DIABETES DRUGS & TRENDS MADE SIMPLE PHARMD TO RD...RESEARCH DESIGN : Subjects were randomized to a...
Transcript of DIABETES DRUGS & TRENDS MADE SIMPLE PHARMD TO RD...RESEARCH DESIGN : Subjects were randomized to a...
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
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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
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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
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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