DPP4 inhibitors vs GLP-1 agonists

1) GLP 1a provides pharmacological levels ( supraphysiological ) of GLP, DPP4-i provides physiological levels ( endogenous secretion ) of GLP

2) Incretins are secreted fro GI that enhances insulin secretion in glucose dependant manner ( = it will only enhance insulin secretion when there is high level of glucose in GI )

- 50% of postprandial insulin production is due to the action by incretins

3) 2 types of incretins - GLP-1 and GIP ( glucose dependant insulinotropic peptide )

4) Actions - enhance insulin secretion, block glucagon secretion and promote satiety by slowing gastric emptying ( as amylin )

5) Why is GIP not used? In T2DM the GIP response is impaired ( does not amplify insulin response ) and together with GLP-1 can antagonize the action of GLP-1 inhibiting glucagon

6) Native GLP-1 is subjected to DPP4 degradation and therefore has short half life

7) DPP4 inhibitors inhibit the enzyme of degradation -> depends on endogenous production; GLP-1a is resistant to DPP4 and causes supraphysiologic levels of GLP receptors stimulation 

8) DPP4i - 3 FDA approved - sitagliptin, saxagliptin and linagliptin

• Only linagliptin is not renally excreted

9) GLP-1a - exenatide, lixisenatide ( slow released form of exenatide ), liraglutide

• Former two are renally excreted
• Liraglutide is metabolized prior to excretion and no specific organs indicated for elimination

10) DPP4i - oral drug, GLP-1a - S/C injectable ( a peptide based hormone like insulin so prone to gastric enzymes degradation )

11) Benefits of GLP-1a over DPP4i

• Both are glucose dependant - so do not cause hypoglycemia ( except when + with S/U )
• Trials have shows that GLP-1a results in weight loss and better glycemic control ( lowers HbA1C more ) - due to supraphysiologic stimulation of GLP-1 receptors 

12) DPP4i is weight neutral ( limited by endogenous secretion )

13) Guidelines support use of either one in metformin failure patients

14) In pts with weight problem but HbA1C is 1-2% from the targe , GLP-1a is better even though only a small reduction of HbA1C is only needed 

• Weight loss provides better long term outcome

15) However, if patient has cardiac failure, weight loss causes increased mortality risk; in this subgroup of patients, DPP4i is better **

16) DPP4i is preferred if the patient has NO weight issues and only requires small reduction of HbA1c to target level ( and obese cardiac failure patient )

17) Most frequent side effect of GLP-1a is nausea, but can be overcome with incremental dosing approach

18) Remember DPP4i and GLP-1a is a team player; monotherapy ONLY when entry HbA1C is < 7.5% ; Once > 7.5%, need combined therapy with metformin

References

GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes

S. Brunton

Int J Clin Pract. 2014;68(5):557-567