Understanding GLP-1

Understanding GLP-1: 

The Revolutionary Hormone Powering Modern Diabetes and Weight-Loss Treatments in Pakistan

PharmaServePK Exclusive | November 2025

Glucagon-like peptide-1 (GLP-1) has become one of the most talked-about molecules in medicine over the last five years. Once an obscure gut hormone studied mainly by endocrinologists, it is now the active mechanism behind blockbuster drugs such as Ozempic®, Wegovy®, Mounjaro®, Rybelsus®, and the newly launched oral semaglutide formulations. In Pakistan, where diabetes prevalence exceeds 19% (IDF 2024 data) and obesity is rising rapidly, GLP-1-based therapies are transforming clinical practice and patient outcomes.

This comprehensive article explains exactly what GLP-1 is, how it works, why it is so effective, what the real-world results look like, and what Pakistani patients and doctors need to know in 2025.

What Exactly Is GLP-1?

GLP-1 is an incretin hormone secreted by L-cells in the distal ileum and colon within minutes of food intake. It is a 30- or 31-amino acid peptide derived from proglucagon.

Its physiological actions are multiple and synergistic:

1. Glucose-dependent insulin secretion (stimulates pancreas only when blood glucose is high → almost zero risk of hypoglycaemia)  

2. Suppression of glucagon release from alpha cells  

3. Slowing of gastric emptying → prolonged satiety  

4. Direct appetite suppression via GLP-1 receptors in the hypothalamus (arcuate nucleus and area postrema)  

5. Improvement in beta-cell function and possibly beta-cell mass (animal data stronger than human)  

6. Cardioprotective and neuroprotective effects (now proven in large CVOTs)

Natural GLP-1 has a plasma half-life of only 1–2 minutes because it is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). This is why pharmaceutical companies developed two approaches:

DPP-4 inhibitors (sitagliptin, vildagliptin, linagliptin) → modestly increase native GLP-1 levels  

GLP-1 receptor agonists (GLP-1RAs) → long-acting, DPP-4-resistant analogues

The second group — the injectable and now oral GLP-1RAs — has completely dominated the market because of dramatically superior efficacy.

Evolution of GLP-1 Receptor Agonists (2005–2025)

1st Generation

Exenatide twice daily (Byetta®, 2005) – first-in-class, exendin-4 based  

Liraglutide once daily (Victoza®, 2010; Saxenda® for weight loss, 2014)

2nd Generation

Exenatide once weekly (Bydureon®, 2012)  

Dulaglutide once weekly (Trulicity®, 2014)  

Semaglutide once weekly injection (Ozempic®, 2017; Wegovy® higher dose, 2021)  

Oral semaglutide (Rybelsus®, 2019) – first oral GLP-1RA

3rd Generation & Dual/Triple Agonists

Semaglutide 2.4 mg once weekly (Wegovy®) – current gold standard for weight loss  

Tirzepatide (Mounjaro®, 2022; Zepbound® 2023) – dual GLP-1/GIP agonist, superior weight loss  

CagriSema (cagrilintide + semaglutide) – phase 3 completed Nov 2025, expected 2026 approval  

Retatrutide (triple GLP-1/GIP/glucagon agonist) – up to 24.2% weight loss at 48 weeks  

Orforglipron (oral small-molecule GLP-1RA) phase 3 ongoing

Clinical Outcomes That Changed Guidelines

Diabetes Control

STEP and SUSTAIN trials showed semaglutide reduces HbA1c by 1.5–1.9% — significantly superior to SGLT2 inhibitors or DPP-4 inhibitors. In Pakistan, where baseline HbA1c often exceeds 9.5–10%, this translates to thousands avoiding insulin initiation.

Weight Loss (Average at 68–72 weeks, 2025 data)

Liraglutide 3.0 mg → 8–10%  

Semaglutide 2.4 mg → 15–17%  

Tirzepatide 15 mg → 20–22.5%  

CagriSema (phase 3) → projected 25–27%

These numbers rival or exceed bariatric surgery with far lower risk.

Cardiovascular Protection

LEADER, SUSTAIN-6, REWIND, and SURPASS-CVOT trials showed 12–26% reduction in major adverse cardiovascular events. Pakistan’s 2024 guidelines now recommend GLP-1RA or SGLT2i as first-line after metformin in patients with established CVD.

Availability & Access in Pakistan (November 2025)

Ozempic® – widely available  

Rybelsus® (oral) – most prescribed in urban centres  

Trulicity® – strong presence  

Mounjaro® – launched March 2025, rapidly gaining share  

Wegovy® & Zepbound® – limited, mostly private import  

Approximate prices (Karachi/Lahore): 

Rybelsus 14 mg × 30 → PKR 28,000–32,000  

Ozempic 1 mg pen → PKR 24,000–28,000  

Mounjaro 15 mg pen → PKR 48,000–55,000  

Wegovy/Zepbound (imported) → PKR 75,000–90,000 per month

Side Effects & Practical Management in Pakistani Patients

Most common: nausea, vomiting, diarrhoea, constipation (usually resolve by week 16)  

Rare but serious: pancreatitis (0.1–0.2%), gallbladder events  

Local tips that work:

Very slow titration (e.g., stay on 0.25 mg semaglutide for 8 weeks)  

Take Rybelsus strictly on empty stomach with ≤120 ml water  

Short-term ondansetron if needed  

High-protein, low-fat meals

The Future (2026–2030)

Oral tirzepatide  

Once-monthly injections  

Triple agonists targeting >30% weight loss  

Fixed-dose combinations with SGLT2i or insulin  

Amycretin (oral amylin + GLP-1) – 13.1% loss in just 12 weeks (phase 1)

GLP-1 receptor agonists are arguably the most important pharmacological breakthrough since statins. For Pakistani patients with type 2 diabetes, obesity, NAFLD, PCOS, or cardiovascular disease, these medicines offer unprecedented efficacy and safety when used correctly.

The only remaining barrier is cost and consistent supply. Until local manufacturing begins, access will remain limited to middle- and upper-income groups. However, the pace of generic/biosimilar development and licensing deals suggests the landscape could improve dramatically within 2–3 years.

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