GLP-1 Agonists and DPP-4 Inhibitors
Glucagon-like peptide-1 (GLP-1) is an incretin hormone—also classified as a gut-derived peptide—secreted by intestinal L-cells in response to nutrient ingestion, particularly carbohydrates and fats.
In individuals with type 2 diabetes (T2D), endogenous GLP-1 secretion is reduced and its metabolic actions are attenuated. This contributes to several key pathophysiological features of T2D:
- Accelerated gastric emptying, leading to more rapid glucose absorption and postprandial hyperglycaemia.
- Impaired glucagon suppression, resulting in inappropriate hepatic gluconeogenesis and elevated fasting glucose.
- Blunted glucose-stimulated insulin secretion, compromising glycaemic control.
- Reduced satiety signalling, contributing to increased appetite and weight gain.
💊 Therapeutic Approaches to Enhance GLP-1 Activity
Two pharmacological strategies are available to enhance GLP-1 signalling:
- DPP-4 Inhibitors
- Mechanism: Inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for degrading endogenous GLP-1.
- Effect: Modestly prolong endogenous GLP-1 activity; weight-neutral and low risk of hypoglycaemia.
- GLP-1 Receptor Agonists (GLP-1RAs)
- Mechanism: Mimic GLP-1 via direct receptor stimulation at supraphysiological levels.
- Effect: Enhance insulin secretion, suppress glucagon, delay gastric emptying, and promote weight loss.
- Route: Administered subcutaneously or orally (semaglutide).
Safety Considerations
- Cardiovascular safety: Most DPP-4 inhibitors and GLP-1RAs are CV-safe.
- Exception: Saxagliptin has been associated with an increased risk of hospitalisation for heart failure (SAVOR-TIMI 53 trial), and should be avoided in patients with established HF or high HF risk.
DPP-4 Inhibitors
Mechanism of action
Competitive inhibition of dipeptidyl-peptidase 4 → slows degradation of endogenous incretins (GLP-1, GIP) →
• ↑ Glucose-dependent insulin secretion
• ↓ Post-prandial glucagon release
• No direct effect on weight or insulin sensitivity
🎯 Glycaemic efficacy
| Outcome | Typical magnitude |
|---|---|
| HbA1c ↓ | 0.6 – 0.8 % (≈ 7 – 11 mmol/mol) RACGP |
| Fasting glucose | ↓ 1 – 2 mmol/L |
| Greatest impact on post-prandial spikes; benefit plateaus when HbA1c > 9 %. |
Advantages
- Weight-neutral → useful when metformin + SU cause weight concern
- Low hypoglycaemia risk (incretin-dependent action)
- Oral, generally once-daily; linagliptin needs no renal adjustment
Limitations & safety
| Issue | Comment |
|---|---|
| Common AEs | Nasopharyngitis, mild GI upset, headache RACGP |
| Uncommon | Arthralgia, bullous pemphigoid, acute pancreatitis (class signal) |
| Heart failure | Saxagliptin ↑ HF hospitalisations (SAVOR-TIMI 53) TIMI STUDY GROUP |
| Renal dosing | Sitagliptin & saxagliptin need adjustment; vildagliptin avoid if eGFR <30; linagliptin none |
Cardiovascular outcome trials (CVOTs)
| Agent | CVOT | Result |
|---|---|---|
| Sitagliptin | TECOS 2015 – 14 671 pts | CV-neutral; no HF signal American College of Cardiology |
| Saxagliptin | SAVOR-TIMI 53 2013 – 16 492 pts | MACE-neutral; HF ↑ 27 % TIMI STUDY GROUP |
| Linagliptin | CARMELINA 2018 & CAROLINA 2019 | CV & renal safety confirmed; no HF excess JAMA NetworkJAMA Network |
| Vildagliptin | No dedicated CVOT | Pooled data show neutrality |
PBS rules (Authority Required – Streamlined)
- Must be used with metformin ± sulfonylurea and/or insulin.
- Combination with an SGLT2-i is subsidised only after step-wise criteria (not for initial therapy).
- Not PBS-funded with a GLP-1 RA.
- All gliptins qualify for 60-day scripts once control is stable.
Usual adult doses & PBS items
| Drug (brand) | Standard dose | Renal adjustment | PBS item code | Key notes |
|---|---|---|---|---|
| Sitagliptin (Januvia® & generics) | 100 mg OD | 50 mg if eGFR 30-45; 25 mg if <30 | 14021Y | Dual/triple therapy only; 60-day dispensing PBS |
| Saxagliptin (Onglyza®) | 5 mg OD | 2.5 mg if eGFR <45 | 13923T | Watch HF risk PBS |
| Vildagliptin (Galvus®) | 50 mg BD (50 mg OD if with SU) | Avoid if eGFR <30; 50 mg OD if eGFR 30-50 | 3415R | Twice-daily agent PBS |
| Linagliptin (Tradjenta®) | 5 mg OD | None | 3387G | Preferred in CKD ≥ Stage 3 PBS |
All listings are Authority Required (Streamlined) with up to two packs & five repeats.
🩺 Practical tips
Select a gliptin when modest HbA1c lowering (~0.7 %) is enough and weight gain or hypoglycaemia must be avoided.
- Document PBS criteria: inadequate control on metformin ± SU/insulin, plus any SGLT2-i contraindication or prior failure if combining.
- Review at 3–6 months; deprescribe if HbA1c drop <0.5 % (5 mmol/mol).
- Educate patients about pancreatitis symptoms and, for saxagliptin, signs of fluid overload.
GLP-1 Receptor Agonists
Indication:
- For patients inadequately controlled on maximal dual oral therapy (e.g. metformin + sulfonylurea)
Mechanism of Action
GLP‑1 RAs are synthetic analogues of endogenous glucagon-like peptide‑1 that bind to the GLP‑1 receptor at supra-physiological concentrations, enhancing glycaemic and non-glycaemic effects. These include:
- Enhanced glucose-dependent insulin secretion
- Suppressed glucagon secretion
- Slowed gastric emptying
- Increased satiety via central hypothalamic action
This results in both glycaemic improvement and clinically meaningful weight loss.
Clinical Effects
| Parameter | Effect | Notes |
|---|---|---|
| HbA1c | ↓ 1.0–1.8% (11–20 mmol/mol) | Dose- and formulation-dependent |
| Weight loss | ↓ 3–6 kg (T2DM); up to 15% (obesity dose) | Semaglutide 2.4 mg is most potent |
| Appetite | ↓ food intake via delayed gastric emptying and central satiety | |
| Cardiovascular | ↓ MACE in high-risk T2DM (LEADER, REWIND, SUSTAIN-6) | SELECT trial: ↓ MACE in non-diabetic obesity (semaglutide 2.4 mg) |
| Renal | ↓ albuminuria and progression in some RCTs | Not PBS-indicated for CKD yet |
Side Effects:
- GI symptoms – nausea, early satiety, reflux; mitigate with slow titration & smaller meals.
- Gall‑bladder events – ~0.3 %/year; educate re biliary colic.
- Injection‑site nodules – mainly exenatide ER.
- Acute pancreatitis – rare; cease if suspected.
- Precautions:
- Avoid in patients with a history of medullary thyroid carcinoma or MEN2.
- Retinopathy may transiently worsen with rapid glucose lowering (semaglutide).
| Agent | Form | Dosing | Approved Use | PBS-Listed? |
|---|---|---|---|---|
| Exenatide (Byetta®/Bydureon®) | SC: Twice-daily (IR), Weekly (ER) | 5–10 µg bd or 2 mg weekly | T2DM; adjunct to metformin or SU | ✅ Yes |
| Liraglutide (Victoza®) | SC: Daily | 0.6–1.8 mg | Monotherapy or add-on; CVD benefit | ✅ Yes |
| Dulaglutide (Trulicity®) | SC: Weekly | 1.5–4.5 mg | Mono or combination; well tolerated | ✅ Yes |
| Semaglutide (Ozempic®) | SC: Weekly | 0.25–2.0 mg | Mono or combination in T2DM | ✅ Yes |
| Semaglutide (Rybelsus®) | Oral | 3–14 mg daily | T2DM; oral alternative | ✅ Yes |
| Semaglutide (Wegovy®) | SC: Weekly | 2.4 mg | Obesity treatment | ❌ No (TGA-approved, not PBS) |
| Liraglutide (Saxenda®) | SC: Daily | 3 mg | Obesity or overweight with comorbidities | ❌ No (TGA-approved, not PBS) |
Use in Non-Diabetic Patients
- Semaglutide 2.4 mg (Wegovy®) has shown CV benefit in SELECT trial for people with obesity without diabetes, reducing the risk of major cardiovascular events.
- TGA-approved for weight management (BMI ≥30, or ≥27 with comorbidities) but not yet PBS-funded.
- Liraglutide 3 mg (Saxenda®) is also TGA-approved for weight loss but not subsidised.
PBS Key take-aways
- Step-before-GLP-1
PBS now demands that an SGLT2-i be trialled (unless contraindicated) and either:- caused intolerance, or
- failed to achieve ≥0.5 % (5 mmol/mol) HbA1c reduction after ≥6 months. PBS
- Allowed drug partners
- ✅ Metformin, sulfonylurea, insulin
- ❌ DPP-4 i, another GLP-1 RA, SGLT2-i (except non-glycaemic indication loophole)
- No PBS monotherapy
A GLP-1 RA on its own (when metformin cannot be used) is not a subsidised option. Private prescription remains possible but at full patient cost.
semaglutide (Ozempic®)
| Item | What it means for prescribers & patients |
|---|---|
| PBS category | Authority Required – Section 85 (General Schedule) under “Blood-glucose–lowering drugs, excluding insulins”. |
| When you may start it (first-prescription rules) | • Must be combined with at least one of the following: — metformin, or — sulfonylurea, or — insulin. • Patient’s T2DM must already be inadequately controlled by at least one of those same agents. • Step-before rule: the patient must either: — have failed to achieve a “clinically meaningful” HbA1c drop with an SGLT2 inhibitor (≥ 0.5 % or 5 mmol/mol after ≥ 6 months) OR — have a contra-indication or intolerance that required stopping the SGLT2 inhibitor. |
| Concurrent PBS-subsidised medicines not allowed | While claiming semaglutide on the PBS the patient cannot also receive PBS-subsidised treatment with: • any SGLT2 inhibitor (unless it is being prescribed privately for HF/CKD) • any DPP-4 inhibitor • another GLP-1 receptor agonist |
| Available PBS items | • 3 mL pre-filled pen (1 × 3 mL, 1.34 mg/mL) – code 12075M • 1.5 mL pre-filled pen (1 × 1.5 mL, 1.34 mg/mL) – code 12080T |
| Supply limits | • Max 1 pen per dispensing, up to 5 repeats (total six months’ supply per authority) • Dispensed price (ex-manufacturer) ≈ $134.27; general co-payment $31.60 (2025 rates) |
| Clinical takeaway | • Not PBS-funded as monotherapy. • Must have already tried an SGLT2-i (unless contraindicated) and show inadequate control on metformin/SU/insulin. • No PBS dual GLP-1 RA + SGLT2-i for glycaemic control. Private scripts are possible but not subsidised. |
Practical tip: When seeking an authority, document:
- Current background therapy (metformin / SU / insulin) and recent HbA1c.
- Details of the prior SGLT2-i trial (dates, dose, HbA1c response) or the specific contraindication/intolerance.
- Confirmation the patient is not receiving PBS-subsidised SGLT2-i, DPP-4 i, or another GLP-1 RA.