DIABETES DRUGS & TRENDS

MADE SIMPLE

PHARMD TO RD

ANGELA GINN-MEADOW RD LDN CDE

OBJECTIVES

At the end of this presentation, participants

should be able to:

Evaluate the emerging role of GLP-1

Agonists for weight loss

Understand SGLT2 inhibitors in T2DM

Explain the role of new insulin therapies in

the treatment of Type 2 Diabetes

Respond to questions regarding the use of

therapies in a specific patients

WHAT’S HOT AND WHAT’S NOT!

WHAT’S HOT AND WHAT’S NOT!

GLP-1 R Agonists (DM)

Albiglutide (Tanzeum®)

Dulaglutide (Trulicity®)

GLP-1 R Agonist (Obesity)

• Liraglutide (Saxenda)®

DPP-4 Inhibitors

• Linagliptin (Tradjenta®)

• Linagliptin/metformin

(Jentadueto®)

SGLT-2 Inhibitors

• Empagliflozin (Jardiance®)

• Empagliflozin/metformin

(Synjardy®)

SGLT-2 Inhibitors/DPP-4

Inhibitor

• Empagliflozin/Linagliptin

(Glyxambi®)

Rapid Acting

• Insulin Lispro (Humalog U-200 Kwikpen®)

Long Acting

• Insulin Degludec (Tresiba®)

• Insulin Glargine (Toujeo®U-300)

• Insulin Glargine (Basaglar U-100 Kwikpen®)

• Insulin human injection (Humulin R U-500 Kwikpen®)

Inhaled Insulin

• Insulin human inhalation powder (Afreeza®)

Mixed Insulin

• Insulin Degludec/Insulin Aspart (Ryzodeg 70/30®)

GLP-1 RECEPTOR AGONIST:

LIRAGLUTIDE

(SAXENDA®) - OBESITY

GLP-1 MODULATES NUMEROUS FUNCTIONS IN HUMANS

Stomach: Helps regulate gastric emptying

Promotes satiety and reduces appetite

Liver: Glucagon reduces hepatic glucose output

Beta cells: Enhances glucose-dependent insulin secretion

Alpha cells: Glucose-dependent postprandial glucagon secretion

GLP-1: Secreted upon

the ingestion of food

Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

LIRAGLUTIDE (SAXENDA®) – A

GLP-1-R AGONIST WITH NEW

INDICATION - WEIGHT LOSS

LIRAGLUTIDE (SAXENDA®) - OBESITY

Indication: Adjunct to lifestyle (reduced calorie diet and increased

physical activity) for chronic weight management

• In individuals with a BMI of >30 kg/m2

• In individuals with a BMI of >27 kg/m2 in the presence of at least

one weight-related comorbidity such as HTN, Diabetes, or

Dyslipidemia

Saxenda prescribing information: http://www.novo-pi.com/saxenda.pdf. Accessed 2/26/16

SAXENDA® SAFETY AND EFFICACY

CLINICAL TRIALS

Three 56-week, randomized, double-blind, placebo-controlled

trials

All patients were overweight (27-29.9 kg/m2) or obese >30 kg/m2

Dosage titration: to 3 mg daily during a 4-week period

All patients received instructions throughout the trial for:

A reduced calorie diet (approximately 500 kcal/day deficit)

Exercise counseling - minimum 150 mins/week)

http://www.novo-pi.com/saxenda.pdf

RESULTS OF THE CLINICAL TRIAL

Study 1

(Obesity/overweight +

comorbidity)

Study 2

(Obesity/overweight +

Type 2 DM)

Study 3

(Obesity or overweight +

comorbidity following > 5%

weight loss with diet)

Saxenda

N=2487

Placebo

N=1244

Saxenda

N=423

Placebo

N=212

Saxenda

N=212

Placebo

N=210

Baseline mean

(SD) (kg)

106.2

(21.2) 106.2 (21.7)

105.7

(21.9)

106.5

(21.3)

100.4

(20.8)

98.7

(21.2)

% change from

baseline (LSMean) -7.4 -3.0 -5.4 -1.7 -4.9 0.3

Difference from

placebo (LSMean)

(95% CI)

-4.5*

(-5.2;-3.8)

-3.7*

(-4.7;-2.7)

-5.2*

(-6.8;-3.5)

% Patients losing

> 5% BW 62.3% 34.4% 49.0% 16.4% 44.2% 21.7%

Difference from

placebo (LSMean)

(95% CI)

27.9*

(23.9;31.9

)

32.6*

(25.1;40.1)

22.6*

(13.9;31.3)

% Patients losing

>10% BW 33.9% 15.4% 22.4% 5.5% 25.4% 6.9%

Difference from

placebo (LSMean)

(95% CI)

18.5*

(15.2;21.7

)

16.9*

(11.7;22.1)

18.5*

(11.7;25.3)

RESULTS OF STUDY ONE

https://www.saxendapro.com/efficacy/weight-loss/significant-weight-loss.html

Saxenda® reduced waist circumference by 3.2 inches vs 1.6 inches with placebo

SAXENDA AND SUSTAINED WEIGHT LOSS

https://www.saxendapro.com/efficacy/weight-loss/significant-weight-loss.html

LIRAGLUTIDE (SAXENDA®)

Do not use Saxenda®:

• To treat Type 2 diabetes

• With Victoza® or other GLP-1 receptor agonists

• Together with insulin

There is no safety data on Saxenda® use:

• With other prescription, over-the-counter, or herbal weight-loss

products

• In people who have had pancreatitis

• In children <18 years of age.

Saxenda® Is Not For Use In Children

DOSAGE FOR SAXENDA® VS. VICTOZA®

SAXENDA® FOR WEIGHT

LOSS

Dose of Saxenda - 3.0

mg daily for weight loss

Evaluate patients after

16 weeks

If patient has not lost

4% of baseline body

weight, discontinue

therapy

VICTOZA® FOR T2DM

Dose of Victoza - 1.2 mg

or 1.8 mg daily for

diabetes

QUESTION ON LIRAGLUTIDE

(SAXENDA®)

Which of the following patients with BMI of > 27 kg/m2 will be

eligible for Saxenda? All patients have HTN and Dyslipidemia

PINK T1 DM Patient on Insulin Glargine +

Insulin Aspart

BLUE T1 DM Patient on 70/30 Insulin

GREEN T2 DM Patient on Metformin

YELLOW T2 DM Patient on Exenatide

SGLT-2 INHIBITORS AND ITS

COMBINATIONS

SGLT-2 Inhibitors

•Empagliflozin (Jardiance®)

•Empagliflozin/metformin (Synjardy®)

SGLT-2 Inhibitors/DPP-4 Inhibitor

•Empagliflozin/Linagliptin (Glyxambi®)

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS:

GLUCOSE TRANSPORTATION AT THE KIDNEYS

Wright, EM. Am J Renal Physiol 2001;280(1):F10 - F18 Taylor SR, Harris KB. Pharmacotherapy 2013; 33(9): 984-99

EMPA-REG OUTCOME STUDY

Aim: To determine the long-term CV safety of Empagliflozin

Inclusion: >7000 drug-naïve patients (HbA1c ≥7.0% and ≤9.0%), or on glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%)at high risk for CV events

Treatment: Randomized (1:1:1) and treated with Empagliflozin 10 mg, 25 mg, or placebo

Primary outcome: Time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke

Zinman B, et al. N Engl J Med 2015;373(22):2117-2128

EMPAGLIFLOZIN MODULATES SEVERAL FACTORS

RELATED TO CV RISK

Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100 21

BP Arterial stiffness

Glucose Insulin

Albuminuria

Uric acid

Other

↑LDL-C ↑HDL-C

Triglycerides

Oxidative stress

Sympathetic nervous system

activity

Weight Visceral adiposity

EMPA-REG OUTCOME®:

SUMMARY

Empagliflozin reduced HF hospitalization

by 35%

Empagliflozin reduced CV death by 38%

Empagliflozin improved survival by

reducing all-cause mortality by 32%

http://www.nejm.org/doi/full/10.1056/NEJMoa1504720

22

NUMBER NEEDED TO TREAT (NNT) TO PREVENT ONE

DEATH ACROSS LANDMARK TRIALS IN PATIENTS

WITH HIGH CV RISK

1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm; 2. 2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-

HOPE.htm

23

Simvastatin1

for 5.4 years

High CV risk 5% diabetes, 26% hypertension

1994 2000 2015

Pre-statin era

High CV risk 38% diabetes, 46% hypertension

Ramipril2

for 5 years

Pre-ACEi/ARB era

<29% statin

Empagliflozin for 3 years

T2DM with high CV risk 92% hypertension

>80% ACEi/ARB

>75% statin

EMPAGLIFLOZIN/LINAGLIPTIN (GLYXAMBI®)

DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38(3):384-393.

OBJECTIVE To evaluate the efficacy and safety of empagliflozin/linagliptin as second-line therapy in subjects with T2DM inadequately controlled on metformin RESEARCH DESIGN : Subjects were randomized to a combination of 1. Empagliflozin 25 mg/linagliptin 5 mg (n = 137) 2. Empagliflozin 10 mg/linagliptin 5 mg (n = 136) 3. Empagliflozin 25 mg (n = 141) 4. Empagliflozin 10 mg (n = 140) 5. Linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks

RESULTS OF THE STUDY

QUESTION ON EMPAREG STUDY

The EmpaREg Study demonstrated positive outcomes in all of the

following CV outcomes, EXCEPT:

RED Myocardial Infarction; Stroke

BLUE Heart Failure Hospitalization

GREEN Cardiovascular Death

YELLOW All Cause Mortality

BIOEQUIVALENCE: HUMALOG U 200 VS 100

SAME DOSE; ½ THE VOLUME

INSULIN GLARGINE – U-300 (TOUJEO®) –

NONBIOEQUIVALENT TO GLARGINE U-100

Noninferior: similar A1c lowering

More basal insulin use of Toujeo in both T1 and T2DM

Rates of hypoglycemia?

For patients controlled on insulin glargine U100, a

higher daily dose of TOUJEO® will be needed

From twice-daily NPH insulin to once-daily TOUJEO®,

the recommended starting TOUJEO® dose is 80% of the

total daily NPH dosage

HUMULIN R – U-500 KWIKPEN®

Available in April 2016

Onset of Action = within 30 min Duration of Action = 1 hour Pen: No Dose Conversion compared to Vial

POTENTIAL CANDIDATES FOR U-500 HUMAN

REGULAR INSULIN

T2DM Patients with obesity/severe insulin resistance

Patients requiring >200 units of insulin per day

•High glucocorticoid therapy

•Severe systemic infection

Gestational diabetes with severe insulin resistance

Genetic defects of insulin action

•Type A insulin resistance syndromes

• Immune mediated diabetes (anti-insulin receptor antibodies)

INSULIN DEGLUDEC (TRESIBA®) U-

200 AND U-100 FLEXTOUCH

INSULIN DEGLUDEC (TRESIBA®): BEGIN STUDIES

Ultra long acting insulin (dosed daily)

Onset of Action: 30 – 90 minutes

Its duration of action is up to 42 hours compared to 18 to 26 hours (glargine and insulin detemir)

Efficacy: Non inferior to Lantus® (glargine)

Benefit: Flexibility in day to day dosing time

Gough SCL, Harris S, Woo V, et al. Insulin degludec: overview of a novel ultra long-acting basal insulin. Diabetes, Obesity and Metabolism. 2013 (15): 301 – 9

TRESIBA DOSING

NO dose conversion between TRESIBA® U-100

or U-200 FlexTouch® pens

The dose window for both FlexTouch® pens

shows the number of insulin units to be delivered

Starting Dose in Insulin Naïve T1DM Patients in

insulin naïve patients with type 1 diabetes is ~ 1/3

to ½ of TDD

Starting dose in insulin naïve T2DM patients is 10

units once daily

QUESTION ON INSULIN

Which of the following insulin(s) is/are bioequivalent (require no

dose conversion)?

RED Toujeo® (Glargine) U-300 vs. Lantus®

(Glargine) U-100

BLUE Humalog® Kwikpen U-200 vs. Humalog®

Kwikpen U-100

GREEN Humulin R Kwikpen® U-500 vs. Humulin® R U-100

YELLOW Tresiba® (Insulin Degludec) U-200 vs.

Tresiba® U-100

MINI-CASE – PATIENT AB

Chief complaint: “I want to lose weight”

HPI: 52-year-old woman with Type 2 DM, HTN

Vitals: Weight: 220 lb; Height 5’4”; BMI 37.8

Labs: HbA1c 8.8%

Diet: None

Medications

• Metformin (Glucophage® XR) 1,000 mg bid

• Empagliflozin (Jardiance®) 25 mg daily

• Liraglutide (Victoza®) 1.8 mg daily

• HCTZ 25 mg once daily

46

QUESTION ON PATIENT - AB

Is this patient, AB a candidate for Saxenda®?

RED Saxenda®(Liraglutide) is safe

BLUE Use if you discontinue her Glucophage®

(Metformin)

GREEN Use if you discontinue her Victoza®

(Liraglutide)

YELLOW Use if you discontinue her Jardiance®

(Empagliflozin)

KEY TAKE AWAY POINTS

Clinical trials show 62% and 34% of patients on

Saxenda® (Liraglutide) 3 mg, decrease weight by

5% and 10% respectively from baseline

Empagliflozin demonstrated positive CV

outcomes in decreasing HF hospitalizations; CV

death and all cause mortality (not MI or Stroke)

PK/PD studies must demonstrate bioequivalence

in order to maintain dosing in concentrated

insulin with their U-100 counterparts

Concentrated insulin has the same dose but less

volume

QUESTION FOR AUDIENCE

On completion of this presentation,

RED I learnt at least one important fact today

BLUE I am still “muddy” about one point

GREEN I need one area clarified today

YELLOW I slept through, so I have no questions

THANKS!

Any questions? You can email me at ameadows@umm.edu