Dr. John Bucheit, Pharm.D., BCACP, CDEClinical Assistant ProfessorMercer University College of Pharmacy

Disclosures to ParticipantsRequirements for Successful Completion:For successful completion, participants are required to be in attendance in the full activity, complete and submit the program evaluation at the conclusion of the educational event.

Conflicts Of Interest and Financial Relationships Disclosures Planners: Katie Mick, MS, RD, LD, CDE- None

Vicki Karnes, RD, CDE- NoneLaShonda Hulbert, MPH- NoneCaSonya Green, MA, CHES- NoneBenicia Malone, MEd., ACSM CEP, CHES- NoneBethany Jagdharyy, RN, BSN, CDE- None

Presenter: Dr. John Bucheit, Pharm.D., BCACP, CDE

Disclosure of Relevant Financial Relationships and Mechanism to Identify and Resolved Conflicts of Interest: Educational Planning Table was reviewed for bias and found to be unbiased. Keeping the presentation unbiased was discussed with presenter multiple times, AADE speaker guidance letter was sent, speaker signed Bio/COI form, slides will be reviewed prior to program to assess bias, and class will be closely monitored for bias.Sponsorship / Commercial Support: NoneNon-Endorsement Of Products:

Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity.

Off-Label Use:Participants will be notified by speakers to any product used for a purpose other than that for

which it was approved by the Food and Drug Administration.Activity-Type : Knowledge-based or Application –based (pick one activity type)

1. Compare and contrast the current guideline approaches for the management of type 2 diabetes

2. Describe the pharmacological agents for Type 2 diabetes including long-term safety and efficacy outcomes

3. Construct patient-centered pharmacotherapy plans for patients with type 2 diabetes

High prevalence, cost, and mortality!

Adapted from: A Snapshot Diabetes in the United States.Infographic.Cdc.gov/diabetes/data/statistics/2014statisticsreport.html.Accessed July 1, 2015

Adherence Non-Adherence

Provider Factor

Medication Factors

Patient Factors

Communication

Regimen Changes

Education

Poor OutcomesGood Outcomes

Diabetes Educator

+

-

-

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Diabetes Care 2015;38:140–149

Trip

le T

he

rap

y

Du

al T

he

rap

y

Mo

no

the

rap

y1.Metformin

2.GLP-1 RA

3.SGLT-2i

4.DPP-4i

5.AGi

6.TZD

7.SU/GLN

AGi=alpha glucosidase inhibitor

TZD=thiazolidinediones

GLN=glitinides

Metformin +

1.GLP-1 RA

2.SGLT-2i

3.DPP-4i

4.TZD

5.Basal Insulin

6.Colesevelam

7.Bromocriptine QR

8.AGi

9.SU/GLN

Metformin + 2nd line agent +

1.GLP-1 RA

2.SGLT-2i

3.DPP-4i

4.TZD

5.Basal Insulin

6.Colesevelam

7.Bromocriptine QR

8.AGi

9.SU/GLN

Entry A1c <7.5%

Entry A1c >7.5%

Progression of Disease

American Diabetes Association 2015

Patient-Centered Approach

A1c goal < 7% for most patients

No preference after Metformin

Fewer agents recommended

Initial therapy with metformin recommended at diagnosis

American Association of Clinical Endocrinologists 2015

Patient-Centered Approach

A1c goal ≤ 6.5% for most patients

Preference given based on safety and efficacy

All agents for diabetes included

Initial therapy with metformin or dual therapy based on A1c

Avoid clinical inertia and both guidelines will lead to similar A1c control

Diabetes Care 2015;38:140–149

CDEs can impact these factors!

Safety

Tolerability

Efficacy

Price

Simplicity

S.T.E.P.S.

Considerations• Comorbidities• Adverse Effects• Pharmacokinetics• Costs

What about cardiovascular

outcomes?

“The U.S. Food and Drug Administration recommended today that manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack. The recommendation is part of a new guidance for industry that applies to all diabetes drugs currently under development.”

December 17, 2008

1

3

5

7

9

11

13

15

6 7 8 9 10 11 12

Diabetic retinopathy

Nephropathy

Severe nonproliferative or proliferative retinopathy

Neuropathy

Microalbuminuria

A1C

17

Re

lati

ve R

isk

*Based on DCCT data

Endocrinol Metab Clin North Am. 1996;25:243

Microvascular Outcomes

S) Risk for lactic acidosis in renal insufficiency

Low risk for hypoglycemia

T) Nausea and diarrhea common

E) High: A1c reduction 1-2%

Weight neutral/loss

P) Inexpensive: $4.00 or less

S) Twice daily

Diabetes Care 2015;38:140–149

S) May inhibit ischemic preconditioning

Moderate risk for hypoglycemia

T) Weight gain

E) High: A1c reduction 1-2%

P) Inexpensive: $4.00 or less

S) Once or twice daily

Twice daily medications cover post prandial glucose

Meglitinides have similar S.T.E.P.S. profile

Diabetes Care 2015;38:140–149

Lebovitz HE. Diab Rev. 1999;7(3):139-153.

S) Heart Failure and Bone fractures

Liver disease

Low risk for hypoglycemia

T) Weight gain

E) High: A1c reduction 1-2%

Insulin sensitizer

May take up to 3 months for maximum effects

P) Inexpensive

S) Once dailyDiabetes Care 2015;38:140–149

S) Medullary Thyroid Carcinoma (animal studies)

Low risk for hypoglycemia

T) Nausea/diarrhea

E) High: A1c reduction 1-2%

Weight loss

P) Brand only: Expensive

S) Twice daily, once daily, and once weekly

Does this improve

adherence???

Diabetes Care 2015;38:140–149

DPP-4 Inhibitor

Rev Diabet Stud, 2008, 5(2):73-94

S) Heart failure hospitalizations?

Low risk for hypoglycemia

T) Rare adverse effects

E) Intermediate: A1c reduction 0.5-1%

Weight neutral

P) Brand only: Expensive

S) Once daily

Diabetes Care 2015;38:140–149

Saxagliptin Risk for Heart Failure Hospitalizations

No difference in composite CV death, M.I., or ischemic stroke

Is this a class effect?SAVOR-TIMI 53.Circulation.2014;130:1579-1588

DPP-4 Inhibitors Cardiovascular Outcome Trials

Drug TrialRate of HF Hospitalizations

Drug vs. Placebo HR 95% CI P-value

Alogliptin EXAMINE 3.1% vs. 2.9% 1.07 (0.79-1.46) 0.657

Sitagliptin TECOS 3.1% vs. 3.1% 1.00 (0.83-1.20) 0.98

Saxagliptin Savior_TIMI_53 3.5% vs. 2.8% 1.27 (1.07-1.51) 0.007

Risk is not a class effect

No other cardiovascular risks, but no improvement in cardiovascular outcomes either

SAVOR-TIMI 53.Circulation.2014;130:1579-1588

DPP-4 Inhibitors A1c Reduction (%) Weight Reduction (kg)

100 mg Sitagliptin -0.67-(-)1 -0.4- (-)1.5

5 mg Saxagliptin -0.68 -0.87

GLP- 1 Receptor Agonists

10 mcg Exenatide Twice Daily -0.78- (-1) -2.8- (-)3.6

2 mg Exenatide Once Weekly -1.55-(-)1.9 -2.7-(-)3.7

1.2 mg Liraglutide once daily -1.1-(-)1.24 -2.6-(-)2.8

1.8 mg Liraglutide once daily -1-(-)1.5 -2.8-(-)3.38

Adapted from: Scheen AJ, et al. Lancet 2010; 375: 1410–1412. ↑ Weight Loss

BH is a 58 yo female with a PMH hypertension, dyslipidemia, and type-2 diabetes is seen for diabetes management. You have optimized her lipid and blood pressure management. Unfortunately, BH’s A1c has steadily increased and is now 8.3%. What agent would you add to treat this patient’s hyperglycemia?

BP: 136/80 mmHg A1c:8.3%

BMI:38 kg/m2 eGFR: 71 mL/min/1.73m2

Microalbumin/Creatinine: 250 mcg/mg

Medications:HCTZ 25 mg daily Aspirin 81 mg dailyAmlodipine 5 mg daily Metformin 1000 mg BID Rosuvastatin 20 mg daily Lisinopril 20 mg daily

A. GLP-1 Agonists C. DPP-4 inhibitorB. Thiazolidinedione D. Sulfonylurea

S) Diabetic ketoacidosis?

Dehydration

Low risk for hypoglycemia

T) Genitourinary infections

E) Intermediate: A1c reduction 0.5-1%

Weight loss

P) Brand only: Expensive

S) Once daily

↑

Diabetes Care.2014;32(1):4-11

Primary Outcome: CV death, non-fatal M.I., and non-fatal stroke

ARR: 1.6%NNT: 63

Will this be the new 2nd-line agent in the management of type 2 diabetes? N Engl J Med.2015. Epub ahead of print. Accessed 11/02/215

BH is a 58 yo female with a PMH hypertension, dyslipidemia, and type-2 diabetes is seen for diabetes management. You have optimized her lipid and blood pressure management. Unfortunately, BH’s A1c has steadily increased and is now 8.3%. What agent would you add to treat this patient’s hyperglycemia?

BP: 136/80 mmHg A1c:8.3%

BMI:38 kg/m2 eGFR: 71 mL/min/1.73m2

Microalbumin/Creatinine: 250 mcg/mg

Medications:HCTZ 25 mg daily Aspirin 81 mg dailyAmlodipine 5 mg daily Metformin 1000 mg BID Rosuvastatin 20 mg daily Lisinopril 20 mg daily

A. GLP-1 Agonists C. DPP-4 inhibitorB. SGLT-2 Inhibitor D. Sulfonylurea

Glargine (U-100)DetemirNPH

Glargine (U-300)Degludec

Preferred Non-Preferred

Data from Monnier L, et al. Diabetes Care 2003; 26:881-885

0%

20%

40%

60%

80%

100%

<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2

30%50% 55% 60% 70%

70%50% 45% 40% 30%

% C

ON

TRIB

UTI

ON

A1C RANGE (%)

Postprandial Glucose Contribution

PostPrandial Plasma Glucose (PPG)

Fasting Plasma Glucose (FPG)

Holman et al. N Engl J Med 2009; 361:1736-1747

Holman et al. N Engl J Med 2009; 361:1736-1747

Grade 2 = symptoms with SMBG <56 mg/dL; Grade 3 = (major) if third party assistance required

Lowest weight gain

and hypoglycemia

risk

NPH Glargine Detemir Glargine Degludec

• U-100 • U-300• U-100• U-200

=2015 Approvals

FDA Approval: February 2015 Long acting (up to 36 hours)

U-100 U-300: convert 1:1

U-300 U-100: dose reduce by 20%

Image source: https://www.toujeopro.com/choosing-toujeo.Accessed 11/05/15

Outcomes Glargine U-100 Glargine U-300

Less Weight Gain

Lower Insulin Dose

Superior A1c Lowering

Lower Hypoglycemia Rates

Lower Cost

√???

√

↔

√

↔

√

*Generic for glargine U-100 expected this year*

Toujeo prescribing information. Accessed 11/02/15Diab Obes and Met. Edition 3.2015;14:386-394

Steve-55 y.o. white male

PMH: T2DM, HTN, and COPDMedications

Lisinopril 20 mg daily linagliptin 5 mg daily (DPP-4I)

Metformin 1000 mg twice daily Tiotropium 2 puffs daily

Insulin glargine: 25 units at bedtime

Labs: A1c: 9.4% FBG: 230 mg/dL

Scr: 0.9 mg/dL

Weight: 250 lbs

BMI: 33

Blood Glucose Log

Pre-Breakfast

200 mg/dL

223 mg/dL

165 mg/dL

179 mg/dL

Average

192 mg/dL

What should we do?A. Add an oral agentB. Increase insulin by 4 unitsC. Add bolus insulinD. Lifestyle modifications only

FDA Approval: September 2015U-100 and U-200 formulations

Biphasic 70/30 with insulin aspart

Clin Drug Investig (2013) 33:515–521Similar pharmacokinetic profile

Insulin Peak (hours) Duration (hours)

NPH 4-12 10-16

Detemir 3-9 hours 6-24

Glargine U-100 No Peak 24

Glargine U-300 No Peak 36

Degludec 9 36-42

Am Fam Physician.2011;84(2):183-190

Degludec?Glargine U-300?

Product Onset (Min) Peak (Min) Duration of Action (hr)

Inhaled Insulin 10-30 12-15 3

FDA Approval: June 2014Type 1 and Type 2 diabetes

Contraindicated in COPD and Asthma

Small delivery device4,8, and 12 unit cartridges Insulin naïve patients start at 4 units with meals

8.26

7.4 7.4

8.358.1

7.9

6.5

7

7.5

8

8.5

Baseline 12 weeks 24 weeks

Hemoglobin A1c Control

Affrezza Placebo

P-VALUE < 0.0001

Diabetes Care.2015. Epub ahead of print. Accessed 11/02/15

Titration occurred over first 12 weeks

Agent Onset (min) Peak (hrs) Duration (hrs)

Aspart 10-20 1-3 3-5

Glulisine 10-15 1-1.5 3-5

Lispro U-100 15-30 0.5-2.5 3-6.5

Lispro U-200 15-30 0.5-1.5 <5

Regular 30-60 1-5 4-12

Inhaled Rapid 0.2-0.25 (12-15min) 3

Newly approved in 2015

Pharmacist/Prescriber’s Letter. 2009.25:1-12

Aspart, Glulisine, and Lispro are interchangeable

Increased hypoglycemia associated with regular insulin

Steve-55 y.o. white male

PMH: T2DM, HTN, and COPDDiabetes Medication

linagliptin 5 mg daily (DPP-4I)

Metformin 1000 mg twice daily

Insulin glargine: 36 units at bedtime

Labs: A1c: 8.7%

FBG: 105 mg/dL

Weight: 250 lbs

Blood Glucose Log

Pre-Breakfast

Pre-Lunch

Pre-Dinner

Bedtime

98 110 116 180

102 - 125 200

100 150 190 -

95 100 180 220

Average

99 120 153 200

Highest Value

What’s the next step?A. Add inhaled insulinB. Add 4 units of lispro to dinnerC. Add 4 units of lispro to bedtimeD. Increase glargine dose

Use a patient-centered approach when selecting pharmacotherapy agents

There is still no 2nd line agent clearly recommended after metformin therapy

Four new insulin products were released in 2015 focusing on concentrated products or new delivery systems

The evidence for treatment of type 2 diabetes is rapidly changing