GLP-1(28-36)amide, the Glucagon-like peptide-1 metabolite: friend, foe, or pharmacological folly?

Figures & data

Table 1 Reported effects of GLP-1, GLP-1 analogs, DPP-4 inhibitors, and GLP-1(28-36)amide

Target	GLP-1	GLP-1 analogs	DPP-4 inhibitors	GLP-1(28-36)amide
Pancreas	↑ proinsulin synthesis^Citation64,Citation65	↑proinsulin synthesis^Citation64	Not determined	Not determined
	↓ proinsulin/insulin ratio^Citation66 Glucose-dependent stimulation of insulin secretion^Citation67	↓ proinsulin/insulin ratio^Citation65 Glucose-dependent stimulation of insulin secretion^Citation70,Citation7	↓ proinsulin/insulin ratio^Citation68 Glucose-dependent stimulation of insulin secretion^Citation72	Not determined No effect on glucose-dependent stimulation of insulin secretion^Citation17
	↓ glucagon secretion^Citation67	↓ glucagon secretion^Citation70,Citation71	↓ glucagon secretion^Citation72	Not determined
	↑ β-cell mass^Citation73	↑ β-cell mass^Citation75	↑ β-cell mass^Citation75	↑ β-cell mass and the number of proliferating β-cells in mice^Citation17
	↓ stressor-induced apoptosis^Citation76,Citation77	↓ stressor-induced apoptosis^Citation78	Possible ↓ in stressor-induced apoptosis^Citation79	↓ stressor-induced apoptosis^Citation16 ↑ intracellular ATP levels and enhances cell viability in human islet and INS-1 cells under stressed conditions^Citation16
Liver	Exerts insulin-sensitizing actions^Citation80 ↓ glucose secretion^Citation81 ↑ glycogen production^Citation82	Exerts insulin-sensitizing actions^Citation80	Not determined	Suppression of ROS formation and protection against falls in ATP levels induced by stressed conditions in isolated mouse hepatocytes^Citation51 ↓ glucose production in DIO mouse hepatocytes^Citation51 ↓ liver triglyceride accumulation in mice fed a VHFD^Citation19
Stomach	↓ gastric emptying^Citation83	↓ gastric emptying^Citation71,Citation85	Minimal ↓ in gastric emptying^Citation71	Not determined
Heart	Cardioprotective^Citation85	Cardioprotective^Citation86	Cardioprotective^Citation87	Cardioprotective^Citation18
Brain/gut	↑ satiety^Citation88	↑ satiety^Citation89	Possible ↑ satiety^Citation90	↑ energy intake in mice^Citation19
Weight	↑ weight loss^Citation91	↑ weight loss^Citation92,Citation93	No effect on weight loss^Citation94	↓ weight gain in mice fed a VHFD^Citation19
Brain	Neuroprotective^Citation95	Neuroprotective^Citation95	Neuroprotective^Citation96	Not determined

Abbreviations: ATP, adenosine triphosphate; DIO, diet-induced obesity; DPP-4, diaminopeptidyl peptidase IV; GLP-1, glucagon-like peptide-1; ROS, reactive oxygen species; VHFD, very high fat diet.

Table 2 Details of approved drugs targeting the GLP-1 axis

Target	GLP-1R agonist				DPP-4 inhibitor
Generic name	Exenatide^Citation97,Citation98	Exenatide (extended-release)^Citation97,Citation99	Liraglutide^Citation100	Lixisenatide^Citation101	Alogliptin^Citation102	Linagliptin^Citation103,Citation105	Saxagliptin^Citation105,Citation106	Sitagliptin^Citation107,Citation108	Vildagliptin^Citation109	Anagliptin^Citation110	Teneligliptin^Citation111	Gemigliptin^Citation112^–^Citation114
Trade name	Byetta^®	Bydureon^®	Victoza^®	Lyxumia^®	Nesina^®	Trajenta^®	Onglyza^®	Januvia^®	Galvus^®	Suiny^®	Tenelia^®	Zemiglo^®
Route of administration	Subcutaneous injection twice daily	Subcutaneous injection once weekly	Subcutaneous injection once daily	Subcutaneous injection once daily	Oral	Oral	Oral	Oral	Oral	Oral	Oral	Oral
Dose/day	10 μg	2 mg exenatide once weekly	0.6 mg	20 μg	25 mg	5 mg	5 mg	100 mg	200 mg	100 mg	20 mg	50 mg
Cmax	211 pg/mL	Multiphasic release over an approximately 10-week period	35 ng/mL	56.7 pg/mL	145.5 ng/mL	9.55 nM	24 ng/mL	950 nM	1,223 ng/mL	476 ng/mL	176.50 ng/mL	43.5 ng/mL
tmax (hours)	2.1	ND	8–12	1–3.5	1.25	1.5	2	1–4	1.5	1.8	1	4.5
t1/2 (hours)	2.4	2.4	13	1.5–4.5	21	12	2.5	12.4	2.96	4.37	26.1	30.8
Vd	28.3 L	28.3 L	11–17 L	90–140 L	417 L	1,110 L	123 L	198 L	71 L	2,470 (mL/kg)	ND	ND
CL/F	9.1 L/hour	9.1 (L/hour)	1.2 (L/hour)	20–67 L/hour	10.43 L/hour	ND	ND	ND	44.96 (L/hour)	620 (mL/hour/kg)	12.2 (L/hour)	ND
AUC0–24/∞	1,036 pg · hour/mL (AUC0–∞)	ND	960 ng · hour/mL (AUC0–∞)	ND	1,058 ng · hour/mL (AUC0–24h)	ND	78 ng · hour/mL (AUC0–∞)	8.52 μM · hour	4,588 ng · hour/mL (AUC0–∞)	2,110 ng · hour/mL (AUC0–∞)	1,772.7 ng · hour/mL (AUC0–∞)	503 ng · hour/mL (AUC0–24h)
PPB (%)	ND	ND	>98	55	20	75%–99% (concentration-dependent)	Negligible	38	9.3	37.1–48.2 (10–100,000 ng/mL)	<80	Not extensively bound
Adverse effects	Common (>1%) GI, injection site hematoma, URTI, dizziness gastroenteritis, NP Rare (<0.1%) Angioedema, skin disorders, alopecia, somnolence, Pancreatitis^Citation115	Common (>1%) GI, NP, headache, injection site pruritus Rare (<0.1%) Angioedema, skin disorders, alopecia, somnolence Pancreatitis^Citation115	Common (>1%) GI, headache, anti-liraglutide antibody formation Rare (<0.1%) Unknown* Pancreatitis^Citation115	Common (>1%) GI, influenza, URTI, UTI, viral infection, dizziness, somnolence, back pain, injection site pruritus Rare (<0.1%) Unknown* Pancreatitis^Citation115	Common (>1%) Headache, diarrhea, pruritus, myalgia Rare (<0.1%) Hepatic dysfunction Pancreatitis^Citation115	Common (>1%) NP Rare (<0.1%) Unknown* Pancreatitis^Citation115	Common (>1%) Headache URTI, UTI Rare (<0.1%) Unknown* Pancreatitis^Citation115	Common (>1%) NP, URTI Rare (<0.1%) Unknown* Pancreatitis^Citation115	Common (>1%) NP, headache, dizziness, back pain, diarrhea Rare (<0.1%) Angioedema, elevated liver enzymes, hepatitis Pancreatitis^Citation115	Information is too limited to characterize the incidence of adverse events Pancreatitis^Citation115	Common (>1%) GI disorder, skin disorder, NP Rare (<0.1%) Unknown* Pancreatitis^Citation115	(In 7% of study group) Constipation, NP, URTI, increase in blood CPK, hypoglycemia and rash Rare (<0.1%) Unknown* Pancreatitis^Citation115

Notes: Terminal half-life is the time required for the plasma concentration of a drug to decrease 50% in the final stage of its elimination. GI effects may include nausea, vomiting, diarrhea, constipation, and dyspepsia. Unknown*, cannot be estimated from available data. Byetta^®; Amylin Pharmaceuticals, LLC, San Diego, CA, USA, and AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA; Bydureon^®; Amylin Pharmaceuticals, LLC, San Diego, CA, USA, and AstraZeneca Pharmaceuticals LP, Wilmington, DE, US; Victoza^®; Novo Nordisk, Princeton, NJ, USA; Lyxumia^®; Sanofi, Paris, France; Nesina^®; Takeda Pharmaceutical Company, Chūō-ku, Osaka, Japan; Trajenta^®; Boehringer Ingelheim Pty Limited, Ingelheim am Rhein, Germany; Onglyza^®; Bristol-Myers Squibb, Manhattan, New York City, USA; Januvia^®; Whitehouse Station, NJ, USA; Galvus^®; Novartis International AG, Basel, Basel-Stadt, Switzerland; Suiny^®; Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Aichi, Japan; Tenelia^®; Mitsubishi Tanabe Pharma Corporation, Chūō-ku, Osaka, Japan, and Daiichi Sankyo Co., Ltd., Chūōō-ku, Tokyo, Japan; Zemiglo^®; LG Life Sciences, Seoul, Korea.

Abbreviations: AUC, area under the curve; C_max, mean peak concentration; t_max, time to reach mean peak concentration; t_1/2, half-life; V_d, mean apparent volume of distribution; CL/F, apparent clearance; AUC_0–t, area under the curve; PPB, plasma protein binding (% bound); GI, gastrointestinal; NP, nasopharyngitis; URTI, upper respiratory tract infection; UTI, urinary tract infection; CPK, creatine phosphokinase; ND, not defined; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; DPP-4, diaminopeptidyl peptidase IV.

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