DIABETES TYPE II

PHARMACOLOGIC THERAPY 2019

Meena Qazizada, Pharm.D, BCMAS Yasuno Sato, Pharm.D.

October 15, 2019

GUIDELINES

American Diabetes Association® (ADA) 2019

The American Association of Clinical Endocrinologists (AACE)

TABLE OF CONTENTS 1. Principles of Treatment of Type 2 Diabetes

2. Glycemic Control Algorithm

3. Main Oral and Injectable Pharmacotherapy

4. Cardiovascular Outcomes Trials

5. Alliance Formulary

6. Link to Alliance Formulary Document and Prior Authorization Criteria

PRINCIPLES

1. Lifestyle modification underlies all therapy (e.g., weight control, physical activity, sleep etc.)

2. Avoid hypoglycemia

3. Avoid weight gain

4. Individualize all glycemic targets (A1C, FPG, PPG)

5. Optimal A1C is ≤6.5%, or as close to normal as safe and achievable

6. Therapy choices are affected by initial A1C, duration of diabetes and obesity

7. Choice of therapy reflects cardiac, cerebrovascular and renal status

8. Comorbidities must be managed for comprehensive care

9. Get to goal as soon as possible

10. Choice of therapy includes ease of use and cost

11. A1C ≤6.5% for those on any insulin regimen as long as CGM is being used

AACE 2019 EXECUTIVE SUMMARY

SUMMARY OF GLYCEMIC RECOMMENDATIONS FOR

MANY NON-PREGNANT ADULTS WITH DIABETES

Tests Recommendations

A1C <7.0% (53 mmol/mol)*

Pre-prandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L)

Peak postprandial capillary plasma glucose† <180 mg/dL* (10.0 mmol/L)

*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on

duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications,

hypoglycemia unawareness, and individual patient considerations.

† Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals.

Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in

patients with diabetes.

ADA Diabetes Care 2019

Alliance Care Management (CM) works with individuals to improve their health and quality of life.

These services are voluntary and available to all eligible members. Alliance Services include:

Healthy Weight for Life

Wellness that Works Support Program (formerly known as Weight Watchers)

Live Better with Diabetes

Tobacco Cessation Program

Complex Case Management

ALLIANCE CARE MANAGEMENT SERVICES

Alliance Care Management Services Referrals and Contact: (800) 700-3874 ext. 5512

or www.ccah-alliance.org/case_management.html.

How would you treat the following:

• Newly diagnosed patients?

• A1C >7.5%? A1C >9%? Symptoms of hyperglycemia?

• Patients with history of established ASCVD?

• CKD or HF patients?

• Patients still not at goal despite dual or triple therapy?

• Older patients?

What medications are on the Alliance formulary?

PHARMACOLOGIC THERAPY RECOMMENDATIONS 1. Metformin is the preferred initial agent.

2. The early introduction of insulin should be considered if evidence of ongoing catabolism, if symptoms of hyperglycemia are present, or when A1C levels or blood glucose levels are very high.

3. Consider initiating dual therapy in patients who have A1C ≥1.5% above target.

4. Patient-centered approach should be used to guide the choice of pharmacologic agents.

5. If established atherosclerotic cardiovascular disease (ASCVD), sodium–glucose cotransporter 2 (SGLT-2) inhibitors, or glucagon-like peptide 1 (GLP-1) receptor agonists with demonstrated cardiovascular disease benefit are recommended.

ADA Diabetes Care 2019

PHARMACOLOGIC THERAPY RECOMMENDATIONS 6. Among patients with ASCVD at high risk of heart failure or in whom heart failure

coexists, SGLT-2 inhibitors are preferred.

7. If chronic kidney disease, consider use of a SGLT-2 inhibitor or GLP-1 agonist shown to reduce risk of chronic kidney disease progression, cardiovascular events, or both.

8. If an injectable medication is needed, GLP-1 agonists are preferred to insulin.

9. Intensification of treatment should not be delayed.

10. Reevaluate at regular intervals (every 3–6 months) and adjust as needed to incorporate new patient factors.

ADA Diabetes Care 2019

Glucose-lowering medication in type 2 diabetes: overall approach.

American Diabetes Association Dia Care 2019;42:S90-S102 ©2019 by American Diabetes Association

BIGUANIDE Drug Metformin, Metformin ER (Glucophage XR) 500mg

MOA ↓ Hepatic gluconeogenesis production ↓ Intestinal absorption of glucose ↑ Insulin sensitivity ↓ Fasting & postprandial hyperglycemia

ADR Bloating, abdominal discomfort, diarrhea

Monitor Renal function (eGFR ≥30 mL/min or ≥45 mL/min for new start) Hepatic function Vitamin B12 deficiency

Which medications are preferred for patients with established ASCVD in addition to metformin?

A. GLP-1 agonists

B. DPP4 inhibitors

C. SGLT2 inhibitors

D. A & B

E. A & C

ASCVD: coronary heart disease, cerebrovascular disease, or peripheral arterial disease (PAD) presumed to be of atherosclerotic origin

POLL QUESTION #1

Glucose-lowering medication in type 2 diabetes: overall approach.

American Diabetes Association Dia Care 2019;42:S90-S102 ©2019 by American Diabetes Association

SGLT2 INHIBITOR Drug Class Steglatro, Invokana, Farxiga, Jardiance

MOA Inhibits sodium-glucose cotransporter 2 (SGLT2) ↓ Glucose reabsorption ↑ Urinary glucose excretion

ADR Genitourinary infections, UTI, volume depletion/hypotension

Caution Renal function (eGFR ≥45 mL/min, ≥60 mL/min for Steglatro) DKA

Benefits ASCVD: Jardiance, Invokana CHF: Jardiance, Invokana, Farxiga CKD: Jardiance, Invokana, Farxiga

CARDIOVASCULAR OUTCOMES TRIALS (CVOT): SGLT2 INHIBITORS

Empagliflozin (Jardiance): ↓ Composite three-point major cardiovascular event (MACE) outcome and mortality.

Canagliflozin (Invokana): ↓ MACE in a group of subjects with/ or at high risk for ASCVD.

Dapagliflozin (Farxiga): ↓ Rate of hospitalization for heart failure.

Empagliflozin, canagliflozin, and dapagliflozin:

↓ Hospitalization for heart failure.

Beneficial effects on composite of CKD progression.

MACE: Major adverse cardiovascular events

According to ADA guidelines, which of the following medications are preferred 2nd line agents after metformin for patients with type 2 diabetes and heart failure or CKD?

A. DPP4 inhibitors (alogliptin, Januvia)

B. SGLT2 inhibitors (Jardiance, Invokana, Farxiga)

C. Sulfonylureas (glipizide, glyburide)

D. All of the above

POLL QUESTION #2

GLP-1 RECEPTOR AGONIST Drugs Trulicity*, Byetta, Bydureon, Victoza, Ozempic, Adlyxin

MOA Activates glucagon-like-peptide-1 (GLP-1) receptor ↑ Insulin secretion; ↓ Glucagon secretion; Delays gastric emptying (incretin mimetic)

ADR Nausea/vomiting/diarrhea, abdominal pain, dyspepsia, ↓ appetite

Caution BBW: Medullary thyroid carcinoma Multiple endocrine neoplasia syndrome type 2 Pancreatitis Gastroparesis or severe GERD CLcr ≥30 mL/min for exenatide

Benefits ASCVD: Victoza, Trulicity, Ozempic

*Requires prior authorization

CARDIOVASCULAR OUTCOMES TRIALS (CVOT): GLP-1 AGONISTS

Liraglutide (Victoza): ↓ MACE and CV-related mortality.

Dulaglutide (Trulicity): ↓ Risk of primary composite outcome of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes.

Semaglutide (Ozempic): Favorable effects on MACE endpoint in high-risk subjects.

Liraglutide, dulaglutide, and semaglutide:

↓ Progression of albuminuria.

Neutral effect for hospitalization for HF. MACE: Major adverse cardiovascular events

According to ADA guidelines, which of the following medications are preferred 2nd line agents after metformin for patients with type 2 diabetes and established ASCVD?

A. GLP-1 agonists (Victoza, Trulicity, Ozempic)

B. SGLT2 inhibitors (Jardiance, Invokana)

C. DPP 4 inhibitors (alogliptin, Januvia)

D. Both A & B

E. All of the above

ASCVD: coronary heart disease, cerebrovascular disease, or peripheral arterial disease (PAD) presumed to be of atherosclerotic origin

POLL QUESTION #3

Glucose-lowering medication in type 2 diabetes: overall approach.

American Diabetes Association Dia Care 2019;42:S90-S102 ©2019 by American Diabetes Association

DPP4 INHIBITOR Drug Class Alogliptin, Tradjenta, Januvia, Onglyza

MOA Inhibits dipeptidyl peptidase-4 ↓ Incretin metabolism ↑ Insulin synthesis/release ↓ Glucagon levels

ADR Nausea/diarrhea, URI, headache, joint pain

Caution Renal impairment- dose adjustment (except Tradjenta) Pancreatitis Heart failure (Onglyza, alogliptin)

Due to overlapping mechanism of action, guidelines recommend against the use of which two classes in combination:

A. DPP-4 Inhibitor + GLP-1 Agonist (alogliptin + Trulicity)

B. GLP-1 Agonist + SGLT 2 Inhibitor (Trulicity + Steglatro)

C. SGLT 2 Inhibitor + DPP-4 Inhibitor (Steglatro + alogliptin)

POLL QUESTION #4

Glucose-lowering medication in type 2 diabetes: overall approach.

American Diabetes Association Dia Care 2019;42:S90-S102 ©2019 by American Diabetes Association

THIAZOLIDINEDIONES (TZD) Drug Class Pioglitazone, Avandia

MOA ↑ Insulin sensitivity in adipose tissue, skeletal muscle, and the liver

ADR Weight gain, URI, edema

Caution BBW: Congestive heart failure ↑ Bone fracture risk in postmenopausal females and elderly males Renal impairment: potential for fluid retention

ALPHA-GLUCOSIDASE INHIBITORS Drug Class Acarbose, Miglitol

MOA Inhibits pancreatic alpha-amylase and intestinal alpha-glucoside hydrolase Delays glucose absorption

ADR Nausea, abdominal pain, bloating, flatulence, diarrhea

Caution GI conditions: malabsorption, IBD, intestinal obstruction Kidney function

SULFONYLUREAS Drug Class Glimepiride, Glipizide, Glyburide

MOA ↑ Pancreatic islet beta cell insulin release ↑ Insulin sensitivity at peripheral target sites

ADR Weight gain, nausea, vomiting, diarrhea

Caution ↑ Hypoglycemia Renal impairment: avoid glyburide

According to ADA guidelines, which agents are recommended to minimize hypoglycemia for patients without established ASCVD or CKD?

A. SGLT2 inhibitors (Steglatro)

B. DPP 4 inhibitors (alogliptin)

C. GLP1 agonists (Trulicity)

D. TZDs (pioglitazone)

E. All of the above

POLL QUESTION #5

Intensifying to injectable therapies.

American Diabetes Association Dia Care 2019;42:S90-S102 ©2019 by American Diabetes Association

PRANDIAL BASAL

RAPID-ACTING SHORT-ACTING INTERMEDIATE-ACTING

LONG-ACTING

Admelog Vials & Solostar pens Humalog Novolog Fiasp

Regular insulin: Humulin R vials Novolin R vials

NPH: Humulin N vials Novolin N vials

Basaglar Kwikpen Lantus Levemir Toujeo Tresiba

INSULIN

PREMIXED INSULIN VIALS

Novolin 70/30 Humulin 70/30 Humalog Mix 75/25 Humalog Mix 50/50 Novolog Mix 70/30

*Red: requires prior authorization

Prandial Insulin Max units/ inj Basal Insulin Max units/ inj

Admelog Solostar 80 units Basaglar Kwikpen 80 units

Humalog Kwikpen U-100, U-200

60 units Lantus Solostar 80 units

Humalog Jr Kwikpen

30 units (0.5 unit increments)

Levemir FlexTouch 80 units

Novolog 60 units Toujeo Solostar 80 units

Fiasp FlexTouch 80 units Toujeo Max Solostar 160 units (2 unit increments)

Tresiba FlexTouch 80 units

Tresiba FlexTouch U-200

160 units (2 unit increments)

INSULIN PENS

OLDER ADULTS

Avoid hypoglycemia and overtreatment.

Consider less stringent goal if multiple coexisting chronic illnesses, cognitive impairment, or functional dependence.

Avoid hyperglycemia leading to symptoms or risk of acute hyperglycemia complications.

Deintensification of complex regimens is recommended to reduce the risk of hypoglycemia, if it can be achieved within the individualized A1C target.

Alliance Preferred Antidiabetic Medications Summary

• Biguanide

Metformin (Glucophage)

Metformin ER (Glucophage XR)

• SU

Glipizide

Glimepiride

Glyburide

• AGi

Acarbose

• TZD

Pioglitazone

• GLP-1 Agonist

Trulicity*

• SGLT-2 Inhibitor

Steglatro

• DPP-4 Inhibitor

Alogliptin

• Prandial Insulin

Admelog Pen and Vial

• Basal Insulin

Basaglar Pen and Vial

* Requires Prior Authorization

The Alliance provider webpage has valuable resources:

Pharmacy Formulary

Quick Reference Guides: Diabetes

Prior Authorization Form

Prior Authorization Criteria

http://www.ccah-alliance.org/pharmacy.html

ALLIANCE FORMULARY DOCUMENT AND PRIOR AUTHORIZATION CRITERIA/SUBMISSION

REFERENCES

American Association of Clinical Endocrinologists © 2019. Endocr Pract.2018;24:90-120.

American Diabetes Association. Diabetes Care 2019 Jan; 42(Supplement 1): S1-S183.

Clinical Pharmacology.

QUESTIONS?

Meena Qazizada, Pharm.D, BCMAS: mqazizada@ccah-alliance.org

Yasuno Sato, Pharm.D: ysato@ccah-alliance.org

Alliance Pharmacy Department: (831) 430-5507

Alliance Care Management: (800) 700-3874 ext. 5512

Alliance Provider Services: (800) 700-3874 ext. 5504