What are injectable peptides and their therapeutic applications?

Injectable Peptides: Therapeutic Applications and Clinical Use

Injectable peptides are biologically active amino acid polymers (typically <50 amino acids, <10 kDa molecular weight) administered parenterally for therapeutic purposes, including diabetes management (insulin, GLP-1 receptor agonists), growth hormone regulation, antimicrobial therapy, and targeted drug delivery, with subcutaneous injection being the most common clinical route. 1, 2, 3

Primary Therapeutic Classes

Diabetes Management Peptides

GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, dulaglutide) and dual GIP/GLP-1 agonists (tirzepatide) represent the most rapidly expanding class of injectable peptides, providing glucose-dependent insulin secretion, glucagon suppression, appetite reduction, and proven cardiovascular benefits including 13-26% reduction in major adverse cardiovascular events. 4, 5

• These agents stimulate both first- and second-phase insulin secretion only when glucose is elevated, resulting in exceptionally low hypoglycemia risk compared to insulin or sulfonylureas 5
• Weekly semaglutide 2.4 mg produces mean body weight reduction of 14.9% in non-diabetic overweight/obese patients 5
• Liraglutide demonstrated 15% reduction in all-cause mortality in patients with type 2 diabetes and established cardiovascular disease 5
• GLP-1 receptor agonists should follow the same injection technique recommendations as insulin regarding needle length, site selection, and systematic rotation schemes to prevent lipodystrophy 4, 6

Insulin remains the cornerstone injectable peptide for both type 1 and type 2 diabetes, with formulations including rapid-acting analogs, short-acting human insulin, intermediate-acting NPH, and long-acting basal analogs (glargine, detemir, degludec). 4

• Basal insulin should be initiated when even greater glucose reduction potency is needed beyond oral agents and GLP-1 receptor agonists 4
• Fixed-ratio combination products (IDegLira, iGlarLixi) combining basal insulin with GLP-1 receptor agonists are available for patients requiring both therapies 4

Growth Hormone-Related Peptides

Tesamorelin is an FDA-approved growth hormone-releasing factor (GHRF) injectable peptide specifically indicated for reducing excess abdominal fat in HIV-infected adults with lipodystrophy, administered as 2 mg subcutaneous injection daily. 7

• Tesamorelin increases IGF-1 levels and requires periodic monitoring of IGF-1 concentrations 7
• The drug is contraindicated in patients with active cancer, pituitary gland tumors, pregnancy, or hypersensitivity to tesamorelin 7
• Patients must rotate injection sites on the abdomen with each dose to reduce injection site reactions 7

Antimicrobial and Specialized Peptides

Antimicrobial peptides represent an emerging therapeutic class with growing interest due to increasing antibiotic-resistant pathogens, though specific FDA-approved formulations remain limited. 8

• Streptomycin and other aminoglycoside peptides are used as injectable agents for drug-resistant tuberculosis treatment at concentrations of 2.0-10.0 μg/mL depending on the testing method 4

Peptide Receptor Radionuclide Therapy (PRRNT)

PRRNT involves systemic administration of β-emitting radionuclides (Yttrium-90 or Lutetium-177) chelated to somatostatin analogue peptides (DOTATOC) for molecularly targeted radiation therapy of neuroendocrine tumors expressing somatostatin receptor subtype 2. 4

• Lutetium-177 has a physical half-life of 162 hours with maximum β-particle soft-tissue penetration of 1.7 mm, allowing posttreatment imaging and dosimetry assessments 4
• Yttrium-90 is a pure β-emitter with 64-hour half-life and maximum soft-tissue penetration of 11 mm 4

Injection Technique and Site Management

All injectable peptides should be administered using the shortest needles available (typically 4-5 mm for subcutaneous injection) with systematic rotation of injection sites to prevent lipodystrophy, which can cause erratic absorption and glycemic variability. 4

• Inject into subcutaneous adipose tissue of the abdomen, thighs, or upper arms, avoiding scar tissue, bruises, or areas of lipodystrophy 4, 7
• Needle reuse, while common globally (40-96% of patients), increases risk of lipohypertrophy development, though one study suggested pen needles could be used 4-5 times without increasing pain intensity 4
• Check syringes for air bubbles by holding vertically with needle up, tapping the barrel, and pushing the plunger to clear air 4
• Always use certified waste receptacles for needles and syringes, never unofficial plastic bottles that needles can puncture 4

The risk of lipohypertrophy is considerably less with non-insulin injectable peptides (GLP-1 receptor agonists) compared to insulin, although palpable subcutaneous nodules have been reported following weekly exenatide and semaglutide. 4, 6

Pharmacokinetic Characteristics

Unmodified therapeutic peptides undergo extensive proteolytic cleavage throughout the body due to ubiquitous availability of proteases and peptidases, resulting in short plasma half-lives (endogenous GLP-1 has approximately 2-minute half-life). 4, 3

• Distribution is mainly driven by diffusion and convective extravasation dependent on peptide size, with volumes of distribution frequently not larger than extracellular body fluid volume 3
• Glomerular filtration and subsequent renal metabolism by proteolysis contribute to elimination of many therapeutic peptides since they are generally freely filtered by kidneys 3
• Molecular modifications to prevent dipeptidyl peptidase-4 cleavage and prolong elimination half-lives include albumin conjugation (albiglutide), increased albumin affinity (semaglutide), and synthetic peptide design (exenatide shares 50% homology with GLP-1) 4

Therapeutic peptides have very limited oral bioavailability (<1% typically) due to low permeability and susceptibility to catabolic degradation, necessitating parenteral administration via intravenous, subcutaneous, or intramuscular routes. 2, 3

Critical Safety Considerations

Perioperative Management

GLP-1 receptor agonists delay gastric emptying and increase risk of gastric stasis with potential aspiration/regurgitation during anesthesia, though insufficient evidence exists to guide minimum cessation periods before surgery. 4, 5

• Avoid GLP-1 receptor agonists in patients with pre-existing gastroparesis or delayed gastric emptying as they may exacerbate symptoms 5

Hypoglycemia Risk

When combining injectable peptides with sulfonylureas or insulin, counsel patients on hypoglycemia symptoms and consider dose reduction of the secretagogue, as hypoglycemia risk increases from 2% with SGLT2 inhibitors alone to 24% when combined with sulfonylureas. 9

• GLP-1 receptor agonists and insulin analogs have intrinsically low hypoglycemia risk due to glucose-dependent mechanisms 5

Malignancy Concerns

Tesamorelin increases background risk of malignancies in HIV-positive patients and risk of cancer reoccurrence in patients with history of neoplasms; any previous cancer should be inactive and treatment complete before starting therapy. 7

Pregnancy and Contraception

Tesamorelin and other growth hormone-related peptides are contraindicated in pregnancy and should be discontinued if pregnancy occurs, as they offer no known benefit and could result in fetal harm. 7

• Women of childbearing potential require effective contraception during GLP-1 receptor agonist treatment due to potential fetal risk 6

Emerging Applications and Drug Delivery

Peptides are increasingly utilized as carrier molecules for targeted drug delivery to specific cell types (cancer cells, immune cells) by conjugating drugs to receptor-selective peptides, lowering systemic side effects. 10

• Peptides derived from intercellular junction proteins (occludins, claudins, cadherins) improve drug delivery through intestinal mucosa and blood-brain barriers via paracellular pathways 10
• These modulator peptides have enhanced brain delivery of molecules ranging from small compounds to 65 kDa albumin 10

Approximately 140 peptide therapeutics are currently in clinical trials, with 60 peptides already FDA-approved, representing a fast-growing class driven by advances in peptide engineering, sequencing technologies, and structural bioinformatics. 1, 8

Common Pitfalls to Avoid

• Never share syringes or needles between patients, even if the needle is changed, as this poses risk of serious infection transmission 7
• Do not delay treatment intensification when glycemic targets are not met, as therapeutic inertia leads to prolonged hyperglycemia and increased complication risk 9
• Do not combine GLP-1 receptor agonists with DPP-4 inhibitors, as there is no added glucose-lowering benefit beyond the GLP-1 receptor agonist alone 4
• Do not inject into sites of lipodystrophy, as this causes erratic absorption and increases risk of hypoglycemia, hyperglycemia, and glucose variability 4
• Do not assume transient gastrointestinal symptoms with GLP-1 receptor agonists require discontinuation, as nausea typically improves with gradual dose titration and smaller meal portions 6