Transcript Diabetes Update 2016: New drugs and New Methods of Care

Diabetes Update 2016:
New Drugs and
New Methods of Care
Kelly Murray, PharmD, BCACP
Clinical Assistant Professor of Clinical Pharmacy
OSU College of Osteopathic Medicine
Emergency Department Clinical Pharmacist
OSU Medical Center
Overview
Standards of Care 2016 Updates
New Diabetes Therapies
Oral medications
Injectable medications
Insulin therapies
Innovative Care Solutions and Ideas
2
Objectives
Describe the mechanisms of action of
the newest type 2 diabetes medications
– DPP4-inhibitors, incretin mimetics,
and SGLT-2 inhibitors.
Recall advantages of insulin degludec
over insulin glargine.
List 3 resources to assist patients with
the costs of their medications.
3
Standards of Care 2016
Updates
General Changes
“Person with diabetes” vs. “diabetic”
Support technology to assist diabetes
management
Obesity management/treatment
recommendations
Cefalu WT. Diabetes Care 2016;29(1):S1-S112.
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Testing
All adults ≥45 years old regardless of
weight
Any person who is overweight/obese
with ≥1 risk factor
Cefalu WT. Diabetes Care 2016;29(1):S1-S112.
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Diabetes Management in
Pregnancy
A1c target 6-6.5% instead of 6%
Insulin or metformin > glyburide
Cefalu WT. Diabetes Care 2016;29(1):S1-S112.
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New Diabetes Therapies
•
•
•
•
•
DPP-4 Inhibitors
GLP-1 Agonists
SGLT2 Inhibitors
New Basal Insulins
New Bolus Insulins
Where do diabetes meds work?
Brain
↑ satiety
• Pramlintide
• Incretin mimetics
Liver
↓ glucose production
• Insulin
• Metformin
• TZDs
• Pramlintide
• DPP-4 inh.
• Incretin mimetics
Muscle and Adipose
↑ peripheral glucose
uptake
• Insulin
• Metformin
• TZDs
Pancreas
↑ insulin secretion
• Insulin
• Sulfonylureas
• Meglitinides
• DPP-4 inh.
• Incretin mimetics
Kidneys
↓ glucose reabsorption
• SGLT2 inh
Intestines
↓ digestion and
absorption of carbs
• Metformin
• a-glucosidase inh.
Delay gastric emptying
• Pramlintide
• Incretin mimetics
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What level do they fix?
FASTING
Metformin
MIXED
POSTPRANDIAL
SU
Regular insulin
TZDs
Rapid insulins
Incretin mimetics Meglitinides
Interm. insulin
a-glucosidase (-)
Long insulin
DPP-4 (-)
SGLT2 (-)
Incretin mimetics (Exen.)
Pramlintide
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Incretin Effect
Eat food  nutrients and glucose in the
gut
Intestinal mucosal cells sense this and
release hormones called incretins
GLP1 = glucagon like peptide 1
GIP = glucose-dependent insulinotropic
polypeptide
The “incretin effect” is decreased in type 2
diabetes, so we need to replace levels.
Idris I. Diabetes Obes Metab 2007;9:153-65.
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Need for Drug Therapy That:
Inhibits degradation of DPP-4 so there
is more circulating incretin;
 DPP-4 inhibitors
OR
Replaces incretin altogether by giving
an analog exogenously
 Incretin mimetic, or GLP-1 receptor agonist
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Dipeptidyl Peptidase - 4 (DPP-4)
Inhibitors
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
• + Metformin (Janumet, XR)
• + Simvastatin (Juvisync)
• + Metformin (Kombiglyze XR)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
• + Metformin (Jentadueto)
• + Empagliflozin (Glyxambi)
• + Metformin (Kazano)
• + Pioglitazone (Oseni)
Lexi-complete Online. Accessed 4/7/16.
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DPP-4 Inhibitors
Mechanism:
 Inhibits DPP-4 (enzyme that breaks down incretin)
 Increased circulating incretin, helping control
glucose absorbed in the diet
 Glucose-dependent increase in insulin secretion
 Glucose-dependent inhibition of glucagon
secretion
Idris I. Diabetes Obes Metab 2007;9:153-65.
Drucker DJ. Lancet 2006;368:1696-705.
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DPP-4 Inhibitors - Safety
AE:
Placebo-like: HA, URI, nasopharyngitis,
UTI
Rare: pancreatitis, skin reactions,
urticaria/angioedema
CI: Hx of pancreatitis, DKA, type 1
diabetes
Counseling:
With or without food
Lexi-complete Online. Accessed 4/7/16.
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DPP-4 Inhibitors - Efficacy
Average A1c reduction: 0.6-0.8%
Primarily acts on postprandial glucose
Remember they are glucose-dependent
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DPP-4 Inhibitors
Advantages:
 No hypoglycemia as monotherapy
 Weight neutral
 Placebo-like AE
 Beta cell preservation
 Linagliptin – no renal adjustments needed
Disadvantages:
 Modest A1c lowering
 Cost
 Long term safety unknown
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DPP-4 Inhibitors Dosing Guide
Sitagliptin 100mg po daily
 CrCl 30-49= 50mg po daily
 CrCl ≤ 30= 25mg po daily
 ESRD= 25mg po daily without regard to HD
 Reduce dose of concomitant insulin/secretagogues
Saxagliptin 2.5 – 5mg po daily
 CrCl ≤ 50 = 2.5mg po daily
 ESRD = 2.5mg po daily, post-HD
 With strong CYP 3A4/5 inhibitors (“conazoles” and
protease inhibitors) = 2.5mg po daily
 Reduce dose of concomitant insulin/secretagogues
Lexi-complete Online. Accessed 4/7/16.
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DPP-4 Inhibitors Dosing Guide
Linagliptin 5mg po daily
 Reduce dose of concomitant insulin/secretagogues
 No renal dose adjustment needed
Alogliptin 25mg po daily
 CrCl 30-59= 12.5mg po daily
 CrCl 15-29= 6.25mg po daily
 ESRD= 6.25mg po daily, without regard to HD
 Reduce dose of concomitant insulin/secretagogues
Lexi-complete Online. Accessed 4/7/16.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
Exenatide (Byetta, Bydureon)
Liraglutide (Victoza, Saxenda)
Albiglutide (Tanzeum)
Dulaglutide (Trulicity)
Lixisenatide (Lyxumia)
 App. for new drug approval submitted 9/2015
Lexi-complete Online. Accessed 4/7/16.
FDA Drugs. Accessed 4/11/16.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
Mechanism: GLP1 analog
 Increases incretin levels
 Glucose-dependent increase in insulin secretion
 Glucose-dependent inhibition of glucagon
 Reduces gastric emptying
 Increases satiety
Lexi-complete Online. Accessed 4/7/16.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
 Adverse Effects:
 Nausea – 8-40% more vs. placebo/comparator
 Exen BID>Lira>Exen Q7D>Alb/Dula
 Diarrhea – 3-118% more vs. placebo/comparator
 Rare – pancreatitis, renal dysfunction, thyroid tumors
 CI:




Gastroparesis
Pancreatitis
Exen: CrCl <30 (maybe others?)
Lira, Alb, Dula, Exen: PMH or FH of thyroid cancer,
multiple endocrine neoplasia
Shyangdan DS. Cochrane Database Syst Rev 2011.
Lexi-complete Online. Accessed 4/7/16.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
Efficacy:
A1c reduction 1-2%
Adjunct for type 2 diabetes
BID = More postprandial reduction
Daily, Q7D Dosing = More fasting reduction
Drucker DJ. Lancet 2006;368:1696-705.
Lexi-complete Online. Accessed 4/7/16.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
Dosing considerations
Inject into thigh, abdomen, upper arm
Exenatide BID 60 minutes prior to 2 main
meals
Reduce incidence of nausea with proper
dose titration (start low, go slow)
 Once-weekly injections < twice daily injections
Lexi-complete Online. Accessed 4/7/16.
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Exenatide IR to ER
Start weekly dose the day after D/C IR
D/C IR Monday, start ER Tuesday
Pt may have increased BG levels for 2
weeks
Pretreatment for this temporary rise is
unnecessary
Lexi-complete Online. Accessed 4/7/16.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
Advantages:
Weight loss – 1-5kg
No priming after initial dose
Extended release option available
Preservation of beta cell function
Decrease insulin resistance
Shyangdan DS. Cochrane Database Syst Rev 2011.
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GLP 1 Receptor Agonists
(a.k.a. incretin mimetics)
Disadvantages:
May reduce absorption rate and extent of
drugs requiring rapid absorption (i.e. pain
relievers, antibiotics, BCPs). Separate by
1 hour.
Requires subcutaneous injection
Cost
GI side effects
Lexi-complete Online. Accessed 4/7/16.
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GLP-1 Agonists Dosing Guide
 Byetta (exenatide) 5mcg subq BID ac, increase to 10mcg
subq BID after 1 month
 CrCl <30= use is not recommended
 Bydureon (exenatide) 2mg subq once weekly
 CrCl <30= use is not recommended
 Victoza (liraglutide) 0.6 mg subq once daily x 1 week,
then increase to 1.2mg subq once daily. May go to 1.8mg
if optimal glycemic response not achieved.
 If missed doses, resume with next scheduled dose.
 If >3 days of missed doses, resume with 0.6mg dose and
retitrate.
 No CrCl limitations on use
Lexi-complete Online. Accessed 4/7/16.
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GLP-1 Agonists Dosing Guide
 Tanzeum (albiglutide) 30mg subq once weekly, may
increase to 50mg once weekly if inadequate response
at week 12.
 Missed dose = administer ASAP within 3 days. If >3 days
have passed, omit dose and resume with next scheduled
dose.
 No renal adjustment necessary.
 Trulicity (dulaglutide ) 0.75mg subq once weekly; may
increase to 1.5mg weekly if inadequate response.
 Same missed dose regimen as albiglutide
 No renal adjustment necessary.
 Lyxumia (lixisenatide) – once daily prandial subq
injection, dose TBA
Lexi-complete Online. Accessed 4/7/16.
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Incretin Mimetic vs. DPP-4 Inhibitors
Incretin Mimetic
DPP-4 Inhibitor
Delay gastric emptying
Increase satiety
No effect on gastric
emptying
No increase in satiety
Lots of N/V
Weight loss
Placebo-like AE
No change in weight
SC administration
PO administration
Drucker DJ. Lancet 2006;368:1696-705.
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SGLT2 Inhibitors
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
• Approved 3/13
• + Metformin (Invokamet)
• Approved 1/14
• + Metformin (Xigduo)
Empagliflozin (Jardiance)
• Approved 8/14
• + Metformin (Synjardy)
• + Linagliptin (Glyxambi)
Lexi-complete Online. Accessed 4/7/16.
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SGLT2 Inhibitors
Mechanism of Action
Blocks renal absorption of ~90% of
excess glucose
Causes renal wasting of glucose, lowering
serum BG and A1c over time
Minimizes chance of hypoglycemia
Jurczak MJ. Diabetes 2011;60:890-8.
Lexi-complete Online. Accessed 4/7/16.
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SGLT2 Inhibitors
 Adverse Effects:
 Urinary/genital infections
 Hypotension
 Bone fractures
 DKA
 Hyperkalemia
 Renal insufficiency
 Contraindications:
 Hypersensitivity
 ESRD/Dialysis
Lexi-complete Online. Accessed 4/7/16.
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SGLT2 Inhibitors
Counseling Points:
With or without food
Before the first meal of the day
Efficacy
0.5-0.9% A1c lowering
Mostly post-prandial glucose lowering
Lexi-complete Online. Accessed 4/7/16.
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SGLT2 Inhibitors
Advantages:
 New mechanism,
another option
 Less hypoglycemia
 Weight loss
 Potential BPlowering
Disadvantages:
 DKA
 Price / insurance
coverage
 May encourage diet
indiscretions?
 Cancer risk?
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Dosing Recommendations
 Canagliflozin (Invokana)
 100mg po once daily before first meal of the day
 eGFR 45-59 = 100mg po daily max
 eGFR <45 = use is not recommended/CI
 Dapagliflozin (Farxiga)
 10 mg po once daily without regard to meals
 eGFR <60 = use is not recommended/CI
 Empagliflozin (Jardiance)
 10mg po once daily without regard to meals
 eGFR <45 = use is not recommended/CI
Lexi-complete Online. Accessed 4/7/16.
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Type 2 Therapies (Fig 7.1)
Cefalu WT. Diabetes Care 2016;29(1):S1-S112.
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New Insulin Therapies
New Insulin Therapies
Ideal basal insulin
 Peakless
 Consistent rate of
absorption
 No weight gain
 True 24-hour coverage
Bolus insulin
 Lots of injections
 Titratable dose
 Minimize side effects
Hess R. ACSAP 2016;1:35-64.
1. Insulin degludec (Tresiba)
2. Insulin glargine (Toujeo)
3. Insulin glargine (Basaglar)
4. Humalog U-200 KwikPen
5. Inhaled insulin (Afrezza)
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1
Insulin degludec (Tresiba)
Image: https://www.diabetesdaily.com/blog/2015/09/tresiba-fda-approves-new-basal-insulin-in-the-usa/. Accessed 4/11/16.
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Insulin degludec (Tresiba)
Long-acting insulin
Onset = 1 hour
Time to peak = 9 hours
t ½ = 25 hours
Duration = 42 hours
Lexi-complete Online. Accessed 4/7/16.
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Insulin degludec Mechanism
 Naturally, insulin dimers form hexameric complexes to
maximize storage within beta-cell vesicles
 Degludec mimics this natural process
 Hexamer  multihexameric
chain = depot formation with
a slow constant release over
time
Jonassen I. Pharm Res 2012;29:2104-14.
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Head-to-Head: Insulin degludec vs.
Insulin glargine
 Noninferiority criteria met (95% CI -0.14 to 0.11)
 Nocturnal hypoglycemia rates 25% lower (p=0.021)
 Mean weight gain similar (1.8 kg with degludec and 1.6 kg with
glargine) (p=0.62)
Insulin detemir (+ aspart)
 Noninferiority criteria met (95% CI -0.23 to 0.05)
 Nocturnal hypoglycemia 34% lower (p=0.0049)
 Weight gain higher with degludec (est. diff. 1.08 kg; p<0.0001)
Heller S. Lancet 2012;379:1489-97. (BEGIN)
Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1)
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HbA1c Comparison
Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1)
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Insulin degludec (Tresiba)
100 units/mL and 200 units/mL available
 No conversion calculation necessary; same unit per
unit dose
Dosing:
 Type 1: 0.2-0.4 units/kg (1/3-1/2 the TDD)
 Type 2: 10 units once daily
 Missed doses: administer ASAP to ensure at least 8
hours between doses
Stable at room temp for 8 weeks
Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1)
Lexi-complete Online. Accessed 4/7/16.
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2 Insulin glargine (Toujeo)
Image: https://www.toujeo.com. Accessed 4/7/16.
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Insulin glargine (Toujeo)
No change in physiological mechanism
 Smaller amount of depot insulin
 Smaller surface area
 More gradual and prolonged release of hexamers
Smaller amount of liquid per unit
 450 units (300 u/mL) vs. 300 units (100 u/mL) in
Lantus pen
Home PD. Am Diabetes Assoc 2014;2014:abstract 80-LB.
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Head-to-Head: Toujeo vs. Lantus
Noninferiority met at 26 weeks (95% CI 0.10.19)
Nocturnal hypoglycemia
 31% lower in first 8 weeks (CI 0.53-0.91)
 No difference at 26 weeks
Less weight gain (est. diff. 0.5 kg, p=0.037)
Home PD. Am Diabetes Assoc 2014;2014:abstract 80-LB.
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3
Basaglar (insulin glargine)
Eli Lilly/Boerhinger Ingelheim. Introducing: Basaglar. https://www.basaglar.com/# (accessed 4/7/16).
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Basaglar (insulin glargine)
Lilly/BI’s answer to Sanofi-Aventis’s
Lantus
Same PK profile, not interchangeable
Approved for use in type 1 kids and
adults, and type 2 adults
Available starting 12/2016
Blevins TC. Diabetes Obes Metab 2015;17:726-33. (ELEMENT 1)
Eli Lilly/Boerhinger Ingelheim. Introducing: Basaglar. https://www.basaglar.com/# (accessed 4/7/16).
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Head-to-Head: Basaglar vs. Lantus
Noninferiority met at 24 weeks
 95% CI -0.002 to 0.219
Symptomatic and nocturnal hypoglycemia
similar
Weight gain similar
 0.36 kg Basaglar vs. 0.12 kg Lantus
Insulin antibodies similar
Blevins TC. Diabetes Obes Metab 2015;17:726-33. (ELEMENT 1)
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4
Humalog U-200 KwikPen
Image: http://www.ulticare.com/pen-needles/. Accessed 4/11/16.
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Humalog U-200 KwikPen
200 units/ml
600 units/pen (versus 300 units/pen)
Good for patients who go through 2 or
more mealtime insulin pens each
month
Lexi-complete Online. Accessed 4/7/16.
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5
Inhaled insulin (Afrezza)
Images: Afrezza. https://www.afrezza.com/hcp
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Inhaled insulin (Afrezza)
“Technosphere insulin”
Helps reduce injection barriers to therapy
Lungs have a large surface area and high
bioavailability
New inhaler device called “Dreamboat”
 Replace every 15 days
Insulin cartridges available:
 4 units, 8 units, 12 units
Concerns: pulmonary toxicity/malignancy
Lexi-complete Online. Accessed 4/7/16.
Bode BW. Diabetes Care 2015;38:2266-73.
Raskin P. Diabetes Obes Metab 2012;14:163-73.
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Head-to-Head: Inhaled insulin
vs. aspart
Mean change in HbA1c noninferior
More aspart patients achieved HbA1c <7.0%
(30.7% vs. 18.3%)
Inhaled insulin had less hypoglycemia (9.8
vs 14.0 events/patient-month, p<0.0001)
Inhaled insulin patients experienced weight
loss (-0.4 kg) vs. gain (+0.9 kg) for aspart
patients (p=0.0102)
Most frequent AE = cough which led to
discontinuation in 5.7% of patients
Bode BW. Diabetes Care 2015;38:2266-73.
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Dosing Chart Configurations
Afrezza. https://www.afrezza.com/AfrezzaConfigurationChart.pdf
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Diabetes Meds in the Pipeline
Novo Nordisk
 Xultophy (insulin degludec + liraglutide)
 Faster-acting insulin aspart
 Semaglutide (oral and injectable)
Eli Lilly
 BioChaperone insulin lispro
R&D Pipeline. http://www.novonordisk.com/rnd/rd-pipeline.html. Accessed 4/11/16.
Anderson G. Diabetes 2014;63(suppl 1).
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Innovative Care Solutions
and Ideas
•
•
•
•
Patient Assistance Programs
Coupons
Medication Pricing Apps
Medication Lists
Patient Assistance Programs
(PAPs)
 Provided by pharmaceutical companies
 To provide brand-name medications
 For low-income individuals who lack prescription drug
coverage
 Vs. coupon, sample, 340B, drug card, bulk
replacement programs, and Medicare Part D
 Advocate
“PAPs are a long term solution to a
current medication access problem”
Am J Health-Syst Pharm. 2006; 63:1254-9.
Sagall RJ. Pharmaceutical companies helping patients get their medications. Accessed at
http://www.needymeds.org/indices/article.htm on 2/21/13.
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Programs Available
 NeedyMeds
 http://www.needymeds.org
 Partnership for Prescription Assistance
 http://www.pparx.org
 RxAssist
 http://www.rxassist.org
 TogetherRx Access
 http://www.togetherrxaccess.com
 National Council on Patient Information and Education
 http://www.talkaboutrx.org
 Manufacturers’ websites
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Finding an application
Medications covered
Type (brand, generic)
Insurance status
Private insurance
Medicare Part D (coverage gap)
No insurance
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Coupons
Discount the price of medications for a set
number of fills
Search patient assistance websites for
coupons
Hard copy cards at physician offices from
drug company representatives
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Medication Pricing - GoodRx
Losartan 50mg #30
Wal-Mart pricing by phone =
$39.41
Price obtained by phone from Wal-Mart Neighborhood Market, 4404 S. Peoria Ave. Tulsa, OK on 4/11/16.
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Medication Pricing - GoodRx
Screenshots taken 4/7/16.
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Medication Pricing - GoodRx
Screenshots taken 4/7/16.
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Medication Lists
MyMedSchedule.com
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Medication Lists
My Medicine List
http://www.safemedication.com
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Questions?
Diabetes Update 2016:
New Drugs and
New Methods of Care
Kelly Murray, PharmD, BCACP
Clinical Assistant Professor of Clinical Pharmacy
OSU College of Osteopathic Medicine
Emergency Department Clinical Pharmacist
OSU Medical Center