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Type 2 Diabetes – Pathophysiology and Pharmacology Review

Joshua J. Neumiller, PharmD, CDE, FASCP

Vice Chair & Associate Professor,

Department of Pharmacotherapy

Washington State University

Spokane, WA

This educational activity is sponsored by Postgraduate Healthcare Education, LLC (PHE) and supported by an educational grant from Boehringer Ingelheim Pharmaceuticals Inc. and Lilly USA, LLC.

Accreditation Statement

PHARMACY

Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

UAN: 0430-0000-17-014-L01-P

0430-0000-17-014-H01-P

Credits: 1.0 hour (0.10 ceu)

Type of Activity: Knowledge

Media: Internet

New Horizons in Diabetes Care: Reducing Cardiovascular Risks Through Advances in

PharmacotherapyThis valuable and engaging 3-part webinar series was designed to inform and educate pharmacists in all practice settings who are involved in the care of patients with T2DM, bridging the gap of learning about the new classes of medications for T2DM, including their pathophysiologic basis of action across the continuum of care for patients with T2DM, while keeping in mind the cardiovascular safety of these glucose-lowering medications.

Attend one, two, or all three webinars and gain confidence in applying the results of recent studies to clinical practice.

Part 1 - “Type 2 Diabetes—Pathophysiology and Pharmacology Review”

Wednesday, March 22, 2017 at 1:00 PM EDT

Part 2 – “Intensifying Therapy after Basal Insulin Optimization in Type 2 Diabetes—Options for Targeting Postprandial Control”

Thursday, March 30, 2017 at 1:00 PM EDT

Part 3 – “Cardiovascular Outcome Trials (CVOTs): Practical Considerations for your Type 2 Diabetes Patients”

Wednesday, April 5, 2017 at 1:00 PM EDT

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Disclosures to Participants

Conflicts of Interest and Financial Relationships

Presenter and Program Chair:

Joshua J. Neumiller, PharmD, CDE, FASCP

• Advisory Board/Consultant: Eli Lilly & Boehringer Ingelheim

• Research Grant Support to WSU: Novo Nordisk

Content Reviewer:

Tricia Russell, PharmD, BCPS, CDE has nothing to disclose.

Learning Objectives

After completing this webinar, participants will be able to:

1. Describe the clinical pharmacology of the dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors

2. Understand the concept of implementing combination pharmacotherapy by addressing complementary pathophysiologic targets

3. Describe the role of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors as monotherapy and in combination with other medications for the treatment of type 2 diabetes (T2DM)

Normal Regulation of Glucose Homeostasis

Glucose output Glucose uptake

Glucagon(α-cell)

Insulin(β-cell)

Pancreas

Liver Muscle

Porte D Jr, Kahn SE. Clin Invest Med. 1995;18(4):247-254.Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145-168.

Normal blood glucose

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Glucose output Glucose uptake

Glucagon(α-cell)

Insulin(β-cell)

Pancreas

Liver

Hyperglycemia

Muscle

Islet cell dysfunction

Del Prato S, MarchettiP. Horm Metab Res. 2004;36(11-12):775-781.Porte D Jr, Kahn SE. Clin Invest Med. 1995;18(4):247-254.Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145-168.

Dysregulation of Glucose Homeostasis in T2DM

*

* Reduced effect of insulin indicating insulin resistance

T2DM

Years from diagnosis 0 5-10 -5 10 15

Pre-diabetes

OnsetDiagnosis

Insulin secretion

Insulin resistance

Postprandial glucose (PPG)

Macrovascular complications

Fasting glucose (FPG)Microvascular complications

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26(4):771-789.Nathan DM. N Engl J Med. 2002;347(17):1342-1349.

Natural History of T2DM

Pathophysiologic Defects in T2DM

DeFronzo RA. Diabetes. 2009;58(4):773-795.

Decreased incretin effect

Neurotransmitterdysfunction

Islet b-cellImpairedinsulin

secretion

Decreased glucose uptake

Islet a-cellIncreased

glucagonsecretion

Increased lipolysis

Increased glucose reabsorption

Increasedhepaticglucose

production

Hyperglycemia

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Select Antihyperglycemic Pharmacotherapy Options

Insulin

• Prandial insulin

• Insulin lispro

• Insulin aspart

• Insulin glulisine

• Insulin human inhaled

• Regular human insulin

• Basal insulin

• Insulin NPH

• Insulin detemir

• Insulin glargine U-100

• Insulin glargine U-300

• Insulin degludec

Oral medications

• Biguanides

• Sulfonylureas

• Meglitinides

• Thiazolidinediones

• a-Glucosidase inhibitors (AGIs)

• DPP-4 inhibitors

• SGLT-2 inhibitors

Non-insulin injectable agents

• GLP-1 receptor agonists

• Amylin mimetic

Cornell S, Dorsey VJ. Postgrad Med. 2012;124(4):84-94.

American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment.

Diabetes Care. 2017;40(Suppl 1):S64-S74.

Pathophysiologic Defects in T2DM

DeFronzo RA. Diabetes. 2009;58(4):773-795.

Decreased incretin effect

Neurotransmitterdysfunction

Islet b-cellImpairedinsulin

secretion

Decreased glucose uptake

Islet a-cellIncreased

glucagonsecretion

Increased lipolysis

Increased glucose reabsorption

Increasedhepatic glucose

production

Hyperglycemia

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Nauck M, et al. Diabetologia. 1986;29(1):46-52.

The Incretin Effect

Oral glucose load

Intravenous glucose infusion

Time (min)

Insu

lin (

mU

/L)

80

60

40

20

0

18060 1200

Time (min)

Insu

lin (

mU

/L)

80

60

40

20

0

18060 1200

Incretineffect

Control subjects (n = 8) People with T2DM (n = 14)

Endogenous GLP-1: Effects in Humans

GLP-1 is secreted fromL-cells of the jejunum

and ileum

GLP-1 then…

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagonsecretion

• Slows gastric emptying• Increases satiety

After food ingestion…

Drucker DJ. Curr Pharm Des. 2001;7(14):1399-1412. Drucker DJ. Mol Endocrinol. 2003;17(2):161-171.

Drucker DJ. Cell Metab. 2006;3(3):153-165.

Pharmacological Strategies to Augment the Incretin Effect

• GLP-1 secretion is impaired in T2DM• Natural GLP-1 has an extremely short half-life

Add GLP-1 analogues with longer half-life:

Exenatide (Byetta)

Liraglutide (Victoza)

Lixisenatide (Adlyxin)

Once-weekly Exenatide (Bydureon)

Albiglutide (Tanzeum)

Dulaglutide (Trulicity)

Block DPP-4 to slow the enzymatic degradation of GLP-1:

Sitagliptin (Januvia)

Saxagliptin (Onglyza)

Linagliptin (Tradjenta)

Alogliptin (Nesina)

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Neumiller JJ. Med Clin North Am. 2015;99(1):107-129.

Comparison of Incretin-based Therapies

Select clinical properties of DPP-4 inhibitors and GLP-1 receptor agonists

DPP-4 inhibitors GLP-1 receptor agonists

Slow gastric emptying No Yes

Effect on postprandial hyperglycemia

Yes Yes (variable)

Effect on weight Weight neutral Weight loss

Route of administration Oral Subcutaneous injection

Associated with hypoglycemia when used as monotherapy

No No

Comparison of DPP-4 Inhibitors Currently Available in the United States (U.S.)

Characteristic Sitagliptin(Januvia)

Saxagliptin(Onglyza)

Linagliptin(Tradjenta)

Alogliptin(Nesina)

Hypoglycemia risk

Low Low Low Low

Initial dose (normal CrCl)

100 mg daily 5 mg daily 5 mg daily 25 mg daily

Dose adjustment for renal impairment

•CrCl < 50 mL/min: 50 mg daily•CrCl ≤ 30 mL/min: 25 mg daily

•CrCl ≤ 50 mL/min: 2.5 mg daily

No adjustment recommended on the basis of renal function

•CrCl < 60 mL/min: 12.5 mg daily•CrCl < 30 mL/min: 6.25 mg daily

Sitagliptin prescribing information, 2009.Saxagliptin prescribing information, 2009.Linagliptinprescribing information, 2012.Alogliptinprescribing information, 2013.

CrCl = creatinine clearance.

Effects of Currently Available DPP-4 Inhibitors

Characteristic Sitagliptin(Januvia)

Saxagliptin(Onglyza)

Linagliptin(Tradjenta)

Alogliptin(Nesina)

Average A1C lowering*

0.65% to 0.79% 0.36% to 0.82% 0.50% to 0.69% 0.47% to 0.85%

Average weight change*

+0.3 to +1.2 kg -0.51 to +1.3 kg +0.33 to +1.1 kg +0.14 to +0.51 kg

Neumiller JJ. Med Clin North Am. 2015;99(1):107-129.Sitagliptin prescribing information, 2009.

Saxagliptin prescribing information, 2009.Linagliptinprescribing information, 2012.Alogliptinprescribing information, 2013.

*PBO-subtracted change from baseline; baseline characteristics of study groups and concomitant medications varied among studies.

A1C = Hemoglobin A1C.

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Key Considerations for the Use of DPP-4 Inhibitors

• Oral administration

• Generally weight neutral

• Side effects:– Headache

– Nasopharyngitis/upper respiratory tract infections

– Generally well tolerated

• Warnings/precautions:– Pancreatitis

– Hypoglycemia (when added to secretagogues or insulin)

– Allergic reactions

– Heart failure? (saxagliptin & alogliptin)

Comparison of A1C Reductions with GLP-1 Receptor Agonists

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

DURATION-1 DURATION-6DURATION-5 LEAD-6 GetGoal-XAWARD-6AWARD-1 HARMONY-7

Exe

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BID

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QW

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Adapted from Trujillo JM, et al. Ther Adv Endocrinol Metab. 2015;6(1):19-28.; Erratum. 2015;6(3):135-136.Madsbad S. Diabetes Obes Metab. 2016;18(4):317-332.

Change in A1C (%)

Study

BID = twice daily; QW = once weekly.

Adapted from Triplitt C, Solis-Herrera C. Diabetes Educ. 2015;41(suppl 1):32S-46S.

GLP-1 Receptor Agonists: Weight Change Ranges in Phase III Trials

- 0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Weight reduction (kg)

Exenatide 10 µg BID

Exenatide 2 mg QW

Liraglutide 1.2 mg QD

Liraglutide 1.8 mg QD

Dulaglutide 0.75 mg QW

Dulaglutide 1.5 mg QW

Albiglutide 30 mg QW

*

+0.28 to -1.21 kg

-1.30 to -3.03 kg

+0.21 to -2.6 kg

-0.20 to -3.60 kg

+0.30 to -2.6 kg

-2.00 to -3.7 kg

-1.07 to -3.60 kg

Lixisenatide 10 - 20 mcg QD -0.28 to -1.21 kg

QD = once daily.

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Drucker DJ, et al. Lancet. 2008;372(9645):1240-1250.

Comparison of Exenatide Products (30-week Data)

Exenatide extended-release

suspension

Exenatide BID

A1C reduction (%)FPG reduction (mg/dL)PPG reduction (mg/dL)Achievement of A1C < 7%

1.9a

41b

9677%d

1.525

124c

61%Change in body weight (kg) -3.7 -3.6aP = 0.0023; bP < 0.0001; cP = 0.0124; dP = 0.0039 versus comparator.

Key Considerations for the Use of GLP-1 Receptor Agonists

• Subcutaneous administration

• Can result in weight loss

• Side effects:– Nausea/vomiting

– Injection site reactions

• Contraindications:– Personal/family history of medullary thyroid carcinoma or

multiple endocrine neoplasia type 2 (long-acting products)

• Warnings/precautions:– Pancreatitis

– Hypoglycemia (when added to secretagogues or insulin)

Pathophysiologic Defects in T2DM

DeFronzo RA. Diabetes. 2009;58(4):773-795.

Decreased incretin effect

Neurotransmitterdysfunction

Islet b-cellImpairedinsulin

secretion

Decreased glucose uptake

Islet a-cellIncreased

glucagonsecretion

Increased lipolysis

Increased glucose reabsorption

Increased hepaticglucose

production

Hyperglycemia

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~180 grams of glucose filtered per day

SGLT-2

Virtually no urinary glucose

excretion

SGLT-1

Reabsorption of ~90% of filtered

glucose

Reabsorption of ~10% of filtered

glucose

Renal Glucose Reabsorption Under Normal Conditions

Neumiller JJ, et al. Drugs. 2010;70(4):377-385.

SGLT-2 Inhibition

Glucose

Glomeruli

Blood vessel

SGLT-1

SGLT-2

SGLT-2 inhibitor Urine

SGLT-1

Small intestine

Idris I, Donnelly R. Diabetes Obes Metab. 2009;11(2):79-88.

~90% of filtered glucose is reabsorbed through SGLT-2 transporters in the

early proximal tubule

Inhibition of SGLT-2 transporters in the proximal tubule blocks the reabsorption of filtered glucose,

leading to increased glucose excretion via urine

Canagliflozin versus Glimepiride as Add-on to Metformin: Change in A1C

Cefalu WT, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 2013; Chicago, IL.CANA = canagliflozin; GLIM = glimepiride.

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Canagliflozin versus Glimepiride as Add-on to Metformin:Change in Weight

Cefalu WT, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 2013; Chicago, IL.

Comparison of SGLT-2 Inhibitors Currently Available in the U.S.

Characteristic Canagliflozin(Invokana)

Dapagliflozin(Farxiga)

Empagliflozin(Jardiance)

Hypoglycemia risk (as monotherapy)

Low Low Low

Dose 100 mg daily before breakfast; increase to 300

mg daily, if needed

5 mg daily in the morning; increase to 10 mg daily, if

needed

10 mg daily in the morning; increase

to 25 mg, if needed

Effect on weight Weight loss Weight loss Weight loss

Renal Dose Adjustment of SGLT-2 Inhibitors

Canagliflozin prescribing information, 2017.Dapagliflozin prescribing information, 2016.Empagliflozin prescribing information, 2016.

Kohan DE, et al. Kidney Int. 2014;85(4):962-971.

Agent Dosing in CKD stages 3, 4 and 5 (non-dialysis)

Canagliflozin(Invokana)

• eGFR ≥ 60 ml/min/1.73 m2

No dosage adjustment needed• eGFR 45 - 59 ml/min/1.73 m2

Do not exceed 100 mg/day by mouth• eGFR < 45 ml/min/1.73 m2

Do not initiate and discontinue in patients currently receiving drug

Dapagliflozin(Farxiga)

Do not initiate; discontinue with eGFR < 60 mL/min/1.73 m2

Empagliflozin(Jardiance)

• eGFR ≥ 45 ml/min/1.73 m2

No dosage adjustment needed• eGFR < 45 ml/min/1.73 m2

Do not initiate and discontinue in patients currently receiving drug

eGFR = estimated glomerular filtration rate.

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Canagliflozin: Less A1C Reduction with Declining eGFR

Woo V, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 2013; Chicago, IL.

Key Considerations for the Use of SGLT-2 Inhibitors

• Unique mechanism of action– Have been studied in combination with a variety of other medication classes

• Oral administration

• Low hypoglycemia risk as monotherapy– Caution when used with secretagogues or insulin

• Can result in weight loss and modest decrease in blood pressure

• Side effects:– Genital mycotic infections

– Urinary tract infections

– Orthostasis (especially in elderly, chronic kidney disease, diuretic use)• Watch volume status

– Increased levels of low-density lipoproteins

– Euglycemic diabetic ketoacidosis

American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment.

Diabetes Care. 2017;40(Suppl 1):S64-S74.

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Unger J, Parkin CG. Postgrad Med. 2010;122(3):145-157.Cornell S, Dorsey VJ. Postgrad Med. 2012;124(4):84-94.

Comparison of Glucose-lowering Abilities of T2DM Pharmacotherapy Options

MonotherapyRoute of

administration Targets insulin

resistanceTarget glucose:

FPG or PPGA1C reduction*

(%)

Sulfonylurea Oral No Both 1.5 – 2.0

Metformin Oral Yes FPG 1.5

Glitazones Oral Yes Both 1.0 – 1.5

Meglitinides Oral No PPG 0.5 – 2.0

AGIs Oral No PPG 0.5 – 1.0

DPP-4 inhibitors Oral No PPG 0.5 – 0.7

Bile acid sequestrant Oral No PPG 0.4

Dopamine agonists Oral No PPG 0.4

SGLT-2 inhibitors Oral ↓ glucose toxicity Both 0.7 – 1.1

GLP-1 receptor agonists Injectable NoShort-acting – PPGLong-acting – Both

0.8 – 1.5

Amylin analogs Injectable No PPG 0.6

Insulin Injectable ↓ glucose toxicity Basal – FPGBolus – PPG

↓ as much as needed

*A1C reduction data are not from head-to-head comparative studies.

Once FBG is optimized, start addressing PPG excursions:• Add GLP-1 receptor agonist or• Add 1 rapid-acting insulin

injection to largest meal or• Change to premixed insulin

twice daily

American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment.

Diabetes Care. 2017;40(Suppl 1):S64-S74.

GLP-1 Receptor Agonist vs. Bolus Insulin in Patients with T2DM and Optimized Basal Insulin

Diamant M, et al. Diabetes Care. 2014;37(10):2763-2773.

ΔA

1C

(%

)

0-1.5

-1.0

-0.5

0.0

302 18 24

Insulin lispro

Exenatide BID

Weeks since randomization

4 6 8 12

ΔFP

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mm

ol/

L)

0-1.0-0.5

0.51.0

302 18 24

Weeks since randomization

4 6 8 12

0.0

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PreBreakfast

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Weeks since randomization

4 6 8 12

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ap < 0.01 for exenatide BID vs. insulin lisprobp < 0.001 for exenatide BID vs. insulin lispro

Exenatide caused more gastrointestinal issues (47% vs. 13%) but fewer non-nocturnal episodes of hypoglycemia (15% vs. 34%) than insulin lispro

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Reprinted with permission from American Association of Clinical Endocrinologists © 2017 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. EndocrPract.2017;23: 207-238.

Reprinted with permission from American Association of Clinical Endocrinologists © 2017 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. EndocrPract.2017;23: 207-238.

Reprinted with permission from American Association of Clinical Endocrinologists © 2017 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. EndocrPract.2017;23: 207-238.

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Don’t Miss the Upcoming Webinars in This Series!

• Intensifying Therapy after Basal Insulin Optimization in Type 2 Diabetes – Options for Targeting Postprandial Control

Presenter: Dr. Susan Cornell

• Cardiovascular Outcome Trials (CVOTs): Practical Considerations for Your Type 2 Diabetes Patients

Presenter: Dr. Curtis Triplitt

Thank you!

Special Thanks:

• Postgraduate Healthcare Education, LLC

• Susan Cornell, PharmD

• Curtis Triplitt, PharmD

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