Type 2 Diabetes Update For 2015

Type 2 Diabetes Update For 2015

Jerry Meece, RPh, CDE, FACA, FAADE Plaza Pharmacy and Wellness Center

jmeece12@cooke.net

Learning Objectives

At the conclusion of this presentation, the participant will be able to:

1. Review the role of 6 new drugs to treat Type 2 diabetes

2. Describe the mechanism of action the newest medications on the market for managing diabetes 3. List 4 indications, contraindications and precautions

for 3 new classes of diabetes medications

Challenges in Type 2 Diabetes Why The Need For More Drugs?

• Large number of patients

–Diabetes --25.8 million people

• PREDIABETES – 79 million people

• Weight gain (2 to 10 lbs)

• Progressive worsening of disease ( ability to secrete

insulin)

(Need to add more drugs)

• Controlling fasting and postprandial glucose

• Glucose fluctuations (variability)

CDC 2010. National Diabetes Fact Sheet. US Department of Health and Human Services. Cefalu, WT. Am J Med. 2012;343(1):21-26.

A Few More Reasons

• Managing complications and co-morbidities

(balloon theory)

• Durability--sustaining optimal long-term

glycemic control

• Hypoglycemia (Do we take it serious

enough?)

Durability

• How long does a oral med work?

• How do we know when it stops working?

Variability: More Harm Than We

Thought?

• Several studies to back up theory

Ideal Diabetes Drug

• No hypoglycemia

• No weight gain

• Well tolerated

• Good A1C lowering ability

• Given orally q d

• Helps with lipid profile and

BP

• Low cost 

How Do We Choose A Drug

• How far are they from these goals?

• What is their current diabetes regimen and/or what have they taken in the past?

• How long have they had diabetes?

• What is the principal problem? Fasting or postprandial

• Is there unacceptable risk from hypoglycemia

• Non‐glycemiceffects:CV,weight,lipids,bloodpressure

• Contraindications, special populations, comorbidities, etc.

• Cost

What Is FDA Looking For In Approving

A New Diabetes Medication?

• Low Incidence of Hypoglycemia

• Low CV risks

Hypoglycemia and Mortality

“

Self-report or admission to ED

for severe hypoglycemia is

associated with 3.4-fold

increased risk of death.”

HbA1c and Risk of Severe Hypoglycemia in Type 2 Diabetes: The Diabetes and Aging StudyKasia J. Lipska, E. Margaret Warton, Elbert S. Huang, Howard H. Moffet, Silvio E. Inzucchi, Harlan M. Krumholz, Andrew J. KarterDiabetes Care. 2013 November; 36(11): 3535–3542.

T2DM: The 3-Legged Stool

Nutrition Physical

Activity

American Diabetes Association (ADA). Diabetes Care. 2013;36(suppl 1):S11-S66. A1C = glycosylated hemoglobin, BP = blood pressure; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; TG = triglycerides

Blood Glucose Monitoring

Medications

New Sites Of Action

• Beta cells of pancreas

• Alpha cells

• Brain

• Muscle and adipose tissue

• Liver

GLP-1 Agonists

• Glucose dependent

–Decrease glucagon

–Increase Insulin from beta cells

–Delay absorption from stomach

–Decrease insulin resistance

GLP-1 Agonists

• Exenatide Extended Release—Bydureon

– Thyroid C cell tumors

– Acute Pancreatitis?

• Once a week dosing vs daily dosing?

• liraglutide Victoza

–medullary thyroid carcinoma (MTC)

–New Indication of weight loss

GLP-1 Agonists

–Dulaglutide Trulicity

•Medullary thyroid carcinoma

•Acute pancreatitis?

•Injection pen

– Albiglutide Tanzeum

•MTC

DPP-4 Inhibitors

• Raise the drawbridge or lower the water?

• Protect a natural enzyme DPP-4, from

breaking down GLP-1

DPP-4 Inhibitors

What Once Was Bad In Some Cases Is

OK

1. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990:653-657.

Yesterday

Glucose in

Urine Glucose in Urine

Kidney and Glucose

• Produces glucose

• Utilizes glucose

• Filters glucose

• Reabsorbs glucose

Normal Renal Handling of Glucose Sodium-Glucose Co-transporters (SGLT2s)

•180 g/day/1.73 m2 _{(filtered glucose load)}1

•SGLT2 transports 90% of filtered glucose out 1-4

•SGLT1 transports the remaining 10% 1-4

SGLT = sodium-glucose co-transporter. 1. Wright EM et al. J Intern Med. 2007;261(1):32-43. 2. Kanai Y et al. J Clin Invest. 1994;93(1):397-404. 3. You G et al. J Biol Chem. 1995;270(49):29365-29371. 4. Wright EM . Am J Physiol Renal Physiol. 2001;280(1):F10-F18.

Normal Kidney: Glucose Reabsorption

(Plasma Glucose ≤180 mg/dL)

Glucose reabsorption into systemic circulation

Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose co-transporter.

1. Kanai Y et al. J Clin Invest. 1994;93(1):397-404. 2. You G et al. J Biol Chem. 1995;270(49):29365-29371. 3. Rothenberg PL et al. Poster presented at: 46th European Association for the Study of Diabetes Annual M eeting; September 20-24, 2010; Stockholm, Sweden.

Decreased glucose reabsorption into systemic circulation

Glucose SGLT2 SGLT2 inhibitor SGLT1

SGLT2 Inhibitors Reduce Renal Glucose Reabsorption and Increase Urinary Glucose Excretion

Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose co-transporter.

1. Rothenberg PL et al. Poster presented at: 46th European Association for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden. 2. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990:653-657. 3. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 4. Oku A et al. Diabetes. 1999;48(9):1794-1800.

Glomerulus

Proximal Convoluted Tubule

Early Distal

Glucose in urine

Renal Threshold for Glucose Excretion

(RT

)

in Healthy Adult Subjects

1. Cowart SL, Stachura M E. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, M A: Butterworths; 1990:653-657. 2. Abdul-Ghani M A, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 3. Nair S, Wilding JP.

J Clin Endocrinol Metab. 2010;95(1):34-42. a

300 250 200 150 100 50 0 25 50 75 100 125 U ri na ry g lu co se e xc re ti o n (g /d ay ) Plasma glucose (mg/dL) Healthy 180 mg/dL RTG

Renal Threshold for Glucose Excretion Is Increased in T2DM

T2DM = type 2 diabetes mellitus.

1. Cowart SL, Stachura M E. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, M A: Butterworths; 1990:653-657. 2. Abdul-Ghani M A, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 3. Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95(1):34-42. 4. INVOKANA™ [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013.

300 250 200 150 100 50 0 25 50 75 100 125 U ri na ry g lu co se e xc re ti o n (g /d ay ) Plasma glucose (mg/dL) Healthy 180 mg/dL T2DM 240 mg/dL RTG RTG

The “Flozin” Family

• Canagliflozin—Invokana®

• Dapagliflozin—Farxiga®

• Empagliflozin Jardiance®

Limitations of SGLT2 Inhibitor Therapy

• Increased risk of genito-urinary infections

–Increase in UTIs but treatable, with no recurrence

–Increased mycotic genital infections, more so in women or with history of genital infections

• Risk of dehydration

–Some dehydration in patients with very high glucose levels ( osmotic diuresis)

–Very few cases of dehydration reported

• Electrolyte disturbances--hyperkalemia

Potassium-sparing diuretics

Group Considerations

Caution in

• Elderly patients at risk of dehydration

• Women with history of infections

• Compromised renal function

Combo Drugs

• Avandamet rosiglitazone/metformin • Duetact glimepiride/pioglitazone • Glucovance Glyburide/metformin • Metaglip metformin/glipizide • Kazano metformin/alogliptin • Oseni Alogliptin/pioglitazone • Prandimet repaglinide/metformin .

Other New Combos

• dapagliflozin/metformin Xigduo

• canagliflozin Invokamet/metformin

New Insulins

• Insulin Glargine Injection Toujeo-300

• True 24 hour

• Unit for unit for pens

• Versus U-500?

• Inhaled Human Insulin Afrezza

• Ultra rapid acting (peaks 15-20 min)

• Duration 2-3 hours

Inhaled Human Insulin--Afrezza

Candidates : Who? When?

• Metformin not tolerated (approx. 15%)1

• Metformin no longer works

• Add on to initial oral therapy (2nd _{or 3}rd₎

• Added to basal + with or without metformin?

• Need of added benefits of weight loss (or

weight neutral) and and slightly above goal for hypertension

1 Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA: Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 134:61–71, 2001

Patient Case: Roy

Presentation:

– 47 yr old AA male Type 2 Dm x 8 yr

Social/Lifestyle Hx:

– Truck Driver x 20 yrs. Limited P/A and lots of fast food

– Wt loss of 5 lbs in last month due to “trying to eat smarter and just working harder at it“ – A trial on a sulfonylurea caused frequent hypoglycemia due to erratic eating habits and he refuses “any kind of shots.”

Diabetes Self-Management:

“Checks 3-4 times a week at different times” – FPG avg 139 mg/dL – PPG avg 188 mg/dL Hx, Physical Lab: – Ht/Wt: 6’ 0” 210 lb, BMI 28.5 – BP 145/84 mm Hg – HbA1c 7.9 % – Serum Creatinine 1.2 mg/dL – Microalbumin < 30mg/L Meds: Enalapril 10mg q d Atorvastatin 20mg q d Metformin 1000mg bid ASA 81 mg d

What would be the next diabetes medication you would add to Roy’s regimen?

Coming Down The Pipe?

• Newer Insulins?

• More orals???

• Artificial Pancreas?