Dapagliflozin + Glimepiride + Metformin is a prescription tablet that combines three diabetes medicines. Each one lowers blood sugar in a different way. It is used for adults with type 2 diabetes, together with diet and exercise. Dapagliflozin helps the kidneys pass extra sugar out in the urine. Glimepiride helps the pancreas release more insulin. Metformin reduces the sugar the liver makes and helps the body use its own insulin better. Your doctor may prescribe Dapagliflozin + Glimepiride + Metformin when one or two medicines are no longer enough. Because it contains three medicines, you have fewer tablets to take each day.

In type 2 diabetes, the body does not respond well to insulin, the hormone that moves sugar from the blood into cells. Over time, the pancreas may also make less insulin. Dapagliflozin + Glimepiride + Metformin works on this problem in three ways at once.

Dapagliflozin belongs to a group called SGLT2 inhibitors (medicines that block a sugar-recycling protein in the kidneys). It makes the kidneys pass extra sugar out of the body in the urine. Glimepiride is a sulfonylurea. It prompts the pancreas to release more insulin. Metformin is a biguanide. It lowers the amount of sugar the liver releases into the blood and helps muscles take up sugar more easily.

Dapagliflozin + Glimepiride + Metformin is used with diet and exercise to control blood sugar in adults with type 2 diabetes. It may be used when blood sugar is not well controlled on metformin and one other medicine, or to replace the same three medicines taken as separate tablets. Good blood sugar control lowers the risk of long-term damage to the eyes, kidneys, nerves and heart. Dapagliflozin + Glimepiride + Metformin is not used for type 1 diabetes or to treat diabetic ketoacidosis, a dangerous build-up of acids called ketones in the blood.

Taking three medicines in one tablet means fewer tablets to swallow, which can make it easier to stick with daily treatment. However, each ingredient carries its own risks, so you need to be under a doctor's care while you take this medicine. Glimepiride can make blood sugar drop too low (hypoglycaemia), especially if you skip meals. Metformin carries a boxed warning on its US label for lactic acidosis, a rare but serious build-up of acid in the blood. Dapagliflozin can cause loss of body fluid, genital yeast infections, urinary infections and, rarely, ketoacidosis even when blood sugar is close to normal.

Your doctor will check your kidney function before you start Dapagliflozin + Glimepiride + Metformin and from time to time after that, because both metformin and dapagliflozin depend on the kidneys. Regular blood sugar and HbA1c tests (a blood test that shows your average blood sugar over the past 2 to 3 months) show whether the treatment is working. Long-term metformin use can lower vitamin B12 levels, so your doctor may check this too.

1. Three ways to lower blood sugar - The three ingredients work on the kidneys, the pancreas and the liver, which together can bring blood sugar down more than one medicine alone.
2. Fewer tablets each day - One combined tablet replaces three separate medicines, which can make it easier to stay on treatment.
3. Insulin-independent sugar removal - Dapagliflozin removes sugar through the urine whether or not your body is making much insulin.
4. Lower sugar output from the liver - Metformin cuts down the extra sugar the liver releases, especially overnight and between meals.
5. Better insulin release at meals - Glimepiride helps the pancreas release more insulin, which helps control the rise in sugar after eating.
6. Helps limit weight gain - Metformin is generally weight-neutral and dapagliflozin can lead to modest weight loss. This may partly offset the weight gain that glimepiride can cause.
7. Possible heart and kidney protection from dapagliflozin - In studies of dapagliflozin on its own, people with type 2 diabetes and heart disease or risk factors for it had a lower risk of being admitted to hospital for heart failure. Dapagliflozin has also been shown to slow kidney decline in certain people with long-term kidney disease. Ask your doctor whether these benefits apply to you.

Common Side Effects (Usually Mild and may lessen with continued use)

• Nausea, stomach upset, diarrhoea, gas or loss of appetite (mainly from metformin)
• A metallic taste in the mouth
• Headache
• Passing urine more often or in larger amounts
• Feeling thirsty
• Genital yeast infections, causing itching, redness or discharge in women and men
• Urinary tract infections, causing burning or pain when passing urine
• Mild low blood sugar, causing shakiness, sweating, hunger, a fast heartbeat or dizziness
• Back pain or a runny, stuffy nose
• Weight gain (linked to glimepiride)

Serious Side Effects (Seek Urgent Medical Attention)

• Severe hypoglycaemia (very low blood sugar): confusion, unusual behaviour, fits or passing out. This is mainly linked to glimepiride.
• Lactic acidosis: a rare but life-threatening build-up of lactic acid in the blood caused by metformin. Warning signs include unusual muscle pain, trouble breathing, unusual sleepiness, stomach pain with nausea or vomiting, feeling cold, dizziness, or a slow or uneven heartbeat. The risk is higher with kidney problems, heavy drinking, dehydration, serious infection, heart failure, liver disease, surgery or X-ray tests that use contrast dye.
• Diabetic ketoacidosis (DKA): a dangerous build-up of acids called ketones in the blood, linked to dapagliflozin. It can happen even when your blood sugar is normal or only a little high, which is called euglycaemic ketoacidosis. Signs include nausea, vomiting, stomach pain, unusual tiredness and trouble breathing.
• Fournier's gangrene: a rare but serious infection of the skin and tissue around the genitals and anus, linked to SGLT2 inhibitors such as dapagliflozin. Get help right away for pain, tenderness, redness or swelling in that area with fever or feeling unwell.
• Dehydration, low blood pressure and sudden kidney problems (acute kidney injury): dizziness, fainting or light-headedness, especially when standing up, or passing much less urine than usual or swelling of the legs or feet. The risk is higher in older adults, people taking water pills (diuretics) and people with existing kidney problems.
• Serious kidney infection (pyelonephritis) or blood infection (urosepsis): fever, chills, back or side pain, or blood in the urine.
• Serious allergic reactions, including anaphylaxis (a sudden, severe allergic reaction with trouble breathing and collapse), angioedema (swelling of the face, lips, tongue or throat) and Stevens-Johnson syndrome, a rare and severe reaction that causes blistering and peeling of the skin and mouth. Glimepiride and dapagliflozin both list serious allergic reactions on their labels.
• Haemolytic anaemia: early breakdown of red blood cells. This is more likely with glimepiride in people with G6PD deficiency, an inherited enzyme condition. Signs include yellow skin, dark urine and unusual tiredness.
• Low vitamin B12 with long-term metformin use. This can cause tingling or numbness in the hands and feet, or tiredness.

• Take Dapagliflozin + Glimepiride + Metformin exactly as your doctor prescribes. It is usually taken once a day with breakfast or with the first main meal of the day.
• Always take it with food. Eating helps reduce stomach upset from metformin and lowers the risk of low blood sugar from glimepiride.
• Swallow the tablet whole with a glass of plain water. Many versions of this combination contain extended-release metformin, so do not crush, chew or break the tablet unless your pharmacist says it is safe.
• Take it at the same time each day so the level of medicine in your body stays steady.
• Do not skip meals while taking this medicine. A skipped or delayed meal can lead to low blood sugar.
• Drink enough fluids during the day, because dapagliflozin makes you pass more urine.
• Keep taking Dapagliflozin + Glimepiride + Metformin even when you feel well. Diabetes is a long-term condition, so do not stop or change your dose without talking to your doctor.

Dapagliflozin + Glimepiride + Metformin brings together three medicines that each act on a different part of the body.

Dapagliflozin (kidneys): Normally, the kidneys filter sugar out of the blood and then take almost all of it back in. A transport protein called SGLT2 (sodium-glucose co-transporter 2), found in tiny kidney tubes, does most of this work. Dapagliflozin blocks SGLT2, so more sugar leaves the body in the urine and blood sugar falls. Because this does not depend on insulin, it keeps working as insulin output drops. The extra sugar in the urine also pulls water out with it, which explains the extra urination and the small drop in blood pressure some people notice.

Glimepiride (pancreas): Glimepiride is a sulfonylurea. It acts on the beta cells of the pancreas, the cells that make insulin. It binds to the sulfonylurea receptor (SUR1) on the potassium channels (K-ATP channels) of beta cells. When these channels close, the cell's electrical charge changes, calcium flows in, and stored insulin is released. Glimepiride only works if the pancreas can still make some insulin. Because it raises insulin whether or not you have eaten, it can cause low blood sugar if a meal is missed.

Metformin (liver and muscles): Metformin is a biguanide. It mainly lowers the amount of new sugar the liver makes and releases, a process called gluconeogenesis. At the cell level, metformin is thought to work partly by switching on an energy-sensing enzyme called AMPK and by slowing energy production in the cell's mitochondria. This tells the liver to make less sugar. It also makes muscle and fat cells more sensitive to insulin, so they take up more sugar, and it slightly reduces how much sugar the gut absorbs. On its own, metformin rarely causes low blood sugar.

Together: Metformin cuts the sugar entering the blood, glimepiride raises insulin to move sugar into cells, and dapagliflozin removes extra sugar through the urine. Because the three work in separate ways, their effects add up.

• Take Dapagliflozin + Glimepiride + Metformin with breakfast or your first main meal, and never skip that meal.
• Carry glucose tablets, sugar or fruit juice with you to treat low blood sugar quickly.
• Learn the signs of low blood sugar: shaking, sweating, hunger, a fast heartbeat and confusion.
• Drink enough water during the day, especially in hot weather, during exercise or when you are ill.
• If you have vomiting, diarrhoea or cannot eat or drink normally, call your doctor. You may need to pause this medicine for a short time.
• Tell your doctor before any surgery or any scan that uses contrast dye. Dapagliflozin is usually stopped at least three days before planned surgery, and metformin may need to be paused around a contrast scan.
• Keep your genital area clean and dry to lower the risk of yeast infections.
• Tell the person testing your urine that you take Dapagliflozin + Glimepiride + Metformin. Dapagliflozin makes urine glucose tests show positive.
• Ask your doctor about checking your vitamin B12 levels if you have been on this medicine for a long time.

• Store at room temperature, as printed on the pack (usually below 30°C or 86°F), away from heat.
• Keep the tablets in their original strip or container to protect them from moisture and direct light.
• Do not store in the bathroom or in a hot car.
• Keep out of the sight and reach of children and pets. Because of the glimepiride, swallowing even a small amount can cause dangerously low blood sugar in a child.
• Do not use tablets after the expiry date. Ask your pharmacist how to throw away unused medicine safely.

• Alcohol: Raises the risk of lactic acidosis (metformin), ketoacidosis (dapagliflozin) and low blood sugar (glimepiride). Heavy or binge drinking should be avoided.
• Skipped or late meals: Not a food interaction as such, but missing meals while taking glimepiride is one of the most common causes of low blood sugar.
• Very low-carbohydrate or crash diets and fasting: Sharply cutting carbohydrates or fasting for long periods can raise the risk of ketoacidosis with dapagliflozin and low blood sugar with glimepiride. Talk to your doctor before starting such a diet or a religious fast.
• Low fluid intake: Because dapagliflozin makes you pass more urine, not drinking enough can lead to dehydration and dizziness.
• Taking it with food: Having Dapagliflozin + Glimepiride + Metformin with a meal lowers stomach upset from metformin.

• Insulin and other medicines that raise insulin (other sulfonylureas, meglitinides such as repaglinide): Raise the risk of low blood sugar. Your doctor may need to lower the dose of these medicines.
• Medicines that can increase the effect of glimepiride: Fluconazole and other azole antifungals, aspirin and other salicylates, NSAIDs (painkillers such as ibuprofen), sulfonamide antibiotics, fibrates (cholesterol medicines such as fenofibrate), ACE inhibitors (blood pressure medicines such as enalapril or ramipril), MAO inhibitors (a group of older antidepressants) and fluoxetine may make blood sugar drop too low.
• Medicines that can weaken the effect on blood sugar: Steroids (corticosteroids), thiazide and other diuretics, thyroid medicines, oral contraceptives and oestrogens, phenytoin, niacin, decongestants and other sympathomimetics (stimulant-type medicines found in some cold remedies), and some antipsychotics can raise blood sugar.
• Beta-blockers (such as propranolol, atenolol): Can hide warning signs of low blood sugar, such as a fast heartbeat and shaking.
• Diuretics (water pills such as furosemide): Together with dapagliflozin, they raise the risk of dehydration, low blood pressure and sudden kidney problems.
• Carbonic anhydrase inhibitors (such as topiramate, acetazolamide): Raise the risk of lactic acidosis with metformin.
• Medicines that reduce metformin clearance (such as ranolazine, dolutegravir, cimetidine, vandetanib): Can raise metformin levels in the blood.
• Iodinated contrast dye used in X-rays and CT scans: Can affect kidney function and raise the risk of lactic acidosis. Metformin may need to be stopped for a short time.
• Colesevelam: Reduces the absorption of glimepiride, so glimepiride is taken at least 4 hours before colesevelam.
• Lithium: Dapagliflozin may lower lithium levels, so your doctor may check them more often.

Always give your doctor and pharmacist a full list of the medicines, supplements and herbal products you take.

• Allergy to any ingredient or to "sulfa" medicines: Do not take Dapagliflozin + Glimepiride + Metformin if you have ever had an allergic reaction to dapagliflozin, glimepiride, metformin, other sulfonylureas or sulfonamide ("sulfa") medicines. Tell your doctor about any drug allergies.
• Type 1 diabetes or diabetic ketoacidosis: Dapagliflozin + Glimepiride + Metformin should not be used for either.
• Kidney disease: Metformin builds up when the kidneys do not work well, which raises the risk of lactic acidosis. Dapagliflozin lowers blood sugar less when kidney function is reduced and can affect fluid balance.
• Liver disease: Raises the risk of lactic acidosis and of long-lasting low blood sugar.
• Heart failure, recent heart attack or conditions with low oxygen levels: Low oxygen in the body raises the risk of lactic acidosis with metformin.
• Heavy alcohol use: Raises the risk of lactic acidosis, ketoacidosis and low blood sugar.
• Dehydration, low blood pressure or low salt levels: Dapagliflozin can make these worse and cause dizziness, fainting or sudden kidney problems.
• Pancreas problems (such as pancreatitis or past pancreas surgery), insulin deficiency, or recent serious illness or surgery: Raise the risk of ketoacidosis with dapagliflozin.
• Repeated urinary or genital infections: Dapagliflozin can make these infections more likely.
• G6PD deficiency: Glimepiride can cause breakdown of red blood cells (haemolytic anaemia).
• Adrenal or pituitary gland problems, or being underweight or malnourished: Raise the risk of low blood sugar with glimepiride.
• Vitamin B12 deficiency or anaemia: Long-term metformin use can lower B12 levels further.

• Dapagliflozin + Glimepiride + Metformin is usually taken as one tablet once a day with breakfast or the first main meal.
• It comes in different strengths, mainly differing in the amount of glimepiride and metformin. The exact strength is printed on your pack. Your doctor will choose the strength based on your blood sugar, your kidney function and the medicines you were taking before.
• Dapagliflozin should not go above 10 mg a day.
• Glimepiride and metformin also have their own daily limits. On their single-ingredient labels, the highest dose is 8 mg a day for glimepiride and 2,000 mg a day for extended-release metformin. Your doctor will check that your total dose stays within these limits.
• Do not take more than one tablet a day unless your doctor tells you to. Because every tablet contains dapagliflozin, taking extra tablets can push it above its daily limit.
• Your doctor may start with a lower strength and raise it slowly to reduce stomach upset and the risk of low blood sugar.
• Take only the dose your doctor prescribes. Do not change your dose, take extra tablets or stop the medicine on your own.

Taking too much Dapagliflozin + Glimepiride + Metformin can be dangerous, mainly because of the glimepiride and metformin.

Possible signs of overdose include:

• Severe low blood sugar: heavy sweating, shaking, confusion, slurred speech, unusual behaviour, fits or loss of consciousness
• Lactic acidosis: severe weakness, muscle pain, fast or difficult breathing, stomach pain, vomiting, feeling cold, a slow heartbeat
• Dizziness, fainting or signs of dehydration

What to do:

• If the person is awake and able to swallow, give them sugar, glucose tablets or a sugary drink straight away.
• Call emergency services or go to the nearest hospital immediately, even if the person seems to recover. Low blood sugar from glimepiride can come back over several hours, so they may need to be watched in hospital.
• Take the medicine strip or pack with you.
• In hospital, doctors may give glucose through a drip. Metformin can be removed from the blood by dialysis if needed.

• If you miss a dose, take it with food as soon as you remember on the same day.
• If it is nearly time for your next dose, skip the missed dose and take the next one at the usual time.
• Do not take two doses together to make up for a missed one. A double dose can cause dangerously low blood sugar.
• Do not take the missed dose if you are not going to eat, because glimepiride can lower your blood sugar without food.
• If you often forget doses, set a phone reminder or link the tablet to breakfast.

Get medical help right away if you notice:

• Signs of severe low blood sugar that do not improve after taking sugar, or confusion, fits or fainting
• Unusual muscle pain, trouble breathing, extreme tiredness, stomach pain with nausea or vomiting, or feeling cold (possible lactic acidosis)
• Nausea, vomiting, stomach pain, unusual tiredness or trouble breathing, even if your blood sugar is normal (possible ketoacidosis)
• Pain, tenderness, redness or swelling of the genitals or the area between the genitals and anus, with fever or feeling unwell
• Fever, chills, back or side pain, or blood in the urine
• Severe dizziness, fainting, passing much less urine than usual, or swelling of the legs or feet (possible sudden kidney problems)
• Swelling of the face, lips, tongue or throat, trouble breathing, or a blistering or peeling skin rash
• Yellow skin or eyes, or dark urine
• Vomiting, diarrhoea or being unable to eat or drink, which may mean the medicine needs to be paused