GLP-1 and GIP analogues in the treatment of obesity – Current State of Knowledge

• Increases insulin secretion in a glucose-dependent manner.

• Inhibits glucagon secretion.

• Delays gastric emptying, enhancing satiety.

• Acts on the central nervous system, suppressing appetite.

GLP-1 agonists are designed to be resistant to degradation by the enzyme DPP-4, which ensures a longer half-life and clinical efficacy [3].

• Stimulates insulin secretion in a glucose-dependent manner.

• Influences lipid metabolism and adipogenesis.

• In insulin-resistant individuals, its effect is partially impaired.

Although GIP was once considered less relevant in therapy, current studies highlight its potential synergistic role with GLP-1 [4].

Modern therapies, such as tirzepatide, combine GLP-1R and GIPR effects, leading to:

• Stronger appetite reduction.

• Increased glucose-dependent insulin secretion.

• Better glycemic control.

• Modulation of visceral fat metabolism.

Preclinical and clinical studies indicate that activation of both receptors produces an additive or synergistic effect on weight reduction and improvement of metabolic parameters [5, 6].

• GLP-1 agonists and dual GLP-1/GIP agonists act on the arcuate nucleus of the hypothalamus.

• They inhibit NPY/AgRP (orexigenic) neurons.

• They activate POMC/CART (anorexigenic) neurons.

• The result is reduced appetite and decreased calorie intake.

Neuroimaging (fMRI) has confirmed decreased activity of brain regions associated with reward after treatment with GLP-1 agonists [7].

• Liraglutide (Saxenda® 3 mg):

• administration: daily subcutaneous injection,

• weight reduction: 6–8% [8],

• SCALE study: effect stabilization after 56 weeks,

• approved for obesity by FDA and EMA.

• Semaglutide (Wegovy® 2.4 mg):

• administration: once weekly subcutaneous,

• weight reduction: 14.9–17% [9],

• STEP 1 study (NEJM 2021): –14.9% in 68 weeks,

• approved for obesity in the USA and EU (2021–2022).

• Dulaglutide (Trulicity®):

• administration: weekly,

• weight reduction: 3–5% [10],

• primarily for DM2, not approved for obesity.

• Tirzepatide (Mounjaro®, Zepbound®):

• world’s first dual GLP-1/GIP agonist,

• administration: once weekly subcutaneous, doses 5–15 mg,

• approvals:

  • –

    FDA 2022–2023 – DM2,

  • –

    FDA 2023 – Zepbound for obesity and OSA,

  • –

    EMA – approved for DM2, obesity approval procedure ongoing (2025).

• Retatrutide – a novel triple-action obesity therapy

Retatrutide (LY-3437943) is an innovative peptide agonist of three incretin receptors: GLP-1, GIP, and glucagon receptor (GCGR). Its unique triple-action structure provides:

• substantial weight reduction (-22–25% within 24–48 weeks),

• improvement in glycemia (HbA1c reduction) and metabolic parameters [11],

• beneficial impact on liver fat reduction (MASLD/NAFLD) [12].

• SCALE (liraglutide):

  • –

    weight reduction: ~8%,

  • –

    sustained effect with continued therapy [8],

• STEP 1 (semaglutide):

  • –

    –14.9% at 68 weeks,

  • –

    HbA1c reduction of 1.5–2.0%,

  • –

    cardioprotective effect (MACE reduction by 26% in SUSTAIN-6) [9, 16].

• SURMOUNT-1 (tirzepatide):

  • –

    weight reduction: up to 22.5% at 72 weeks,

  • –

    HbA1c reduction: 2.0–2.4% [17].

• SURMOUNT-5 (2025):

  • –

    comparison: tirzepatide 10–15 mg vs semaglutide 2.4 mg,

  • –

    tirzepatide: –20.2% vs semaglutide: –13.7% (P < 0.001) [18].

• Confirm the superiority of tirzepatide over semaglutide by ~4–5% body weight reduction [19].

• Analyses indicate lower incidence of gastrointestinal symptoms with gradual dose escalation [19, 20].

• GLP-1R:

  • –

    Glucose-dependent stimulation of insulin.

  • –

    Glucagon inhibition.

  • –

    Anorexigenic effect.

• GIPR:

  • –

    Additional insulin stimulation.

  • –

    Influence on adipocytes.

  • –

    Synergistic appetite suppression.

Tirzepatide acts on both receptors, producing additive or synergistic effects [6, 18].

• HbA1c reduced by 1.0–2.5% in phase III trials.

• Particularly beneficial in type 2 diabetes.

• FDA and EMA recommend them in patients with DM2 and coexisting obesity [21].

• Liraglutide 3 mg (Saxenda®):

  • –

    average weight reduction: 6–8% [8],

  • –

    SCALE study: –8% after 56 weeks,

  • –

    stable effect with continued therapy.

• Semaglutide 2.4 mg (Wegovy®):

  • –

    weight reduction: 14.9–17% at 68 weeks [9],

  • –

    STEP 1: –14.9% mean vs –2.4% placebo,

  • –

    effectiveness comparable to bariatric surgery in some post-hoc analyses.

• Dulaglutide:

  • –

    weight reduction: 3–5%,

  • –

    effect confirmed mainly in patients with DM2 [10].

• SURMOUNT-1:

  • –

    body weight reduction: up to –22.5% at 72 weeks,

  • –

    placebo-adjusted reduction ~18% [17].

• SURMOUNT-5 (2025):

  • –

    tirzepatide 10–15 mg: –20.2%,

  • –

    semaglutide 1.7–2.4 mg: –13.7%,

  • –

    tirzepatide superior to semaglutide by ~6.5% [18].

• Appetite reduction (central anorexigenic action).

• Delayed gastric emptying.

• Improved insulin sensitivity.

• Reduction of visceral adipose tissue volume.

• Modulation of reward and satiety pathways in CNS [7].

• Observational studies (2023–2025) show that discontinuation of therapy leads to partial weight regain (~2/3 within 1–2 years) (21).

• Chronic treatment is necessary to maintain effect.

• Pancreatitis:

  • –

    rare cases reported in trials and safety reports,

  • –

    no confirmed increased risk in large meta-analyses.

• Medullary thyroid carcinoma (MTC):

  • –

    theoretical risk based on rodent studies,

  • –

    no evidence of increased risk in humans (FDA, however, requires a warning label) [20].

Cardioprotective mechanisms include reduction in blood pressure (2–5 mmHg), improved lipid profile, and reduced low-grade inflammation.

Large CVOT studies have demonstrated MACE reduction (Figure 2):

• Liraglutide (LEADER): –13% (HR 0.87) [16].

• Semaglutide (SUSTAIN-6): –26% (HR 0.74) [16].

• Dulaglutide (REWIND): –12% (HR 0.88) [15].

• Tirzepatide: SURPASS-CVOT results expected in 2025/26.

Figure 2.

Effects of MACE reduction (%) in clinical trials using modern incretin mimetics

Orlistat was not studied in large randomized CVOTs, thus no data exist on its effect on MACE reduction. Tirzepatide is currently being evaluated in the SURPASS-CVOT study – results expected after 2025. Liraglutide, dulaglutide, and semaglutide have confirmed MACE reduction effects in dedicated clinical trials.

Source: Wilding JPH et al. N Engl J Med. 2021; 384:989–1002. PMID: 33567185; Jastreboff AM et al. N Engl J Med. 2022; 387:205–216. PMID: 35704300; Frias JP et al. Nature Med. 2023; 29:845–854. PMID: 37166354.

Additional effects:

• Blood pressure reduction (2–6 mmHg).

• Lipid profile improvement (↓TG, ↑HDL-C).

• Reduction of low-grade inflammation (CRP) [3, 6].

• Semaglutide (Wegovy®, Ozempic®, Rybelsus®):

  • –

    Wegovy® (2.4 mg s.c.) approved by FDA (2021) and EMA (2022) for obesity treatment (BMI ≥30 or ≥27 with comorbidities).

  • –

    Ozempic® – registered for DM2, used off-label for weight reduction.

  • –

    Rybelsus® – only oral GLP-1, registered for DM2.

• Liraglutide (Saxenda® 3 mg):

  • –

    approved by FDA (2014) and EMA (2015) for obesity treatment,

  • –

    daily s.c. injections.

• Tirzepatide (Mounjaro®, Zepbound®):

  • –

    Mounjaro® – FDA and EMA approval for DM2.

  • –

    Zepbound® (2023) – FDA approval for obesity and obstructive sleep apnea (OSA).

  • –

    EMA – registration procedure for obesity ongoing in 2025.

• USA:

  • –

    Wegovy® and Zepbound®: reimbursement depends on insurer; manufacturer discount programs available.

  • –

    Ozempic®, Rybelsus®: reimbursed in DM2.

• EU (including Poland):

  • –

    semaglutide and liraglutide reimbursed only in DM2,

  • –

    no reimbursement for obesity indication (off-label use in clinical practice),

  • –

    tirzepatide: reimbursed in DM2, no reimbursement for obesity in 2025.

• UK:

  • –

    NICE in 2023 recommended limited funding of Wegovy® on NHS for selected groups (BMI ≥35 or ≥30 with complications),

  • –

    reimbursement negotiations for tirzepatide ongoing in 2025.

• High cost:

  • –

    Annual cost of Wegovy®, Zepbound® >10,000 USD in USA.

  • –

    Limited availability in public systems.

• Inequalities in access:

  • –

    Low- and middle-income countries practically without access to modern therapies.

  • –

    Reimbursement barriers even within EU.

• Systemic challenges:

  • –

    Need for medical staff education.

  • –

    Therapy outcome monitoring

  • –

    Implementation of public health strategies.

Obesity is a chronic metabolic disease of global scope and growing epidemiological significance. In 2025, the number of obese individuals worldwide exceeded 1 billion, posing a serious public health, economic, and social challenge.

The pathophysiology of obesity is based on complex mechanisms: chronic low-grade inflammation, insulin resistance, impaired incretin secretion, and dysregulation of the central nervous system. Numerous comorbidities – type 2 diabetes, hypertension, dyslipidemia, NAFLD, OSA, and cardiovascular diseases – exacerbate the problem and increase mortality.

Incretin pharmacotherapy (GLP-1 agonists and dual GLP-1/GIP agonists) represents the greatest breakthrough in obesity treatment in decades. These drugs allow for body weight reduction of 6–22.5%, improve glycemic control (HbA1c –1–2.5%), decrease visceral adipose tissue volume, and in some cases reduce cardiovascular risk (MACE reduction up to 26% for semaglutide in SUSTAIN-6).

The dual GLP-1/GIP agonist tirzepatide achieves efficacy comparable to bariatric surgery, surpassing semaglutide by 4–6.5% in body weight reduction in phase III trials (including SURMOUNT-5 in 2025). Cardiovascular outcome trial results for tirzepatide (SURPASS-CVOT) are expected in 2025/26 and may confirm additional cardioprotective benefits.

Treatment limitations include high costs, lack of widespread reimbursement for obesity (outside of DM2), need for chronic use, and adverse effects – mainly gastrointestinal. The weight loss effect partially disappears after discontinuation, requiring long-term strategies and patient support.

In summary, incretin therapies represent the foundation of modern obesity treatment. However, their effective implementation requires systemic strategies, reimbursement, patient and medical staff education, as well as an integrated approach including behavioral, dietary, and – in selected patients – bariatric surgical interventions.