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

19

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


t1/2 = 3.3-4 hours

and renal filtration

Steady state over 6-7 weeks


t1/2 = ~3 hours


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


Approved GLP-1 RAs – Structure and Half-life

Albiglutide t1/2 = ~ 5 days

and multiple organ filtration

Recombinant fusion protein

linked to human albumin


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


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.


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.


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.


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 Therapy For T2DM: Recommendations (2)

Combination Injectable Therapy in T2DM



dr. joseph pitone · 2019-09-26 · glucoregulatory role of glp-1 and gip –effects in humans...

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