Polycystic ovary syndrome (PCOS) affects up to one in five women of reproductive age in the UK, often causing irregular periods, weight gain, and insulin resistance. Rybelsus (semaglutide) is an oral medication licensed for type 2 diabetes that works by improving blood glucose control and promoting weight loss. Whilst research into GLP-1 receptor agonists for PCOS shows promise, Rybelsus is not currently approved or routinely recommended by NICE for this condition. This article examines the evidence, explores NICE-recommended treatments, and outlines important considerations for women with PCOS considering Rybelsus.

What Is Rybelsus and How Does It Work?

Rybelsus (semaglutide) is an oral medication belonging to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists. It was originally developed and licensed for the treatment of type 2 diabetes mellitus in adults. In the UK, Rybelsus is approved by the Medicines and Healthcare products Regulatory Agency (MHRA) specifically for glycaemic control in adults with type 2 diabetes, either as monotherapy when metformin is inappropriate or in combination with other glucose-lowering medicines.

The mechanism of action involves mimicking the naturally occurring hormone GLP-1, which is released from the gut in response to food intake. Semaglutide works by stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner, meaning it only promotes insulin release when blood glucose levels are elevated. This reduces the risk of hypoglycaemia compared to some other diabetes medications, although this risk increases if used with insulin or sulfonylureas. Additionally, it suppresses glucagon secretion, slows gastric emptying, and acts on appetite centres in the brain to promote satiety and reduce food intake.

These combined effects lead to improved blood glucose control and often result in weight loss, which has generated interest in its potential use for other conditions associated with insulin resistance and obesity. Rybelsus is taken as a once-daily tablet, typically starting at 3 mg for one month before increasing to 7 mg, with a possible further increase to 14 mg depending on response and tolerability. The tablet must be taken on an empty stomach with no more than 120 mL of water, swallowed whole, at least 30 minutes before food, drink, or other oral medications to ensure adequate absorption. If you take levothyroxine, your thyroid function should be monitored as Rybelsus may increase thyroxine exposure.

Understanding PCOS and Its Treatment Challenges

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age, with an estimated prevalence of 5–20% depending on diagnostic criteria used. PCOS is characterised by a combination of features including irregular menstrual cycles or absent periods (oligomenorrhoea or amenorrhoea), clinical or biochemical signs of excess androgens (such as hirsutism, acne, or elevated testosterone levels), and polycystic ovarian morphology on ultrasound scan.

The underlying pathophysiology of PCOS is complex and multifactorial. A key feature is insulin resistance, which is common and affects up to approximately 70% of women with PCOS, with higher prevalence in those with overweight or obesity, though it can also occur in women of normal weight. This insulin resistance leads to compensatory hyperinsulinaemia, which in turn stimulates ovarian androgen production and disrupts normal ovarian function. Many women with PCOS also experience weight gain or obesity, which further exacerbates insulin resistance, creating a challenging cycle that is difficult to break.

Treatment of PCOS presents several challenges because there is no single cure for the condition, and management must be tailored to individual symptoms and reproductive goals. According to NICE Clinical Knowledge Summary (CKS) guidance, first-line management typically involves lifestyle modifications including weight loss through diet and exercise, which can improve insulin sensitivity and restore ovulatory function in some women. However, achieving and maintaining significant weight loss is notoriously difficult for many patients.

Pharmacological options currently recommended include the combined oral contraceptive pill for menstrual regulation and management of hyperandrogenic symptoms, metformin for metabolic features (particularly in women with glucose intolerance), and anti-androgen medications such as spironolactone for hirsutism (with effective contraception due to teratogenicity risk). For women seeking fertility, ovulation induction with clomifene citrate or letrozole may be offered under specialist care. Women with prolonged amenorrhoea (>3 months) should be offered progestogen therapy to induce withdrawal bleeding for endometrial protection.

Despite these options, many women continue to struggle with inadequately controlled symptoms. Referral to a specialist is recommended for women with features of virilisation, markedly elevated testosterone levels, rapid symptom onset, diagnostic uncertainty, or fertility issues requiring specialist management.

Evidence for GLP-1 Medications in PCOS Management

Research into GLP-1 receptor agonists for PCOS management has grown considerably in recent years, driven by the recognition that these medications address several key pathophysiological features of the condition. Multiple clinical trials have investigated various GLP-1 agonists, including liraglutide (injectable), semaglutide (both injectable and oral formulations), and others, in women with PCOS.

Studies have demonstrated that GLP-1 receptor agonists can produce significant weight loss in women with PCOS, often greater than that achieved with metformin or lifestyle modification alone. Recent systematic reviews have found that GLP-1 agonists led to meaningful reductions in body mass index (BMI), waist circumference, and body weight compared to placebo or other treatments. This weight loss is clinically relevant because even modest weight reduction (5–10% of body weight) can improve insulin sensitivity, restore menstrual regularity, and enhance fertility outcomes in women with PCOS.

Beyond weight loss, research suggests that GLP-1 medications may improve several metabolic parameters in PCOS. Studies have shown improvements in insulin sensitivity, fasting glucose, and lipid profiles. Some trials have also reported improvements in menstrual regularity and ovulation rates, though results have been somewhat variable across studies. There is emerging evidence that GLP-1 agonists may reduce androgen levels and improve markers of hyperandrogenism, though the magnitude of these effects appears modest.

However, it is crucial to note that most research has focused on injectable GLP-1 agonists rather than oral semaglutide (Rybelsus) specifically. Whilst the mechanism of action is the same regardless of route of administration, there are differences in bioavailability and dosing between oral and injectable formulations. Furthermore, the majority of studies have been relatively short-term (typically 12–24 weeks), and long-term safety and efficacy data in women with PCOS remain limited. There is currently no official licence for Rybelsus or any GLP-1 receptor agonist for the treatment of PCOS in the UK.

NICE-Recommended Treatments for PCOS in the UK

The National Institute for Health and Care Excellence (NICE) provides guidance on the management of PCOS through its Clinical Knowledge Summary (CKS). According to current NICE recommendations, first-line management should focus on lifestyle modifications, including a healthy balanced diet, regular physical activity, and weight management for those who are overweight or obese. Even modest weight loss can lead to significant improvements in symptoms and metabolic health.

For pharmacological management, NICE recommends several evidence-based options depending on the presenting symptoms and treatment goals:

• Combined oral contraceptive pill (COCP): Recommended as first-line treatment for menstrual irregularity and management of hyperandrogenic symptoms such as hirsutism and acne. The COCP helps regulate menstrual cycles and reduces androgen production.

• Metformin: May be offered to women with PCOS who have not responded adequately to lifestyle modifications, particularly those with impaired glucose tolerance or other features of metabolic syndrome. Metformin improves insulin sensitivity and may help with weight management and menstrual regularity, though it is not licensed specifically for PCOS in the UK.

• Clomifene citrate or letrozole: Offered for ovulation induction in women with PCOS who are trying to conceive. Letrozole is often preferred based on evidence but is used off-label in the UK and should be prescribed under specialist supervision.

• Anti-androgen medications: Spironolactone or cyproterone acetate (usually in combination with the COCP) may be considered for persistent hirsutism that has not responded to the COCP alone. Effective contraception is essential with anti-androgens due to risks of foetal abnormalities. The MHRA has issued a Drug Safety Update regarding cyproterone acetate and the risk of meningioma with long-term use at high doses.

For women with PCOS who are significantly overweight or obese (BMI ≥30 kg/m² or ≥28 kg/m² with comorbidities), orlistat may be considered as an adjunct to lifestyle modifications to support weight loss. Orlistat is also available over-the-counter as alli® for adults with BMI ≥28 kg/m². In exceptional circumstances, bariatric surgery may be discussed for women with severe obesity and PCOS.

For eligible patients with obesity (BMI ≥35 kg/m² or ≥30 kg/m² with weight-related comorbidities), NICE Technology Appraisal 875 recommends semaglutide (Wegovy) as an option for weight management within NHS specialist weight management services.

It is important to emphasise that Rybelsus is not currently included in NICE guidance for PCOS management and is not routinely prescribed by the NHS for this indication. Any use of Rybelsus for PCOS would be considered 'off-label' prescribing, meaning it is being used outside its licensed indication.

Important Considerations Before Using Rybelsus for PCOS

If you are considering Rybelsus for PCOS management, there are several crucial factors to discuss with your healthcare provider. Firstly, Rybelsus is not licensed for PCOS treatment in the UK, and there is currently insufficient evidence to support its routine use for this indication. Any prescription would be off-label, which means it falls outside standard NHS prescribing protocols and may not be available through NHS services.

From a safety perspective, Rybelsus is generally well-tolerated, but common adverse effects include gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and constipation. These effects are usually mild to moderate and tend to improve over time, but they can be troublesome for some patients. More serious but rare adverse effects include pancreatitis and gallbladder disease. The UK SmPC notes that in rodent studies, GLP-1 receptor agonists caused C-cell tumours, though a causal relationship in humans has not been established. You should report any unusual neck symptoms to your doctor.

An important consideration for women with PCOS is fertility and pregnancy planning. GLP-1 receptor agonists like Rybelsus may improve ovulation and fertility in women with PCOS, which could lead to unplanned pregnancy. Semaglutide is not recommended during pregnancy or breastfeeding, and women of childbearing potential should use effective contraception whilst taking this medication. If you are planning to conceive, you should discuss stopping Rybelsus at least two months before attempting pregnancy.

For proper administration, take Rybelsus with up to 120 mL of water, swallow the tablet whole, and wait at least 30 minutes before eating, drinking, or taking other oral medicines. If you take levothyroxine, your thyroid function should be monitored as Rybelsus may increase thyroxine exposure. If you also take insulin or sulfonylureas, dose adjustments may be needed to reduce the risk of hypoglycaemia.

Cost is another significant factor. If prescribed privately for off-label use, Rybelsus can be expensive, and ongoing treatment would be required to maintain benefits. Weight regain commonly occurs after discontinuation of GLP-1 medications.

Before considering Rybelsus, ensure you have:

• Tried evidence-based first-line treatments recommended by NICE

• Discussed realistic expectations and potential risks with your GP or specialist

• Considered whether the benefits outweigh the costs and potential adverse effects

• Explored NHS-funded weight management programmes if weight loss is a primary goal

If you experience severe abdominal pain, persistent vomiting, or signs of an allergic reaction whilst taking Rybelsus, seek medical attention promptly. Report any suspected side effects via the MHRA Yellow Card Scheme. Regular monitoring by a healthcare professional is essential if this medication is prescribed off-label for PCOS.

Frequently Asked Questions