Dr. Joseph Pitone · 2019-09-26 · Glucoregulatory Role of GLP-1 and GIP –Effects in Humans...
Transcript of Dr. Joseph Pitone · 2019-09-26 · Glucoregulatory Role of GLP-1 and GIP –Effects in Humans...
• Does not address core needs as well as other agents (ominous octet)
• Does not address metabolic parameters (blood pressure, Hgb A1C) as well as other agents
• Micro and Macrovascular benefits not as robust as other agents
• Mortality data not as promising as other agents
Metformin although effective has become obsolete
Case Presentation
• 62 y/o female T2DM, hypertension, hyperlipidemia. Hx MI, • T2DM 15 years Rxed metformin 1000 mg daily, linagliptin 5 mg daily ,
glargine insulin 46 units daily• Other meds rosuvastatin 20 mg daily, lisinopril 10 mg daily
• Px 130/80 Ext DPN no ret. BMI 32
• Labs A1C 8.4% eGFR 64 cc/min • Glycemic profile mean 160, lowest 122 , highest 242 acb and acd smbg.• Lipids TC 142 LDL-C 68, HDL-C 46, TG 124,• Other labs negative
A1C and Mortality in Clinical Practice
12
A1C (%)
All
-ca
use m
ort
ality
hazard
ra
tio
Retrospective Cohort Study
(N=27,965)
Currie CJ, et al. Lancet. 2010;375:481-489.
Con’t
• What therapeutic choices ?
• 1. uptitrate metformin
• 2. add SU
• 3. substitute GLP-1 for linagliptin
• 4. add SGLT-2 inhibitor
• 5. Increase glargine insulin
• 6. split dose glargine insulin
• 7. begin mealtime insulin
• 8. start patch pump (VGO)
• 9. start insulin pump
• 10. revisit lifestyle modification assess adherence
GLP-1 Receptor Agonists
14
15
GLP1 Receptor Agonists
FDA-Approved Agents
• Albiglutide*
• Dulaglutide
• Exenatide
• Exenatide ER
• Liraglutide
• Lixisenatide
• Semiglutide
Key Features
• Subcutaneous administration
• Mimic action of native GLP1
• Increase glucose-dependent insulin
secretion
• Suppress glucagon production
• Slow gastric emptying
ER, extended release; GLP1, glucagon-like peptide 1.
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
Therapeutic Potential of Enhancing GLP-1 Activity: GLP-1
Receptor Agonists and DPP-4 Inhibitors
Two classes of agents have been developed based on the
therapeutic potential of enhancing GLP-1 activity1
GLP-1 receptor agonists: agents that mimic the actions of GLP-1
Protease DPP-4 inhibitors: agents that prolong the activity of endogenous GLP-1
GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4 1. Garber. Rev Diabet Stud 2011;8:307-22
Glucoregulatory Role of GLP-1 and GIP – Effects
in Humans
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide 1. Flint et al. J Clin Invest 1998;101:515-5202. Larsson et al. Acta Physiol Scand 1997;160:413-4223. Nauck et al. Diabetologia 1996;39:1546-1553 4. Drucker. Diabetes 1998;47:159-169
Promotes satiety and
reduces appetite
β-cells: enhance
glucose-dependent
insulin secretion
Liver:
↑ Insulin/glucagon:
reduces hepatic glucose
output
-cells:
↓ Postprandial
glucagon secretion
Stomach:
slows gastric
emptying
On ingestion of food:
GLP-1 secreted by L-cells,
GIP secreted by K-cells
β-cell response
β-cell workload
GLP-1 Has a Broad Range of Biological Activity
1. Smilowitz et al. Circulation. 2014;129(22):2305-2312.
2. Gupta. Indian J Endocrinol Metab. 2013;17(3):413-421.
3. Kalra S, et al. Indian J Endocrinol Metab. 2016;20(2):254-267.
Brain
Stomach
Pancreas
Muscle and Adipose Tissue
Cardiovascular System1
Intestine
↓ Cardiovascular risk factors
• Weight
• Blood pressure
• Lipid profile↓ Gastric emptying1
↑ Insulin secretion1
↓ Glucagon secretion3
↑ Glucose uptake2
↓ Glucose production2
↓ Appetite1
↑ Satiety2
Liver GLP-1
Indirect actions
Direct actions
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DPP4 Inhibitors GLP1 Receptor Agonists SGLT2 Inhibitors
Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12
Baseline A1C (%) 7.9 8.1 8.1 8.0 8.1 8.1 8.2 8.6 8.4 7.8 7.9 7.9
Glucose ReductionDPP4 Inhibitors, GLP1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin
(Absolute Changes from Baseline; Not Head-to-Head Trials)
1. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 2. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 3. DeFronzo RA, et al. Diabetes
Care. 2009;32:1649-1655. 4. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 5. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148.
6. Dungan KM, et al. Lancet. 2014;384:1349-1357. 7. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 8. Bergenstal RM, et al. Lancet.
2010;376:431-439. 9. Pratley RE, et al. Lancet. 2010;375:1447-1456. 10. Cefalu WT, et al. Lancet. 2013;382:941-950. 11. Nauck MA, et al. Diabetes
Care. 2011;34:2015-2022. 12. Haring HU, et al. Diabetes Care. 2014;37:1650-1659.
A
1C
(%
)
-0.6-0.5
-0.7 -0.7-0.63
-1.42
-0.8
-1.5 -1.5
-0.93
-0.52
-0.77
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
6-Week Continuous GLP-1 Infusion Increases Satiety and
Reduces Food Intake
Sensations of appetite in patients treated with GLP-1
GLP-1=glucagon-like peptide-1; AUC=area under curveMean±SE; N=10; Only data of patients treated with GLP-1 shownOverall p values labeled for each sensation; *Only significant for week 0 vs week 1 after Bonferroni testZander et al. Lancet 2002;359:824-830
Mea
n (
SE
) A
UC
fo
r V
isu
al
An
alo
g S
co
re (
mm
) vs. T
ime (
hou
r)
Time (week)
0
100
200
300
400
500
0 1 6
p=.008*p=.03 for Satiety
Satiety
Fullness
Prospective food intake
Hunger
p=.02
p=.007
21
Weight ReductionDPP4 Inhibitors, GLP1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin
(Separate Studies; Not Head-to-Head Trials)
NR, not reported.
1. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 2. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 3. DeFronzo RA, et al. Diabetes
Care. 2009;32:1649-1655. 4. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 5. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148.
6. Dungan KM, et al. Lancet. 2014;384:1349-1357. 7. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 8. Bergenstal RM, et al. Lancet.
2010;376:431-439. 9. Pratley RE, et al. Lancet. 2010;375:1447-1456. 10. Cefalu WT, et al. Lancet. 2013;382:941-950. 11. Nauck MA, et al.
Diabetes Care. 2011;34:2015-2022. 12. Haring HU, et al. Diabetes Care. 2014;37:1650-1659.
NR
DPP4 Inhibitors GLP1 Receptor Agonists SGLT2 Inhibitors
Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12
-0.3 -0.4-0.9
-1.2
-2.6-2.8
-2.0
-2.8
-4.0
-3.2
-2.5
-5
-4
-3
-2
-1
0
W
eig
ht
(kg
)
22
Safety Considerations
with GLP1 Receptor AgonistsGI adverse
events
• Common • Usually dose dependent and transient• Usually reduced with dose titration
Pancreatitis
• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents
• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected• Labeling for GLP1 receptor agonists suggests consideration of other therapies for patients with a history of
pancreatitis
Pancreatic
cancer
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents
• Further assessments required from long duration-controlled studies or epidemiological databases
Medullary
thyroid
cancer
• Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking
• Labeling for albiglutide, dulaglutide, exenatide ER, and liraglutide:• Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid
tumors• Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia
syndrome type 2
Renal
impairment
• Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea,
or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide
should not be used in patients with severe renal insufficiency or ESRD. Liraglutide was found to be safe in
patients with moderate renal impairment and may confer a beneficial effect.
ER, extended release.
Garber AJ, et al. Endocr Pract. 2016;22:84-113. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news
release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June
28, 2013. http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html. Davies MJ, et al. Diabetes Care. 2016;39:222-230.
Marso SP, et al. N Engl J Med. 2016;375:311-322.
Exenatide BIDHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
DPP-4Resistant to DPP-4
LixisenatideHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK
DPP-4Resistant to DPP-4
t1/2 = 3.3-4 hours
and renal filtration
Steady state over 6-7 weeks
and renal filtration
t1/2 = ~3 hours
and renal filtration
t1/2 = 11-13 hours
and multiple organ filtrationLiraglutide
Albumin
HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG
C-16 free fatty acid derivative
via a glutamoyl spacer
DPP-4Partial resistant to DPP-4
Exenatide QW
Poly (D,L lactic-co-glycolic acid) microspheres
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
DPP-4Resistant to DPP-4
Approved GLP-1 RAs – Structure and Half-life
Albiglutide t1/2 = ~ 5 days
and multiple organ filtration
Recombinant fusion protein
linked to human albumin
DPP-4Resistant to DPP-4
HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR
HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR Albumin
DulaglutideHGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG
DPP-4
t1/2 = ~5 days
Resistant to DPP-4
HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG
Modified IgG4 Fc domain
Modified IgG4 Fc domain
t1/2 = 165 hoursSemaglutide
Albumin
HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG
C-18 free fatty acid derivative
via a glutamoyl-2xOEG spacer
DPP-4Resistant to DPP-4
Currently Available GLP-1 RAs Administration
*Titrate if necessary; †When administered in the prefilled pen, exenatide QW does not require reconstitution; however when administered in the single-dose kit, reconstitution is needed; ǂshake the autoinjector hard in up
and down motion until the medicine is mixed evenly. If you do not see any white medicine along the sides, bottom or top then shake for at least 15 seconds; BD=Becton Dickinson; QW=once weekly. 1. Byetta [Prescribing
Information]. San Diego, CA: Amylin Pharmaceuticals, LLC; 2015 2. Adlyxin [Prescribing Information]. Bridgewater, NJ: Sanofi-Aventis; 2016 3. Victoza [Prescribing Information]. Plainsboro, NJ: Novo Nordisk A/S; 2016
4. Tanzeum [Prescribing Information]. Research Triangle Park, NC: GlaxoSmithKline LLC; 2017 5. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2017 6. Bydureon [Summary of Product
Characteristics]. AstraZeneca AB SE-151 85 Södertälje Sweden; 2017 7. Bydureon Bcise [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017 8. Ozempic [Prescribing Information].
Plainsboro, NJ: Novo Nordisk A/S; 2017
DAILY WEEKLY
Exenatide BID1 Lixisenatide2 Liraglutide3 Albiglutide4 Dulaglutide5 EQW Pen6 EQW Bcise7 Semaglutide8
Reconstitution
requiredNo No No Yes No Yes† Noǂ No
Pre-injection
waiting time after
reconstitution
None None None 15 min/30 min
(30 mg/50 mg Pen)
None None None None
Ready-to-use solution
Yes Yes Yes Reconstitution within device
Yes Reconstitution
within device
Mix
within device
Yes
Dose volume 0.02 ml (5 mg)
0.04 ml (10 mg)
0.20 ml (10 mg)
0.20 ml (20 mg)
0.20 ml (1.2 mg)
0.30 ml (1.8 mg)
0.50 ml (30 mg)
0.50 ml (50 mg)
0.50 ml (0.75 mg)
0.50 ml (1.5 mg)
0.65 ml (2 mg) 0.85 ml (2 mg) 0.75 ml (1 mg)
0.375 ml (0.5 mg)
0.1875 (0.25 mg)
Titration required Yes* Yes Yes Yes* No No No Yes
Single-use/multi-use Multi-use Multi-use Multi-use Single-use Single-use Single-use Single-use Multi-use
Hidden needle No No No No Yes No Yes No
Needle attachment
requiredYes Yes Yes Yes No Yes No Yes
Needle size (mm)/gauge
4 mm
29-31 g
Supplied
separate
4 mm
29-31 g
Supplied separate
4 mm
32 g
Supplied
separate
5 mm / 29 g
Unknown supply
5 mm / 29 g
Pre-staked
Unknown / 23 g
Unknown supply
Unknown 4-8 mm / 32 g
4mm needles enclosed
Auto needle retraction
No No No No Yes No No No
Dose confirmation Visual Visual Visual Audible Visual/audible Audible Visual Audible/(Tactile)
Overview of Approved GLP‐1 Receptor Agonists
GLP-1=glucagon-like peptide-1
Madsbad et al. Diabetes Obes Metab 2011;13(5):394-407
Click here for more details on the backbone of GLP-1 analog
GLP-1 receptor agonists
subcutaneously administered peptides
Human GLP-1 backbone Exendin-4 backbone
Albiglutide
Dulaglutide
Liraglutide ExenatideExenatideTwice daily
LixisenatideOnce daily
Weekly Once daily Once daily or Twice dailyWeekly
Semaglutide
GLP-1 RAs: Key Efficacy and Safety
WeightPotential for
weight loss1,2,3
HypoglycaemiaLow potential for
incidents1,2
GI adverse eventsNausea, diarrhoea, and
vomiting that are mild to
moderate in severity and
transient in nature2,4
HbA1c
Effective in
lowering
HbA1c1,2,3
1. Karagiannis T, et al. Diabetes Obes Metab. 2015;17(11):1065-1074.
2. Liu FP, et al. J Diabetes. 2015;7(3):322-328.
GLP-1 RAs
3. Singh S, et al. Diabetes Obes Metab. 2017;19(2):228-238.
4. Prasad-Reddy L, et al. Drugs Context. 2015;9(4). DOI: 10.7573/dic.212283.
AVAILABLE BASAL INSULINS
• NPH
• Glargine
• Toujeo (Glargine U300)
• Levemir
• Degludec (Tresiba U100 and U200)
31
Copyright © 2018 Eli Lilly and Company
Insulin Monomers
• This is the active form of Insulin that circulates in blood and binds to the insulin receptor
Insulin Hexamers
• Composed of 6 monomers
• These are the storage form of insulin both in the β-cell and in insulin vials
Meah F and Juneja R. Med Clin North Am 2015;99:157-86
Structural Forms of the Insulin Polypeptide
Insulin Detemir: Mechanism of Sustained
Release and PK/PD1
♦ Soluble, long-acting basal human
insulin analog
♦ Delayed absorption due to self-
association of the drug molecules
upon injection; delayed distribution
to peripheral target tissues because
of binding to albumin
♦ Half-life: 5-7 hours
♦ Relatively constant, reduced peak
concentration-time profile
♦ Median duration of action was 7.6
to >24 hours
Mechanism of Sustained Release
1. Levemir® [Prescribing Information] 20152. Data from Pettus J et al. Diabetes Metab Res Rev 2015 Sep;32(6):478-96
Comparison of Time-Action Profile of Single
Doses of Insulin Detemir and Insulin Glargine2
Time (Hours)
Rela
tive In
su
lin
Eff
ect
Insulin Detemir
Insulin Glargine
0 12 24
Copyright © 2018 Eli Lilly and Company
Clinical Outcomes with Insulin Degludec
• N=7637 patients with T2D at high risk of CV events– Age ≥50 years with with CVD or renal disease
– Age ≥60 years with ≥1 CV risk factor
• Randomization– Degludec: n=3818
– Glargine: n=3819
• Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the HR for the primary endpoint; superiority tested if noninferiority criterion met– Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke
– Key secondary endpoints• Adjudicated severe hypoglycemia
• Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina
• All-cause death
34
DEVOTE Study Design
CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin
Degludec With Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events; HR, hazard ratio; MI, myocardial
infarction.
Marso SP, et al. N Engl J Med. 2017;377:723-732.
Clinical Outcomes with Insulin Degludec and Glargine
35
DEVOTE CV Outcomes
(N=7637)
*CV death, nonfatal MI, or nonfatal stroke; †Confirmed
noninferiority; superiority, P=0.21. ‡CV death, nonfatal MI,
nonfatal stroke, or hospitalization for unstable angina.
CI, confidence interval; CV, cardiovascular; MI, myocardial
infarction; NI, noninferiority.
Marso SP, et al. N Engl J Med. 2017;377:723-732.
0.50 1.00 1.50
Favors degludec
Median follow-up: 1.99 years
Hazard ratio (95% CI) P value
Primary composite endpoint* 0.91 (0.78-1.06) <0.001 (NI)†
Expanded composite endpoint‡ 0.92 (0.80-1.05) 0.22
All-cause death 0.91 (0.76-1.11) 0.35
Noncardiovascular death 0.84 (0.60-1.16) 0.28
CV death 0.96 (0.76-1.21) 0.71
CV death excluding undetermined cause of death 0.91 (0.69-1.20) 0.52
Nonfatal MI 0.85 (0.68-1.06) 0.15
Nonfatal stroke 0.90 (0.65-1.23) 0.50
Unstable angina hospitalization 0.95 (0.68-1.31) 0.74
Favors glargine
Clinical Outcomes with Insulin Degludec and Glargine
36
DEVOTE Safety Outcomes
(N=7637)
*Episode requiring assistance from another person to actively administer carbohydrate or glucagon or take other corrective actions.
CI, confidence interval.
Marso SP, et al. N Engl J Med. 2017;377:723-732.
0.00 1.00 2.00 3.00
Median follow-up: 1.99 years
Hazard ratio (95% CI) P value
Severe hypoglycemia* 0.60 (0.48-0.76) <0.001†
Unconsciousness or coma 0.81 (0.55-1.19) 0.28
Seizure 1.02 (0.38-2.73) 0.97
Nocturnal severe hypoglycemia 0.47 (0.31-0.73) <0.001
≥1 severe hypoglycemia event 0.73 (0.60-0.89) <0.001
Favors degludec Favors glargine
Insulin Therapy in T2DM
• The progressive nature of T2DM should be
regularly and objectively explained to T2DM
patients.
• Avoid using insulin as a threat, describing it as a
failure or punishment.
• Give patients a self-titration algorithm.
Pharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
• Consider initiating insulin therapy (with or without
additional agents) in patients with newly
diagnosed T2DM who are symptomatic and/or
have A1C >10% and/or blood glucose levels
≥300 mg/dL. E
• Consider initiating dual therapy in patients with
newly diagnosed T2DM who have A1C >9%. E
Pharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
Pharmacologic Therapy For T2DM: Recommendations (2)
Combination Injectable Therapy in T2DM
Pharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85