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GLP-1 Receptor Agonists: Mascots & Mnemonics

Updated: 6 days ago


Glucagon-like peptide-1 (GLP-1) receptor agonists, the “-tides”


GLP-1 Receptor agonists updated 1-22-23
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GLP-1 receptor agonists are type 2 diabetes medications, also called GLP analogs or incretin mimetics. The 3 most-prescribed GLP-1 receptor agonists are “-glutides”—mnemonic “glue tide”. The other two GLP analogs are “-enatides”—mnemonic “in a Tide Pod”. Two GLP analogs were recently approved for weight management. All GLP analogs were subcutaneous injectables until the arrival of Rybelsus (oral semaglutide) in 2020. The -glutides have been proven to reduce risk of cardiovascular events, while -enatides have not.


GLP analogs should not be used for type 1 diabetes.


​“Glue tide”...

Semaglutide liraglutide dulaglutide mnemonic

-glutides reduce cardiovascular risk. Liraglutide and semaglutide are approved for DM and weight loss.

Dulaglutide

Liraglutide

Semaglutide


​...“in a Tide” Pod

tide pod mnemonic for GLP-1 receptor agonists / GLP analogs "tides" mnemonic

​-enatides lower postprandial (rather than fasting) blood glucose —“after you eat a Tide Pod”

Exenatide

Lixisenatide

Gastrointestinal side effects with GLP analogs are common, including nausea/vomiting and diarrhea, mainly during dose escalation. Rarely these drugs may be associated with acute pancreatitis or cholelithiasis, although causal link is questionable. GLP analogs do not damage the kidneys, but there have been cases of acute renal failure due to dehydration secondary to vomiting/diarrhea. Serious hypersensitivity reactions such as anaphylaxis and angioedema have occurred.


Thyroid tumors have been reported in rodents given GLP analogs and thyroid C-cell hyperplasia has been reported in humans. GLP analogs (other than lixisenatide) are contraindicated in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) or a family history of medullary thyroid carcinoma.


GLP analogs bind GLP-1 receptors in the brain involved in appetite regulation. These medications are considered neuroprotective. Neuropsychiatric reactions including suicidal thoughts have been reported with GLP analogs, although barely exceeding placebo and unlikely to warrant clinical concern (O'Neil et al, 2017). There is preclinical evidence that GLP analogs can attenuate behaviors that model abuse of substances including alcohol, cocaine, and nicotine.


Role of GLP analogs (and alternatives) in type 2 diabetes:


The goal of drug therapy is generally to keep hemoglobin A1C <7%.


The biguanide metformin (Glucophage) is the recommended first-line treatment of type 2 diabetes—“begin with the biguanide”—except in renal insufficiency with GFR <45. Metformin ($10, oral) works through several mechanisms including increased secretion of GLP-1. Metformin improves insulin resistance, causes modest weight loss, and reduces all-cause mortality. Even in nondiabetic individuals, metformin appears to slow the aging process, extending lifespan and healthspan.


When metformin is inadequate it should be augmented with (if affordable) either a GLP analog ($1,000, SC/oral) or a SGLT2-inhibiting “-gliflozin” drug ($500, oral). With -gliflozins “glucose flows in urine / SuGar LeakT into urine”. SGLT2 inhibitors can cause genital yeast infections and gangrene. In order of popularity, the available SGLT2 inhibitors are empagliflozin (Jardiance), canagliflozin (Invokana), dapagliflozin (Farxiga), and ertugliflozin (Steglatro). SGLT2 inhibitors cause modest weight loss and decrease blood pressure via diuresis.


None of these first- and second-line options (metformin, -tides, -gliflozins) cause hypoglycemia when used as monotherapy.


If a -glutide or -gliflozin is unaffordable, a sulfonylurea ($10, oral) can be added to metformin—“a sulfonylurea can suffice”. While GLP analogs increase insulin release in a glucose-dependent fashion, release of insulin with sulfonylureas is not dependent on blood glucose and thereby may lead to hypoglycemia, especially with glyburide (Micronase). The preferred sulfonylureas are glimepiride (Amaryl) and glipizide (Glucotrol)—“ride a ‘zide if you can’t buy a -tide, but bury glyburide”. Another disadvantage of sulfonylureas is potential for weight gain. All diabetes medications with generic name starting with G cause weight Gain—glimepiride, glipizide, glyburide, and insulins glargine and glulisine.


Less effective that GLP analogs are the “gliptins” ($500, oral) which inhibit the breakdown of GLP-1 by dipeptidyl peptidase-4 (DPP-4)—keeping “GLP intact”. The most-prescribed DPP-4 inhibitors are sitagliptin (Januvia) and linagliptin (Tradjenta). Gliptins are associated with acute pancreatitis. They reduce hemoglobin A1c by 0.5–1.0% but do not appear to decrease all-cause mortality. They are weight neutral—“weight just sits in line” with sitagliptin and linagliptin.


The thiazolidinediones (TZDs) should generally be avoided. TZDs including pioglitazone (Actos) and rosiglitazone (Avandia) increase risk of heart failure, anemia, and osteoporosis—“The glitter zone is The Zone of Danger”. TZDs also have potential for large weight gain—“pig-glitazone” and “whole lotta Rosie”.


Insulin is recommended if initial A1C is >9% or if glycemic control is inadequate with a combination of the above-mentioned drugs. Insulin is associated with weight gain. Two available products combine a GLP analog with insulin for once-daily SC injection. XULTOPHY [ZUL toh fye] pairs liraglutide with insulin degludec (Tresiba). SOLIQUA [soh LEE kwa] combines lixisenatide with insulin glargine (Lantus).


GLP-1 action on target tissues


Glucagon-like peptide-1 (GLP-1) is a hormone released from the gut after eating to decrease blood glucose by several mechanisms. GLP-1 is an incretin, i.e., hormone that increases insulin secretion. To restate, incretin increases insulin secretion. GLP-1 is not the only incretin, but it constitutes >90% of all endogenous incretin function. GLP analogs (-tides) are considered incretin mimetics


The structure of glucagon-like peptide-1 is “like” that of glucagon but GLP-1 and glucagon serve opposite functions. Glucagon, also known as hyperglycemic factor, is released by the pancreas to increase breakdown of glycogen in the liver thereby releasing glucose into the blood. Synthetic forms of glucagon are available for treatment of severe acute hypoglycemia, including the intramuscular Gvoke HypoPen and a nasal powder called Baqsimi [BAK see mee]—“come back to see me”.


GLP-1 action on target tissues by Dr Jason Cafer MD

Glucagon-like peptide-1 (GLP-1) receptor agonists

aka the “-tides”, GLP analogs, incretin mimetics

Rx 2021

GLP analog

Trade

Dosing


Indic-ation

Reduce CV risk*

Effect

​#1

Liraglutide

VICTOZA

SC QD

DM2

​Yes

↓ A1c 1.5%

SAXENDA

SC QD

weight

N/A

↓ 6% body weight

​#2

Dulaglutide

TRULICITY

SC weekly

DM2

​Yes

↓ A1c

1.5–1.8%


#3

​Semaglutide

OZEMPIC

SC weekly

DM2

​Yes

↓ A1c 1.5%

​RYBELSUS

PO QD

DM2

Unproven

↓ A1c 1%

​WEGOVY

SC weekly

weight

N/a

↓ 12% body weight

​#4

Exenatide

BYDUREON

SC weekly

DM2

Unproven

↓ A1c 1.5%

BYETTA

SC BID

DM2

Unproven

↓ A1c 1%

#5

Lixisenatide

ADLYXIN

SC QD

DM2

Unproven

↓ A1c 1%

​New

Tirzepatide (Mounjaro)

MOUNJARO

​SQ weekly

DM2

Unproven

​↓ A1c 2.3% ↓ 20% body weight

*The FDA has approved the use of -glutides to reduce the risk of major cardiovascular events (myocardial infarction, stroke, cardiovascular death) in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors.



Dulaglutide (TRULICITY)

Phonetic pronunciation: DOO la GLOO tide / TRU li si tee

Mnemonic: “Truly a Doula” glue tide

US Sales rank: #149

Year of release: 2014

Price range: $735–$1000

FDA-approved for: Type 2 diabetes

Used off-label for: Weight loss

Mechanism: GLP-1 receptor agonist

Available doses: 0.75 mg, 1.5 mg, 3 mg , 4.5 mg

Dynamic interactions: Glucose lowering

Kinetic interactions: Delayed gastric emptying, otherwise none—“in a bubble

Fulaglutide Trulicity mnemonics by Dr Jason Cafer MD

Dulaglutide (Trulicity) is a GLP analog that reduces hemoglobin A1C by 1.5% to 1.8%, which is slightly more than other GLP analogs. Like other -glutides, dulaglutide is proven to reduce risk of cardiovascular events. Expect a weight loss of 2.5–4.6 kg (5.5–10 pounds) at the maximum dose of 4.5 mg SC weekly.


Trulicity is supplied in single-dose pens with needle included. The base of the pen is placed against the abdomen and the injection is administered subcutaneously when the green injection button is pushed. The pen is to be kept refrigerated but may be stored at room temperature for up to 14 days.

Dulaglutide Trulicity interactions by Dr Jason Cafer MD

Dosage adjustment is not necessary with renal or hepatic impairment. Dulaglutide is less likely to cause injection site reactions (0.5%) than most other GLP analogs (although Ozempic is lower at 0.2%).


Dosing: Start 0.75 mg SC once weekly at any time of day, with or without meals. If additional A1C lowering is needed, may increase to 1.5 mg once weekly, 3 mg (after ≥4 weeks on 1.5 mg dose), then 4.5 mg (after ≥4 weeks on 3 mg dose). Max is 4.5 mg weekly.

 

Liraglutide (VICTOZA, SAXENDA)

Phonetic pronunciation: LIR a gloo tide / sax end ah

Mnemonic: “Lir’s glue tide (is a) Sax ender”

US Sales rank: #143

Year of release: 2010

Price range: $1,000–$1,220 DM; $1,325–$1,630 weight

FDA-approved for: Type 2 diabetes (Victoza); Weight management, long-term (Saxenda)

Mechanism: GLP-1 receptor agonist

Dynamic interactions: Glucose lowering

Kinetic interactions: Delayed gastric emptying, otherwise none—“in a bubble

Liraglutide victoza Saxenda mnemonics by Dr Jaosn Cafer MD

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist available as a once-daily subcutaneous injectable. It was approved in 2010 for type 2 diabetes as Victoza, and in 2017 for weight loss as Saxenda. Saxenda for weight management is dosed higher (3 mg) than Victoza for diabetes (1.2–1.8 mg). Victoza reduces hemoglobin A1c by about 1.5% and reduces all-cause mortality.


Specifically, Saxenda is indicated for chronic weight management in obese adults (BMI ≥30) or those merely overweight with a BMI ≥27 and a weight-related comorbidity such as hypertension, dyslipidemia, or diabetes.


At doses approved for weight loss, Saxenda is about 50% as effective as Wegovy (semaglutide 2.4 mg SC weekly). At one year, patients on Saxenda had an average placebo-corrected weight loss of 12 pounds or about 6% of body weight. 63% of patients taking Saxenda lost ≥5% body weight. Saxenda should be stopped if loss of body weight <4% after 16 weeks or if the full 3 mg dose is not tolerated.


Saxenda reduces risk of developing type 2 diabetes in individuals taking it for weight loss.


When used for diabetes, Victoza has an advantage over other GLP-1 receptor agonists because it is proven to reduce overall mortality—”Victory!”. Disadvantages of Victoza include the need for daily injections and a high incidence of nausea (20%).


Victoza lowers hemoglobin A1c by about 1.5%. Incidence of injection site reaction is about 2%, which is more common than with dulaglutide (0.5%) or semaglutide (0.2%).

Liraglutide victoza Saxenda interactions by Dr Jaosn Cafer MD
 

Semaglutide (OZEMPIC, RYBELSUS, WEGOVY)

Phonetic pronunciation: SEM a gloo tide / oh ZEM pick / reb EL sus / wee GOH vee

Mnemonic: “Olympic, Rebel, & Wig governor”

Year of release: 2017

Price range: $835–$1,020 DM; $8,400– $10,215 weight

FDA-approved for: Type 2 diabetes (Ozempic, Rybelsus); Weight management, long-term (Wegovy)

Mechanism: GLP-1 receptor agonist

Dynamic interactions: Glucose lowering

Kinetic interactions: Delayed gastric emptying, otherwise none—“in a bubble

Semaglutide Ozempic Rybelsus Wegovy interactions by Dr Jason Cafer MD

Three forms of this GLP analog are available, including the first oral agent in this class, Rybelsus, released in 2019. Original semaglutide, Ozempic, has been available since 2017 for type 2 diabetes. SC Ozempic lowers A1c by 1.0–1.5%. PO Rybelsus is slightly less effective, lowering A1c by about 1.0%.

Semaglutide ozempic Rybelsus Wegovy interactions

1 of 3:

Semaglutide formulation

OZEMPIC

Mascot

"Olympic"

Semaglutide ozempic mnemonic

Image