GLP-1 Receptor Agonists: Mascots & Mnemonics

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”...	-glutides reduce cardiovascular risk. Liraglutide and semaglutide are approved for DM and weight loss.	Dulaglutide Liraglutide Semaglutide
​...“in a Tide” Pod	​-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”.

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