Ozempic (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist licensed in the UK for treating type 2 diabetes mellitus. Many patients with type 2 diabetes experience insulin resistance, a condition where cells become less responsive to insulin. Whilst Ozempic is not classified as a direct insulin sensitiser, it does improve insulin sensitivity indirectly through weight reduction, enhanced glucose-dependent insulin secretion, and suppression of glucagon release. This article examines the evidence for Ozempic's effects on insulin resistance, who may benefit from treatment, potential side effects, and alternative management approaches in line with UK clinical guidance.

Understanding Ozempic and Its Mechanism of Action

Ozempic (semaglutide) is a prescription medication licensed in the UK for the treatment of type 2 diabetes mellitus. It belongs to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists, which mimic the action of a naturally occurring hormone that regulates blood glucose levels.

The mechanism of action of Ozempic is multifaceted. When administered as a once-weekly subcutaneous injection, semaglutide binds to GLP-1 receptors found throughout the body, particularly in the pancreas, brain, and gastrointestinal tract. This binding triggers several physiological responses:

• Enhanced insulin secretion: Ozempic stimulates the pancreatic beta cells to release insulin, but only when blood glucose levels are elevated, which reduces the risk of hypoglycaemia

• Suppressed glucagon release: It inhibits the secretion of glucagon, a hormone that raises blood glucose by promoting hepatic glucose production

• Delayed gastric emptying: The medication slows the rate at which food leaves the stomach, leading to more gradual glucose absorption

• Reduced appetite: Ozempic acts on appetite centres in the brain, promoting satiety and often resulting in weight loss

Ozempic is available in multi-dose pre-filled pens for weekly administration. Treatment starts with 0.25 mg once weekly for 4 weeks as an initiation dose (not for glycaemic control), then increases to 0.5 mg once weekly. After at least 4 weeks, the dose can be increased to 1 mg weekly, and if necessary, to a maximum of 2 mg weekly for improved glycaemic control. It's important to note that Ozempic is not licensed for weight loss in the UK, although weight reduction may occur as a side effect of treatment.

How Ozempic Affects Insulin Resistance

Insulin resistance is a metabolic condition in which cells in muscle, fat, and liver tissues become less responsive to insulin, requiring higher levels of the hormone to achieve normal glucose uptake. This condition is central to the pathophysiology of type 2 diabetes and is often associated with obesity, physical inactivity, and metabolic syndrome.

Ozempic addresses insulin resistance through several interconnected mechanisms. Whilst it is not classified as an insulin sensitiser in the same way as metformin or thiazolidinediones, it does improve insulin sensitivity indirectly. The primary pathway involves weight reduction—clinical trials have demonstrated that patients taking Ozempic typically lose approximately 3-7% of their body weight (about 3-6 kg) over several months at diabetes treatment doses. This weight loss, particularly the reduction in visceral adipose tissue, can improve insulin sensitivity as excess fat tissue contributes significantly to insulin resistance.

Additionally, by enhancing glucose-dependent insulin secretion, Ozempic helps to overcome the relative insulin deficiency that occurs when pancreatic beta cells cannot produce enough insulin to compensate for insulin resistance. The medication also reduces hepatic glucose production by suppressing glucagon, which is often inappropriately elevated in insulin-resistant states.

The improvement in glycaemic control achieved with Ozempic creates a positive feedback loop: better blood glucose levels reduce glucotoxicity (the harmful effects of chronically elevated glucose on beta cells and peripheral tissues), which in turn may further improve insulin sensitivity. Clinical studies have shown that HbA1c levels—a marker of long-term glucose control—typically decrease by approximately 0.9-1.6% (10-17 mmol/mol) in patients treated with Ozempic, reflecting these combined metabolic improvements.

Clinical Evidence for Ozempic in Insulin Resistance

The evidence base for Ozempic's effects on insulin resistance comes primarily from the SUSTAIN clinical trial programme, a series of large-scale, randomised controlled trials involving thousands of participants with type 2 diabetes. These studies, which informed regulatory approval by the MHRA and EMA, have consistently demonstrated significant improvements in glycaemic control and metabolic parameters.

In the SUSTAIN trials, semaglutide was compared against placebo, other GLP-1 receptor agonists, and established diabetes medications including insulin. Results showed that Ozempic not only reduced HbA1c levels but also improved markers indirectly related to insulin sensitivity, such as fasting plasma glucose and postprandial glucose excursions. The SUSTAIN 6 cardiovascular outcomes trial additionally demonstrated a reduction in major adverse cardiovascular events, which is particularly relevant given that insulin resistance is a key risk factor for cardiovascular disease. It's important to note that in the UK, Ozempic is licensed for glycaemic control in type 2 diabetes, not specifically for cardiovascular risk reduction.

While some studies have examined surrogate markers such as HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), improvements in insulin resistance with semaglutide are primarily indirect and mediated through weight loss and improved glycaemic control. The weight reduction observed across trials—typically 3-6 kg more than placebo groups at diabetes treatment doses—provides indirect evidence of improved metabolic function, as weight reduction is one of the most effective interventions for insulin resistance.

NICE guidance (NG28) on type 2 diabetes management recognises GLP-1 receptor agonists as effective second- or third-line therapies, particularly for patients with obesity or those requiring additional glycaemic control. The evidence supports Ozempic as an effective option for addressing the metabolic dysfunction underlying insulin resistance, though it should be noted that individual responses vary.

Who Can Benefit from Ozempic for Insulin Resistance

Ozempic is specifically licensed for adults with type 2 diabetes mellitus who have inadequate glycaemic control despite lifestyle modifications. According to NICE guidance (NG28), GLP-1 receptor agonists like Ozempic are typically considered as part of triple therapy when HbA1c remains above target despite other treatments.

Suitable candidates include:

• Patients with type 2 diabetes and a BMI of 35 kg/m² or higher (or 32.5 kg/m² or higher for people of South Asian or other minority ethnic backgrounds), or where weight loss would benefit other significant obesity-related comorbidities

• Those with type 2 diabetes who have not achieved target HbA1c levels with metformin and other oral medications

• People for whom weight loss would benefit other obesity-related comorbidities or where weight-neutral treatment options are preferred

• Individuals with occupational implications where insulin therapy would be problematic

Importantly, NICE recommends continuing GLP-1 receptor agonist treatment only if there is a beneficial metabolic response: after 6 months, treatment should continue only if HbA1c has decreased by at least 11 mmol/mol (1.0%) and weight has decreased by at least 3% from initial body weight.

Ozempic is not licensed for people without diabetes who have insulin resistance alone (such as those with prediabetes or polycystic ovary syndrome). The medication is also not appropriate for type 1 diabetes or diabetic ketoacidosis.

Cautions include patients with a history of pancreatitis or severe gastrointestinal disease. Ozempic is not recommended during pregnancy or breastfeeding and should be discontinued before planned pregnancy. Prescribing decisions should be individualised, taking into account the patient's overall metabolic profile, comorbidities, treatment goals, and preferences. Healthcare professionals should conduct a thorough assessment before initiating Ozempic and ensure patients understand both the potential benefits and risks of treatment.

Potential Side Effects and Considerations

Like all medications, Ozempic can cause side effects, and patients should be fully informed before starting treatment. The most commonly reported adverse effects are gastrointestinal in nature and include nausea, vomiting, diarrhoea, constipation, and abdominal pain. These symptoms typically occur during the initial weeks of treatment or following dose escalation and often diminish over time as the body adjusts to the medication.

To minimise gastrointestinal side effects, Ozempic is initiated at a low dose (0.25 mg weekly) and gradually increased every four weeks. Patients should be advised to eat smaller, more frequent meals and avoid high-fat foods, which can exacerbate nausea. If symptoms are severe or persistent, dose adjustment or temporary discontinuation may be necessary.

More serious but less common side effects include:

• Pancreatitis: Patients should be advised to seek immediate medical attention if they experience severe, persistent abdominal pain radiating to the back

• Gallbladder disease: Rapid weight loss can increase the risk of gallstones; symptoms include right upper quadrant pain, particularly after meals

• Diabetic retinopathy complications: Rapid improvement in glucose control may temporarily worsen retinopathy in susceptible individuals

• Hypoglycaemia: Risk is low when Ozempic is used alone but increases when combined with insulin or sulphonylureas; dose reduction of these medications may be needed when starting semaglutide

• Acute kidney injury: Usually associated with severe dehydration from gastrointestinal side effects

Patients should seek emergency help (call 999 or go to A&E) if they experience signs of anaphylaxis such as sudden swelling, breathing difficulty, or collapse. They should contact their GP or diabetes team if they experience persistent vomiting, signs of dehydration, severe abdominal pain, or visual changes.

In animal studies, semaglutide was associated with thyroid C-cell tumours, but the relevance to humans is unknown. Patients should report any neck masses, hoarseness, or difficulty swallowing to their healthcare provider.

Regular monitoring of renal function and HbA1c is recommended during treatment, in line with standard diabetes care protocols. Patients and healthcare professionals are encouraged to report suspected side effects via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app).

Alternatives and Complementary Approaches to Managing Insulin Resistance

Whilst Ozempic can be effective for managing insulin resistance in people with type 2 diabetes, it is not the only option, and a comprehensive approach typically yields the best outcomes. Lifestyle modification remains the cornerstone of insulin resistance management and should be emphasised alongside any pharmacological intervention.

Dietary approaches that improve insulin sensitivity include reducing intake of refined carbohydrates and added sugars, increasing fibre consumption, and following a Mediterranean-style eating pattern rich in vegetables, whole grains, legumes, and healthy fats. Weight loss of even 5–10% of body weight can significantly improve insulin sensitivity. Regular physical activity—particularly a combination of aerobic exercise and resistance training—directly enhances glucose uptake by muscles and reduces visceral fat.

Pharmacological alternatives recommended by NICE for type 2 diabetes include:

• Metformin: The first-line medication, which reduces hepatic glucose production and improves insulin sensitivity

• SGLT2 inhibitors: These promote glucose excretion through urine and offer cardiovascular and renal benefits; NICE recommends these early in treatment for many people with established cardiovascular disease or chronic kidney disease

• Pioglitazone: An insulin sensitiser, though less commonly used due to side effects including weight gain and fluid retention

• DPP-4 inhibitors: These enhance incretin activity with a lower side effect burden than GLP-1 agonists but less weight loss benefit

• Tirzepatide: A newer dual GIP/GLP-1 receptor agonist available for type 2 diabetes (subject to local formulary approval)

For patients who cannot tolerate or do not respond adequately to Ozempic, other GLP-1 receptor agonists such as dulaglutide (Trulicity) or liraglutide (Victoza) may be considered. Remember that NICE recommends continuing GLP-1 receptor agonists only if, after 6 months, HbA1c has decreased by at least 11 mmol/mol (1.0%) and weight has decreased by at least 3%.

Some patients may ultimately require insulin therapy, which directly addresses insulin deficiency but does not improve insulin resistance and may cause weight gain.

Complementary approaches should not replace evidence-based treatments but may support overall metabolic health. These include stress management, adequate sleep (as sleep deprivation worsens insulin resistance), and smoking cessation. Patients should work closely with their diabetes care team to develop an individualised treatment plan that addresses all aspects of their metabolic health.

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