Semaglutide tablets: everything you need to know about oral treatment

Semaglutide tablets are sold as Rybelsus.

They are an important step forward in diabetes care, because they are the first oral GLP-1 receptor agonist (a medicine that helps your body lower blood sugar).

Background:

GLP-1 receptor agonists used to come only as injections. The reason is simple: peptide molecules (the type of molecule in this medicine) are broken down in your gut.

Oral semaglutide gets around this problem. It is combined with salcaprozate sodium (SNAC), an absorption enhancer. SNAC shields semaglutide from being broken down in the stomach.

It also helps the medicine pass through the stomach lining and into your body.

Available strengths:

• 3 mg: the starting dose, used for the first 30 days
• 7 mg: the middle dose, which can be a long-term dose for some patients
• 14 mg: the full long-term dose, which works the best

Licensed indication:

Rybelsus is licensed in the UK for adults whose type 2 diabetes is not well controlled. It is used alongside diet and exercise. You can take it on its own when you cannot tolerate metformin.

You can also take it with other glucose-lowering medicines.

Important distinction:

Oral semaglutide (Rybelsus) is licensed only for type 2 diabetes, not for weight management.

Injectable semaglutide comes as Ozempic (for diabetes) and Wegovy (for weight management). These products are not interchangeable.

How you take Rybelsus matters a lot. It affects how well your body absorbs it. Most oral medicines are easy to take, but this one has very specific rules.

Step-by-step instructions:

• Take the tablet first thing in the morning on a completely empty stomach
• Swallow the tablet whole with no more than 120 mL (half a glass) of plain water
• Do not crush, chew or split the tablet. This breaks the SNAC absorption mechanism
• Wait at least 30 minutes before you eat, drink anything else or take other oral medicines
• Take only one tablet per day

Why these rules matter:

The SNAC enhancer raises the pH (lowers the acidity) in a small area on the stomach wall. This lets semaglutide pass into your body through the cells of the stomach lining.

Food, lots of liquid or other medicines in the stomach get in the way of this process. They cut down how much you absorb by a large amount.

Studies show that absorption drops by about 40% if you take the tablet with food.

Common mistakes to avoid:

• Taking the tablet with a full glass of water or other drinks
• Eating within 30 minutes of taking the tablet
• Taking other medicines at the same time, including antacids or proton pump inhibitors (medicines that reduce stomach acid)
• Splitting the tablet to change the dose

The BNF stresses that patients need clear advice on how to take the medicine, so that it works properly. If you find the fasting rule hard to follow, talk to your prescriber about it.

We know how well oral semaglutide works from the PIONEER trial programme. It included over 9,000 patients with type 2 diabetes.

HbA1c reduction:

HbA1c is a blood test that shows your average blood sugar over time.

• PIONEER 1 (on its own): oral semaglutide 14 mg lowered HbA1c by 1.5 percentage points at 26 weeks, versus 0.0 with a placebo (a dummy treatment)
• PIONEER 2 (versus empagliflozin): oral semaglutide 14 mg worked better than empagliflozin 25 mg at 26 weeks
• PIONEER 4 (versus liraglutide): oral semaglutide 14 mg was as good as liraglutide 1.8 mg at 26 weeks, and better at 52 weeks

Weight loss:

• Oral semaglutide 14 mg leads to about 4 to 5 kg of weight loss on average in diabetes trials
• This is less than injectable semaglutide (Ozempic 1 mg usually leads to 5 to 7 kg), because your body absorbs less of the oral form

Comparison with injectable semaglutide:

• PIONEER 7 let patients use a flexible dose of oral semaglutide, compared with injectable semaglutide 0.5 mg. The oral form was just as good at lowering HbA1c
• On the whole, oral semaglutide 14 mg works about as well as injectable semaglutide 0.5 mg for blood sugar control
• Injectable semaglutide 1 mg and 2 mg are stronger than the oral form

NICE technology appraisals support using oral semaglutide as part of the treatment pathway for type 2 diabetes, when other medicines are not enough.

Oral semaglutide has much the same side effects as injectable GLP-1 agonists. Most of them affect the gut.

Very common (more than 1 in 10 people):

• Nausea (feeling sick): the most reported side effect. It affects about 16 to 20% of patients on the 14 mg dose. It is usually worst while your dose is going up
• Diarrhoea: reported by about 10% of patients

Common (1 in 10 to 1 in 100 people):

• Less appetite: this adds to the weight loss
• Vomiting (being sick): usually short-lived
• Stomach pain and bloating
• Constipation
• Indigestion and acid reflux (when stomach acid rises into the throat)
• Wind

Serious but rare:

• Pancreatitis (swelling of the pancreas): get medical help straight away if you have severe, lasting stomach pain
• Diabetic retinopathy complications: when blood sugar control improves fast, it can sometimes make existing diabetic eye disease worse. NICE advises eye screening before and after you start treatment if you already have retinopathy
• Gallbladder problems: such as gallstones and cholecystitis (an inflamed gallbladder), more so with weight loss

Hypoglycaemia (low blood sugar):

The risk of low blood sugar is low when you take this medicine on its own or with metformin.

But if you take it with insulin or sulphonylureas, you may need a lower dose of the other medicine to avoid low blood sugar.

The BNF advises that patients should be told the signs of pancreatitis. If these signs appear, stop the medicine and seek a medical review.

Oral semaglutide may suit some patients with type 2 diabetes especially well.

Ideal candidates:

• Patients who would rather not have injections, or who have a fear of needles
• Those who have not reached their target HbA1c with metformin alone, or with metformin plus other oral medicines
• Patients who would gain from some weight loss alongside blood sugar control
• Those who can follow the specific instructions reliably each morning

Patients who may not be suitable:

• Those with gastroparesis (slow stomach emptying) or severe gut disease: the medicine slows stomach emptying, which may make symptoms worse
• Patients with a history of pancreatitis: GLP-1 agonists carry a rare risk of pancreatitis
• Those who cannot follow the fasting rules: taking it the wrong way greatly reduces how well it works
• Pregnant or breastfeeding women: stop semaglutide at least 2 months before a planned pregnancy
• Patients with type 1 diabetes or diabetic ketoacidosis: GLP-1 agonists are not used for these

Switching from injectable to oral semaglutide:

Patients on injectable semaglutide (Ozempic) may want to switch to tablets. You can start oral semaglutide the day after your last injection.

Keep in mind that the oral form may be less strong than the injectable one, so your prescriber should know about the switch.

NICE places oral semaglutide alongside injectable GLP-1 agonists and SGLT2 inhibitors in the type 2 diabetes treatment pathway.

It usually comes after metformin and lifestyle changes have not worked well enough.

Fitting oral semaglutide into your day takes some planning. Most patients get used to it quickly.

Building a morning routine:

• Set an alarm 30 to 45 minutes before you normally eat breakfast
• Keep the tablets and a small glass on your bedside table
• Take the tablet as soon as you wake up, before you get out of bed if you wish
• Use the 30-minute wait for your morning routine, such as showering, getting dressed and making breakfast

Managing the fasting window:

• If you wake early and eat breakfast at 6am, take the tablet at 5:30am
• If you usually skip breakfast, you have more freedom with timing
• Do not take other medicines during the 30-minute window. Take them after breakfast instead

What to do if you miss a dose:

• If you miss a day, skip that dose. Take the next one as usual the following morning
• Do not take two tablets on the same day to make up for a missed dose
• If you miss several days, contact your prescriber for advice

Storage:

• Keep the tablets in the original blister pack to protect them from moisture
• Keep them below 30 degrees Celsius
• Do not remove a tablet from the blister until you are ready to take it

Monitoring:

• Regular HbA1c checks (every 3 to 6 months) will show whether the medicine is working
• Your blood pressure, weight and kidney function should be checked at review appointments
• Report any lasting gut symptoms that do not get better after the first few weeks