely to result in seizures, LOC, or needing help from others. Mild guidelines. hypoglycemia = recognized signs and symptoms or neuro-glycopenia (e.g. ² Individualize A1c goal based on risk of hypoglycemia, duration of DM, life expectancy, co- hunger or sweating) that the patient can effectively self-treat. morbidities, vascular complications, patient resources and support system. ⁵ Choice dependent on patient and disease-specific factors. Each new class of ³ Self Monitoring Blood targets: postprandial < 180mg/dL; bedtime 100-150 mg/dL. non-insulin agents lowers A1c ~ 1%. If A1c target is still not achieved after 3 months of dual therapy, proceed to three-drug combination. Medications for Management of

- t Medication / Maximum Optimal Caution/ side effects risk

Recommended Titration Cost eigh Hypo

W Dose Interval Efficacy Advantages glycemic

Biguanides 2,000mg daily 1-2 weeks Serum creatinine; repeat q 12 months , 2 or or - Do not use if HF class 3-4; LFTs>3xULN; or eGFR<30. metformin (500, 850, 1000mg)

/ event

1 2 ss Maximum dose 1000mg if eGFR 30-45 ER (500, 750, 1000mg) ow $ L Lo High

mono Increased risk GI side effects -> consider extended release therapy First line Neutral risk CVrisk oral agent

 Long-term use associated with vitamin B12 deficiency Sulfonylureas (SU) 20mg twice 2 weeks Sulfa allergy

glipizide2 (2.5, 5, 10mg) daily Hypoglycemia line line - 2 Weight gain

1 D/C SU with initiation of insulin igh ain glyburide ER (2.5, 5, 10mg) $ risk H G microvascular 

Combination Med / oral therapy Glyburide/metformin1, 2 (1.5- Dual,second 250mg, 2.5/5mg-500mg) High (TZD) 45mg daily Heart failure 2 Edema pioglitazone (15, 30, 45mg) /

1 Increased fractures Combination Med $ Low Gain insulin 4 High  Bladder cancer concerns

Pioglitazone/metformin sensitivity (15/500/850mg) Meglitinides (Glinide) 16mg daily / repaglinide2 (0.5,1, 2mg) 360mg daily

2

(60,120mg) 1 $$ High Gain glucose

p A1C loweringA1C p   Alpha-glucosidase inhibitors (AGI) 300mg 1-2 Often poorly tolerated acarbose2 (25,50, 100mg) months Modest efficacy (0.4-0.7% reduction A1C) miglitol2 (25,50, 100mg) Need to be dosed more than once/day $$ Effective in reducing PPG with high carb intake

DPP-4 Inhibitors 25mg daily Rare 3

Dual agent alternative therapy; (6.25, 12.5, 25mg) 4

4

linagliptin4

1, 3 Low Combination Med $$$$ Neutral alogliptin/pioglitazone2 (12.5- 15/30/45, 25-15/30/45mg) Intermediate alogliptin/metformin2 (12.5- 500/1,000mg)

Medication c Maximum Optimal Caution/side effects

Risk Recommended Titration Dose Interval Weight Efficacy / Cost Advantages Hypoglycemi

SGLT-2 inhibitors 5mg daily  genital mycotic infections canagliflozin4 Dehydration CV dapagliflozin4 Fracture risk empagliflozin4 Polyuria Combination Med  LDL-C

/metformin, ay improve  creatinine Low m 4 Loss $$$$ Invokamet Possible  risk of lower-limb amputation with canagliflozin /metformin,

Synjardy4

4 BP

/metformin, Xigduo  empagliflozin/, ; Glyxambi4 Intermediate/ risk GLP-1 R Agonist (SQ pen injector) 1.8mg daily GI side effects 3

, Victoza 1.5mg daily Pancreatitis risk CV

dulaglutide4   Heart rate Low Loss $$$$

High/ High/ risk Long-acting Insulin, basal 10U SQ HS or 10-15%, Hypoglycemia; duration 18 - 26hrs

2

Insulin glargine, Basalgar , 0.1-0.2U/kg/d or 2-4U Training/monitoring requirements 4 ain Lantus $$$ 1-2x/wk - ighest G 4 $ H , Levemir Highest

Intermediate-acting Insulin, NPH Hypoglycemia; duration 16 - 24hrs

3

insulin isophane, HumulinN ,

NovolinN3

$$$ Gain Highest Highest Insulin

Short-acting Insulin Hypoglycemia; duration 5 - 8hrs

regular insulin, HumulinR3, $$$

3 4 - Gain

NovolinR , Afrezza (inhalation) $ Highest Highest

Fast-acting Insulin Hypoglycemia; duration 3 - 4hrs

3

, Humalog Monitor blood glucose before breakfast and before meals 2-

3 $

, Novolog Gain 4 times/day Highest , Apidra3 Highest

1Generic available; 2Partnership Healthplan of California formulary; 3PHC formulary restrictions apply: quantity limit or step therapy – previous claims for metformin, a secondary formulary oral antidiabetic agent &/or basal insulin required (see formulary); 4PHC non-formulary – TAR required; 5PHC not available https://client.formularynavigator.com/Search.aspx?siteTestID=1196