Practical guide: Glucagon-like peptide-1 and dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus

Table 1 Characteristics of glucagon-like peptide-1 receptor agonists

Name	MOA	ROA	Available doses	Frequency	HbA1C reduction	Elimination and dose adjustment	Half-life	Dosing instructions	Drug-interactions
Lixisenatide	GLP-1 receptor agonist	SC	Initial: 14 doses of 10 μg per dose	Once daily	-0.65 (after 12 wk of monotherapy) compared with placebo, -0.46 (in 24 wk), -0.27 in combination with metformin +/- sulfonylurea (in 24 wk), -0.48 in combination with pioglitazone +/- metformin (in 24 wk), -0.28 in combination with insulin glargine and metformin +/- thiazolidinediones (in 24 wk)	Renal elimination, dependent on GFR	Approximately 3 h	1 h before meals	Delayed gastric emptying, decreased absorption and decreased effectiveness of some oral medications
			Followed by: 14 doses of 20 μg per dose			Insufficient data on ESRD. No dose adjustment for mild or moderate renal impairment		Oral medications 1 h before injection
Exenatide	GLP-1 receptor agonist	SC	Initial: 60 doses of 5 μg per dose	BID	After 30 wk: -0.5 for 5 μg once daily, -0.7 for 10 μg once daily, -0.5 for 5 μg BID, -0.9 for 5 μg BID	Renal elimination	2.4 h	1 h before the two main meals	Increased INR in patients with warfarin
			Followed by: 60 doses of 10 μg per dose		-0.8 and -1.0 for 5 and 10 μg, respectively, in combination with metformin and sulfonylurea	Avoided in ESRD and severe renal impairment. No dose adjustment for mild renal impairment		The meals must be 6 h apart
Exenatide extended release	GLP-1 receptor agonist	SC	2 mg	Every 7 d	No significant difference from metformin and pioglitazone after 26 wk, -0.39 as compared to sitagliptin use	Renal elimination	2-4 wk	At any time of the day	Increased INR in patients with warfarin
					-0.63 in combination with metformin as compared to sitagliptin, and -0.32 when compared to pioglitazone (in 26 wk), -0.64 in combination with glargine (in 28 wk)	Avoided in ESRD and severe renal impairment			May impact the absorption of oral medications
Liraglutide	GLP-1 receptor agonist	SC	Initial: 0.6 mg for 1 wk	Once daily	-0.3 and -0.6 for 1.2 and 1.8 mg, respectively, after 52 wk compared to glimepiride. Both doses showed -1.1 when combined with metformin compared to placebo in 26-wk trial. -0.3 and -0.6 for 1.2 and 1.8 mg, respectively, in 26-wk trial when combined with metformin compared with sitagliptin; -1.06 in combination with metformin and basal insulin compared to placebo	No specific organ as main part of elimination	13 h	At any time of the day	Delayed gastric emptying
			Followed by: Increase to 1.2 mg			No dose adjustment is needed for renal disease
			If additional glycemic control needed increase to 1.8 mg after 1 wk			Should be used cautiously in patients with hepatic impairment as sufficient data is absent for this population
Dulaglutide	GLP-1 receptor agonist	SC	0.75 mg	Every 7 d	-0.5 and -0.7 for 0.75 and 1.5 mg, respectively, when compared to sitagliptin in 52-wk trial; -1.1 for 1.5 mg combined with glimepiride when compared to placebo; -0.7 for 1.5 mg combined with basal insulin in 26-wk trial	No specific organ as main part of elimination	5 d	At any time of the day	Potential decrease in absorption of oral medications
			1.5 mg if additional glycemic control is needed
			Increase the dose by 1.5 mg, at least 4 wk after the previous dose, maximum dose 4.5 mg
Tirzepatide	Glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist	SC	Initial: 2.5 mg	Every 7 d	-1.7, -1.6, and -1.6 for 5, 10, and 15 mg, respectively, when compared to placebo in 40-wk trial; -0.2, -0.4, and -0.5 for 5, 10, and 15 mg, respectively, when compared to semaglutide in 40-wk trial; -0.6, -0.8, and -0.9 for 5, 10, and 15 mg, respectively, when compared to insulin degludec in 52 wk	Hepatic and renal elimination	5 d	At any time of the day	Potential decrease in absorption of oral medications
			After 4 wk increase the dose to 5 mg		-0.7, -0.9, and -1 for 5, 10, and 15 mg, respectively, when compared to insulin glargine in 52 wk	No dose adjustment is needed for renal and hepatic diseases
			Increase the dose at 2.5 mg, at least 4 wk apart from the previous dose, maximum dose 15 mg
Semaglutide	GLP-1 receptor agonist	SC	Initial dose 0.25 mg	Every 7 d	-1.4 and -1.6 for 0.5, and 1 mg, respectively, when compared to placebo in 30 wk trial; -0.6 and -0.8 for 0.5 and 1 mg, respectively, when compared to placebo in 56-wk trial; -0.5 for 1 mg in comparison with exenatide in combination with metformin or metformin with sulfonylurea	Hepatic and renal elimination	1 wk	At any time of the day	Potential decrease in absorption of oral medications
			After 4 wk increase the dose to 0.5 mg			No dose adjustment is needed for renal and hepatic diseases
			If additional glycemic control needed increase to 1 mg after 4 wk, and if further control is required increase to 2 mg after 4 wk of 1 mg dose
Oral Semaglutide	GLP-1 receptor agonist	Oral	Initial dose: 3 mg for 30 d	Once daily	-0.9 and -1.1 for 7 and 14 mg, respectively, when compared to placebo in 26 wk trial	Hepatic and renal elimination	1 wk	30 min before any oral intake	Potential decrease in absorption of oral medications
			Followed by: 7 mg			No dose adjustment needed for renal and hepatic diseases
			If additional glycemic control needed increased to 14 mg after 30 d of 7 mg dose		-0.3 and -0.5 for 7 and 14 mg, respectively, when compared to sitagliptin in 26-wk trial; -0.1 for 14 mg dose when compared with liraglutide; 0.9 and -1.2 for 7 and 14 mg, respectively, combined with insulin when compared to placebo in 26-wk trial

MOA: Mechanism of action; ROA: Route of administration; HbA1C: Glycated hemoglobin; GFR: Glomerulus filtration rate; ESRD: End-stage renal disease; BID: Twice daily; GLP-1: Glucagon-like peptide-1; INR: International normalized ration; SC: Subcutaneous injection.

Table 2 Cardiovascular outcome trials of glucagon-like peptide-1 and dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists

Trial name	No. of patients	Study population	Active comparator	Follow-up	Outcomes
LEADER	9340	T2DM, ≥ 50 yr with established CVD, or age ≥ 60 yr with CV risk factors	1.8 mg of liraglutide once-daily SC	3.8 yr	13% reduction in MACEs; 15% reduction in overall mortality; 22% reduction in CV-related deaths
SUSTAIN-6	3297	T2DM, ≥ 50 yr with established CVD, or CKD ≥ stage 3, or age ≥ 60 yr with CV risk factors	0.5 mg or 1.0 mg semaglutide once-weekly SC	2.1 yr	26% reduction in MACEs; 39% reduction in non-fatal stroke
PIONEER 6	3183	T2DM, ≥ 50 yr with established CVD, or CKD ≥ stage 3, or age ≥ 60 yr with CV risk factors	14 mg of semaglutide once-daily oral	1.3 yr	No significant reduction in MACEs; 51% significant reduction in CV-related deaths
AMPLITUDE-O	4076	T2DM, ≥ 50 yr with established CVD, or CKD ≥ stage 3 with CV risk factors	4 or 6 mg of efpeglenatide once-weekly SC	1.81 yr	27% reduction in MACEs; reduced risk of hospitalization for heart failure
HARMONY	9463	T2DM, age ≥ 40 yr with CVD	30-50 mg of albiglutide once-weekly SC	1.6 yr	22% reduction in MACEs
SURPASS-4	2002	T2DM, ≥ 18 yr with established CVD, or with CV risk factors	5 mg, 10 mg, or 15 mg of tirzepatide once-weekly SC	2 yr	Tirzepatide treatment was not associated with increased CV risk

MACEs: Major adverse cardiac events, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina; CKD: Chronic kidney disease; CV: Cardiovascular; CVD: Cardiovascular disease; T2DM: Type 2 diabetes mellitus; SC: Subcutaneous; LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 6.

Table 3 Suggested equivalent doses for different glucagon-like peptide-1 and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists based on their impact on glycemic control

Agent	Route	Frequency	Equivalent dose
Exenatide	SC	Twice daily	5 μg1	10 μg
Lixisenatide	SC	Daily	10 μg1	20 μg
Liraglutide	SC	Weekly	0.6 mg1	1.2 mg	1.8 mg
Exenatide XR	SC	Weekly			2 mg
Dulaglutide	SC	Weekly		0.75 mg1	1.5 mg	3 mg	4.5 mg
Semaglutide	SC	Weekly		0.25 mg1	0.5 mg		1 mg	2 mg
Semaglutide	PO	Daily	3 mg1	7 mg	14 mg
Tirzepatide	SC	Weekly			2.5 mg1			5 mg	7.5 mg	10 mg	12.5 mg	15 mg

¹The comparative efficacy of starting doses is not known and is based on the clinical experience of the authors in this group in various settings in different countries.

SC: Subcutaneous; PO: Oral.

Table 4 Pharmacokinetic properties and renal outcomes of clinical trials with glucagon-like peptide-1 receptor agonists

Drug	Dose	Half-life (h)	Elimination	Clinical study	Renal benefit
Short-acting GLP-1 receptor agonists
Exenatide	5-10 μg twice-daily SC	2.4	Mostly renal	None	None
Lixisenatide	10-20 μg once-daily SC	3.0	Mostly renal	ELIXA[65]	Lower rate of increase in urinary albumin-to-creatinine ratio
Long-acting GLP-1 receptor agonists
Exenatide	2 mg QW SC	2.4	Mostly renal
Liraglutide	0.6 mg, 1.2 mg or 1.8 mg once-daily SC	11.6-13.0	Peptidases and renal 6%; feces 5%	LEADER[64]	Nephropathy was decreased. UACR was decreased. RAS hormone was decreased. Progression to macroalbuminuria was decreased. Doubling of serum creatinine levels was decreased. eGFR of ≤ 45 mL/min per 1.73 m2 was decreased. The initiation of renal replacement therapy was decreased. Risk of end-stage renal disease or renal death was decreased. Plasma renin concentration, renin activity, and angiotensin II were decreased
Semaglutide	0.5-1.0 mg once-weekly SC	165.0-184.0	Peptidases and renal	SUSTAIN-6[67]	Nephropathy > 35% was decreased. Progression to macroalbuminuria was decreased. Doubling of serum creatinine levels was decreased. eGFR of ≤ 45 mL/min per 1.73 m2 was decreased. The initiation of renal replacement therapy decreased
Dulaglutide	0.75-1.5 mg once-weekly SC	About 112.8	Peptidases and renal	AWARD VII[66]	Reduced albuminuria, slower decline in renal function
Albiglutide	30-50 mg once-weekly SC	About 120.0	Peptidases and renal	None	None

GLP-1: Glucagon-like peptide-1; SC: Subcutaneous; UACR: Urinary albumin-to-creatinine ratio; RAS: Renin-angiotensin-system; eGFR: Estimated glomerular filtration rate; LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 6.