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| Oral treatments to control blood sugar |
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Reviewed by Professor Ian Campbell, consultant physician
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When are oral medicines used?
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| Oral medicines can increase the effect of insulin in the body |
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In Type 1 diabetes (insulin-dependent diabetes), the cells in the pancreas that produce insulin are progressively destroyed by an immune reaction, stopping the production of insulin.
Insulin replacement treatment is therefore needed for life, because we cannot make the beta cells in the pancreas work again to produce insulin.
Insulin can't be taken in tablet form, because it is broken down in the digestive system. This destroys its effect.
Insulin is given by injection.
Type 2 diabetes
Type 2 diabetes (non-insulin dependent diabetes) is different because the pancreas still produces insulin.
Instead, problems are caused because:
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insulin is produced inefficiently in response to surges of blood sugar, eg following a meal
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the insulin produced gets less effective at controlling blood sugar, because the cells in the body become increasingly resistant to it.
Treatment for Type 2 diabetes involves either improving insulin release in response to meals, or reducing the resistance of the body cells to the effect of insulin.
Diet and exercise are the first treatment used to improve insulin resistance in Type 2 diabetes.
If blood sugar
is not adequately controlled after at least three months of healthy eating and increasing exercise, oral medicines are used.
What oral medicines are used in Type 2 diabetes?
There are five types of oral medicine that can be used to control blood sugar in Type 2 diabetes.
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Biguanides: metformin (Glucophage)
is now the only one available.
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Sulphonylureas: gliclazide (eg Diamicron), glibenclamide (eg Daonil), glimepiride (Amaryl), glipizide (eg Glibenese, Minodiab), gliquidone (Glurenorm) and tolbutamide. Chlorpropamide is no longer recommended because it has more side effects than the others.
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Thiazolidinediones are newer medicines: pioglitazone (Actos) and rosiglitazone (Avandia).
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Meglitinides are another new type of medicine. Nateglinide (Starlix)
and repaglinide (NovoNorm) are currently available.
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Acarbose (Glucobay).
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Gliptins, eg sitagliptin (Januvia), vildagliptin (Galvus). Vildagliptin is also available as a combined product with metformin (Eucreas).
How do they work?
Oral medicines work in three basic ways to lower blood glucose in Type 2 diabetes.
1. Reducing insulin resistance: metformin and thiazolidinediones
Metformin works mainly by reducing the amount of glucose produced by cells in the liver, and by increasing the sensitivity of muscle cells to insulin.
This enables the cells to remove sugar from the blood more effectively.
Metformin also reduces the amount of sugar produced by cells in the liver and reduces the absorption of glucose from the gut after eating.
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Term watch
Beta cells: cells in the pancreas that produce insulin.
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Pioglitazone and rosiglitazone work by increasing the sensitivity of liver, fat and muscle cells to insulin. These medicines may also preserve the function of the beta cells in the pancreas.
Pioglitazone also reduces the amount of glucose produced by the liver.
2. Stimulating insulin release: sulphonylureas and meglitinides
The sulphonylureas work mainly by stimulating the beta cells in the pancreas to release more insulin.
Nateglinide
and repaglinide also stimulate the pancreas to produce more insulin, but have a shorter duration of action than the sulphonylureas.
They are taken to enhance insulin production during meals.
3. Slowing the absorption of sugar from the gut: acarbose
Carbohydrates that we eat need to be broken down into simple sugar molecules in the gut before they can be absorbed
This is done by an enzyme called alpha-glucosidase that is found in the lining of the gut.
Acarbose works by blocking the action of this enzyme.
This delays the absorption of sugar molecules from the gut, so that high peaks of blood glucose after eating are avoided.
4. DPP-4 inhibition: sitagliptin and vildagliptin
Hormones from the small bowel, known as incretins, stimulate insulin release from the pancreas after meals. These hormones include one called glucagon-like peptide-1 (GLP-1) which is broken down by an enzyme called dipeptidyl peptidase-4 (DPP-4).
Newly introduced DPP-4 inhibitors, called gliptins (eg sitagliptin and vildagliptin) prevent this breakdown and permit more insulin to be secreted after meals and reduce post-prandial hyperglycaemia (increased blood glucose levels).
The gliptins also suppress the release of another hormone from the pancreas called glucagon which works against insulin. This further action of these new drugs improves glucose control. They are licensed to be used with metformin or a sulphonylurea.
Which is most suitable for me?
The medicine your doctor prescribes for you will depend on various characteristics such as your age, body weight and kidney and liver function.
Since it does not cause weight gain, metformin is usually the first choice of medicine for overweight people with Type 2 diabetes whose blood sugar is not controlled by diet alone.
A sulphonylurea is the first choice for people who are not overweight, or who cannot take metformin. Gliclazide is the most commonly used.
Glibenclamide is longer-acting than other medicines in this group, which makes it more likely to cause hypoglycaemia. For this reason, it isn't recommended for elderly people.
If blood sugar is not controlled sufficiently with either of these first choices, the next step would be to add a sulphonylurea to treatment with metformin, and vice versa.
Newer medicines
If these combinations fail, one of the newer medicines can be tried.
Pioglitazone and rosiglitazone can be added to treatment with either metformin or a sulphonylurea.
Combination products that contain both metformin and rosiglitazone (Avandamet) or metformin plus pioglitazone (Competact) are also now available. They can reduce the number of tablets that people on these combinations need to take.
The meglitinides are a further option:
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nateglinide is only licensed for use in combination with metformin
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repaglinide can be used either with metformin or on its own.
The gliptins are also a further option, presently being evaluated (see above).
When are oral treatments not suitable?
If your blood sugar is not adequately controlled using a combination of these medicines, you may eventually need insulin treatment.
This can either be added to the oral medicines, or may replace them entirely.
During pregnancy, oral medicines were not previously recommended and are usually replaced by insulin, but the recent NICE guidelines in 2008 endorse metformin for use in pregnancy either alone or with insulin.
Exenatide (Byetta)
is an incretin mimetic which has a structure similar to GLP-1 which is found in the bowel. It is not broken down by the DPP-4 enzyme system.
Exenatide increases insulin secretion, especially after meals, reduces glucagon secretion, which restricts the liver from releasing glucose and it also reduces appetite and slows down the stomach emptying food by up to an hour after eating preventing a rise in blood glucose levels after eating.
Exenatide has to be given, not by mouth, but by twice daily subcutaneous (under the skin) injections up to 15-20 minutes before meals.
It is indicated for the treatment of Type 2 diabetes in combination with metformin and/or a sulphonylurea in patients poorly controlled on these drugs. It is therefore an alternative to insulin injections. Insulin tends to increase weight whereas exenatide has the advantage of causing weight reduction.
How are they taken?
All the medicines for Type 2 diabetes are tablets that are taken by mouth.
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Metformin is taken two or three times a day with or after meals.
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Pioglitazone and rosiglitazone are usually taken once a day, with or without food.
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Sulphonylureas are usually taken once or twice a day with breakfast, though this depends on the individual medicine and dosage.
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Nateglinide and repaglinide are taken about 30 minutes before each main meal.
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Acarbose tablets should be chewed with the first mouthful of food, or swallowed whole with a little liquid immediately before a meal.
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Sitagliptin is taken once daily, vildagliptin twice daily.
What are the side effects?
All medicines have side-effects, but it doesn't mean everyone will experience them. People respond to medicines in different ways.
Oral medicines for Type 2 diabetes have few side effects when taken properly.
Metformin
The most common side effects of metformin are digestive in nature – feeling or being sick, diarrhoea, abdominal pain, loss of appetite and a metallic taste.
Side effects usually improve quickly and can be minimised if the dose is increased gradually. There is now a slow-release preparation of metformin available (Glucophage SR) which reduces gastrointestinal side-effects by up to 80 per cent.
Sulphonylureas
Sulphonylureas can encourage weight gain, and because they stimulate insulin release they can cause hypoglycaemia (low blood glucose) in diabetic patients.
Sulphonylureas can also cause mild digestive side effects such as feeling or being sick, constipation
or diarrhoea.
On rare occasions they may cause allergic reactions, or problems with the liver or blood.
Thiazolidinediones
The most common side effects of the thiazolidinediones are weight gain and swelling of the legs cause by fluid retention (oedema).
Up to 10 per cent of postmenopausal females may get fractures of wrists, hands, ankles or feet but not major fractures of hips or vertebrae.
Meglitinides
Side effects of repaglinide and nateglinide are rare, but include hypoglycaemia, digestive side effects and allergic reactions.
Acarbose
The main side effect associated with acarbose is flatulence, though this tends to decrease with time.
It's caused by an increase in gas due to the fermentation of undigested carbohydrate in the bowel.
It can also cause hypoglycaemia. If it does, you should take glucose not sucrose - acarbose delays the effect of sucrose.
Gliptins
Sitagliptin and vildagliptin cause less hypoglycaemia than sulphonylureas and do not cause weight gain.
Exenatide
With exenatide (Byetta) the main side-effect is nausea and vomiting.
These side-effects can be limited by starting with a small dose for four weeks and then building up to a maximum dose at about one month.
There has been a warning that exenatide can rarely cause acute pancreatitis, a serious inflammatory condition of the pancreas and therefore the diabetic patient should be warned to stop the drug at the first sign of severe abdominal pain.
What can I do to help myself?
Oral medicines are not a substitute for healthy eating and more exercise - which you should continue to do while on treatment.
Learn to monitor either your blood sugar or urine glucose so you can see how effective a medicine is and make alterations to your diet and lifestyle if necessary.
Check with your doctor or pharmacist before taking other medicines in combination with tablets for diabetes – some medicines can affect the action of diabetes tablets, particularly the sulphonylureas.
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References
Holm P, Mant J, Diaz J, Turner C on behalf of the Guidelines Development Group. management of type 2 diabetes: summary of updated NICE Guidance. British Medical Journal 2008; 336: 1306-08.
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Based on a text by Helen Marshall, pharmacist
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Last updated 26.09.2008
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