1. GLP-1 agonists Ian Gallen Consultant Community Diabetologist
Royal Berkshire Hospital
Reading UK

2. What do GLP-1 agonists do?

3. Physiology of postprandial glucose regulation
PPG
Hepatic
glucose
output
Meal
Gastric
emptying
Glucose
uptake +
Insulin ❶
Insulin
Glucagon
Rising plasma glucose stimulates pancreatic β-cells to secrete insulin1 ❷
Glucagon
Plasma glucose inhibits glucagon secretion by pancreatic α-cells1
Speaker Notes
In non-diabetic individuals, postprandial glucose is tightly regulated by a number of mechanisms. Three critical factors that regulate postprandial glucose following ingestion of a meal are:
An increase in insulin secretion by pancreatic β-cells
Potent suppression of glucagon secretion from pancreatic α-cells
Slowing of the rate of gastric emptying
In order to maximize post-prandial glucose reduction, these three critical factors should be addressed.
References
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88(4):
2. Horowitz M, O’Donovan D, Jones KL, Feinle C, Rayner CK, Samsom M. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med. 2002;19(3):
Annotations
Bullet 1: DeFronzo.Med Clin North Am.July.2004/p787/lines 19-23
Bullet 2: DeFronzo.Med Clin North Am.July.2004/p789/lines 1-4
Bullet 3: Horowitz.Diabet Med.March.2002/p177/lines A14-A15 ❸
Gastric emptying
Delaying and/or slowing gastric emptying is a major determinant of postprandial glycaemic excursion2
PPG = postprandial glucose
1DeFronzo RA. Med Clin North Am 2004;88:
2Horowitz M et al. Diabet Med 2002;19:177-94

4. Glucagon-like peptide-1 and incretin effect
β-cell
α-cell
Food intake
GLP-1
Pancreatic islet
Incretin effect
GLP-1 is a major intestinal hormone mediating the incretin effect
GLP-1 potentiates insulin release and reduces glucagon secretion in
glucose-dependent manner
Adapted from Drucker D. Diabetes Care. 2003;26: ; and Wang Q, et al. Diabetologia. 2004;47(3):

5. The incretin effect iv glucose infusion Incretin effect Plasma glucose
oral glucose load (50 g)
iv glucose infusion
Plasma glucose
Plasma insulin
mU/L 80 60 40 20
–10 –5
120
180
Time (min)
Incretin effect
mmol/L
–10 –5 60
120
180 10
Time (min) 5 15 90
270
mg/dL
The incretin hormones play a crucial role in a healthy insulin response
The effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before they received an oral glucose load of 50 g/400 ml or an isoglycaemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venous plasma glucose concentration was similar with both glucose interventions. However, insulin concentration was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion.
Reference
Nauck et al. Diabetologia 1986;29:46–52
Insulin response is greater following oral glucose than iv glucose, despite
similar plasma glucose concentrations
Nauck MA et al. Diabetologia 1986;29:46–52. Healthy volunteers n=8 5 5

6. GLP-1 restores insulin and glucagon responses in type 2 diabetes
Adapted from Nauck MA et al. Diabetologia 1993;36:741–4.
†GLP-1(7–36 amide) infused at 1.2 pmol/kg/min for 240 min *p<0.05
C-peptide (nmol/L)
Glucagon (pmol/L)
Time (min)
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
3.0
2.0
1.5
1.0
0.5 30 25 20 15 10 5 –
Infusion *
GLP-1†
Saline
Glucose (mmol/L)
GLP-1 Restores Insulin and Glucagon Responses in a Glucose-Sensitive Manner in Patients with T2DM
The glucose-dependent effects of glucagon-like peptide-1 (GLP-1) on insulin and glucagon responses were demonstrated in a study of type 2 diabetes mellitus (T2DM) patients with poor metabolic control.1
Ten patients with T2DM in whom diet and medications had yielded unsatisfactory glycemic control (HbA1c ± 1.7%) underwent intravenous infusion of saline (placebo) or GLP-1(7–36 amide) (infused at 1.2 pmol/kg/min for 240 minutes) in the fasting state.
GLP-1 infusion led to a significant drop in plasma glucose (left-hand graph) compared with the effect of saline solution.
Insulin levels in response to the GLP-1 infusion, measured as C-peptide (middle graph), rose significantly during the initial phase when glucose was in the higher range. As glucose level asymptotically approached normal range, the insulin level concomitantly dropped despite continuous GLP-1 infusion.
Glucagon (right-hand graph) levels were significantly reduced in response to higher glucose levels; glucagon levels then increased as the glucose level asymptotically approached normal range despite continuous GLP-1 infusion.
These findings suggest that GLP-1 stimulates sensitivity of pancreatic α- and β-cells to secrete glucagon and insulin, respectively, in a glucose-dependent manner.
This slide thus illustrates why GLP-1 is an effective means of addressing post-prandial glucose excursions
Reference
Nauck MA, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993; 36: 741–744. –

7. GLP-1 delays gastric emptying
Subcutaneous injection of GLP-1 delays gastric emptying by about 30 min in type 2 diabetes
Time (min)
Gastric volume (ml)
Liquid meal
400 ml
*p<0.0001
GLP-1†
Placebo
GLP-1 or placebo
Liquid meal (amino acids 8%, sucrose 50g in 400 ml)
Note no gastric emptying for mins post meal (p< vs placebo)
Adapted from Nauck MA et al. Diabetologia 1996;39:1546–53
†GLP-1 (7-36 amide) 1.5 nmol/kg sc

8. Incretin-based therapies GLP-1 receptor agonists and DPP-4 inhibitors
Short-acting BD Exenatide (Byetta)
OD Lixisenatide (Lyxumia) Long-acting OD Liraglutide* (Victoza)
Longer-acting QW Exenatide (Bydureon)
Dulaglutide (Trulicty)
DPP-4 inhibitors
Sitagliptin OD
Vildagliptin BD
Saxagliptin OD
Linagliptin OD
Subcutaneous injection
Tablets
The circulating levels of native GLP-1 decrease rapidly because of inactivation, mainly by dipeptidyl peptidase-4 (DPP-4) (1). To be effective, native GLP-1 would need to be infused continuously. Consequently, it is of limited clinical utility.
There are two other ways to restore the GLP-1 response:
Protect GLP-1 from inactivation by DPP-4
Develop GLP-1 receptor agonists that are resistant to DPP-4 and can mimic native GLP-1.
Both of these strategies have now been introduced into clinical practice by the development of DPP-4 inhibitors and GLP-1 receptor agonists respectively. Both classes of drug are described as incretin-based therapies.
The GLP-1 receptor agonists include exenatide and liraglutide (1). Exenatide is an exendin-based therapy. Liraglutide is a human GLP-1 analogue.
Reference
1. Drucker DJ, Nauck MA. Lancet 2006;368:1696−1705
Mimics endogenous
GLP-1
Enhance endogenous GLP-1
*Human GLP-1 analogue, others are exendin-based
DPP-4 = dipeptidyl peptidase-4; OD = once daily; BD = twice daily; QW = once weekly
Drucker DJ, Nauck MA. Lancet 2006;368:1696−1705 8

9. Actions of GLP-1 agonists
Promote 1st phase insulin secretion
Reduce glucagon release
Delay gastric emptying
Weak satiety effect
Thus lowering blood glucose with modest weight loss without hypoglycaemia

10. Choice of GLP-1 receptor agonist: short acting versus long acting
The pharmacological profile and half-life of a GLP-1 receptor agonist influences its effects on postprandial and basal (fasting) glycaemia
SHORT ACTING GLP-1 receptor agonists
Lixisenatide OD, Exenatide BD
LONG ACTING GLP-1 receptor agonists
Liraglutide OD, Exenatide/Dulaglutide QW or
Effect on FPG
Effect on PPG
Effect on FPG
Effect on PPG
Speaker Notes
It is becoming increasingly apparent that the GLP-1 receptor agonist class can be subdivided into 2 types which result in different effects on fasting and postprandial glucose levels:
As a consequence of their pharmacological profiles, prandial GLP-1 receptor agonists such as exenatide and lixisenatide, have a greater effect on lowering postprandial glucose levels, than they do fasting glucose levels.
Similarly as a consequence of their pharmacological profile and more protracted half lives Non-prandial GLP-1 receptor agonists such as liraglutide and once weekly exenatide have relatively greater effects on fasting plasma glucose levels.
Reference
Fineman MS, et al. GLP-1 based therapies: differential effects on fasting and postprandial glucose. Diabetes Obes Metab. 2012;14(8):
Annotation
Fineman. Diabetes Obes Metab.January.2012/p1/lines A6-A8; p9/c2/table 3
FPG = fasting plasma glucose PPG = postprandial glucose
Fineman MS et al. Diabetes Obes Metab 2012;14:675-88

11. Short acting GLP-1 agonists: Lixisenatide
Change in HbA1c at endpoint*
Change in body weight at endpoint*
-0.18
n=107
Placebo
HbA1c (%)
-1.0
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1 -1 -2 -3 -4 -5 -6 -7 -8 -9
-10
-11
20 mcg OD
-0.69
p<0.0001
n=53
10 mcg BD
n=54
-0.78
-1.94
Placebo
-3.5
-3.0
-2.5
-2.0
-0.5
-1.5
-1.0
20 mcg OD
-3.01
n=53
10 mcg BD
n=54
-2.21
HbA1c (mmol/mol)
n=108
Speaker Notes
This Phase IIb, 13-week, randomized, placebo-controlled, parallel-group study demonstrated similar efficacy and tolerability between OD and BD dosing of lixisenatide, with the most favorable efficacy – tolerability ratio seen in the 20 mcg dose.
This study thus illustrates that 20 mcg once daily is the optimum dose of lixisenatide. Both 10mcg BD and 20mcg OD have similar levels of HbA1c reduction from baseline and a similar proportion reach an HbA1c target. Weight loss is greater in the 20mcg OD group.
(kg)
*LS mean
Adapted from Ratner RE. Diabet Med 2010:2;1024–32

12. Differences with Short and Long acting GLP-1 agonists

13. Short and Long acting GLP-1 (other effects)

14. Short and Long acting GLP-1
Wysham C. et al. Diabetes Care 2014;37:

15. Long acting GLP-1

16. Long acting GLP-1

17. ABCD National GLP-1 agonist audits

18. ABCD National GLP-1 agonist audits

19. Adding GLP-1 to insulin therapy: Weight
Jiten Vora Dia Care 2013;36:S226-S232

20. Adding GLP-1 to insulin therapy: Control and hypoglycaemia
Jiten Vora, Dia Care 2013;36:S226-S232

21. IDegLira; Glycaemic Control

22. IDegLira; Side effects

23. Lixisenatide and Glargine

24. GLP1 agonists and HbA1c

25. GLP1 agonist and weight

26. GLP1 agonist and cost per month
Lixisenatide 20mg od; £54.14
Exenatide (10µg bd); £68.24
Byduron; £73.76
Liraglutide (1.2mg od); £78.48.
Liraglutide (1.8mg od); £117.72
Dulaglutide (1.5mg) ; £73 pm
IDegLira (50 dose daily); £159.22

27. When to use GLP1-agonists
HbA1c>58 mmol/l +oral agents;
Overweight.
With metformin/Pioglitizone/SGLT2 inhibitors.
Stop DPP4 and Sulphonylureas.
Or with basal insulin;
To avoid further weight gain.
To reduce hypoglycaemia.

28. How to use GLP1-agonists
With Oral Treatment;
Use least expensive agent (lixisentatide).
Continue with Metformin and/or Pioglitazone.
Add SGLT2 inhibitor if post-prandial hyperglycaemia.
Move from lixisenatide/exenatide to a Glutide;
if nauseous or sub-optimal response.
Transfer to biphasic insulin (Humulin M3);
if no weight loss or improved glycaemic control.
With OD human basal (Humulin I);
with dose increasing by 10% alternate days to reduce FBG < 6mmol.