See also separate article Management of Type 2 Diabetes
Oral hypoglycaemic agents are the group of drugs that may be taken singly or in combination to lower the blood glucose in type 2 diabetes. Type 2 diabetes can be due to increased peripheral resistance to insulin or to reduced secretion of insulin. They should be used together with changes in diet and lifestyle to achieve good glycaemic control, and it is customary to monitor such changes for three months before considering medication.
Oral hypoglycaemic agents are not usually used in type 1 diabetes, but metformin may be of use in combination with insulin for overweight type 1 diabetics.
Blood glucose-lowering therapy
Setting a target HbA1c
- Involve the person in decisions about their individual HbA1c target level, which may be above the general target of 6.5%.
- Encourage the person to maintain their individual target unless the resulting side effects (including hypoglycaemia) or their efforts to achieve this impair their quality of life.
- Avoid pursuing highly intensive management to levels of less than 6.5%.
- If treatment target is not achieved despite concordance with advice and therapy, proceed to the next step as follows.
Step 1: lifestyle interventions
See also separate article Diabetes Diet and Exercise.
Step 2: metformin
- Titrate the dose; initially 500 mg with breakfast for at least one week. The usual maximum dose is 2 g daily, in divided doses.
- Consider sulfonylurea for step 2 if the person is not overweight, or metformin is not tolerated or is contra-indicated, or a rapid therapeutic response is required because of hyperglycaemic symptoms.
Step 3: metformin plus sulfonylurea
- Consider a rapid-acting insulin secretagogue (nateglinide or repaglinide) for people with erratic lifestyles.
- Consider substituting a dipeptidylpeptidase-4 (DPP-4) inhibitor (sitagliptin or vildagliptin) or a thiazolidinedione (TDZ) for the sulfonylurea if there is a significant risk of hypoglycaemia (or its consequences) or a sulfonylurea is contra-indicated or not tolerated. The National Institute for Health and Clinical Excellence (NICE) has recommended that treatment with sitagliptin or vildagliptin be continued only if HbA1c concentration is reduced by at least 0.5 percentage points within six months of starting treatment.
- If a sulfonylurea has been used in step 2 because metformin is contra-indicated or not tolerated, consider adding a DPP-4 inhibitor or a TDZ.
Step 4: insulin plus metformin plus sulfonylurea
- If HbA1c targets are not achieved despite adequate concordance with step 3, insulin therapy with active dose titration should be considered. See also separate article Insulin Regimens.
- Consider adding sitagliptin or a TDZ instead of insulin if insulin is unacceptable (because of employment, social, recreational or other personal issues, or obesity).
- Consider adding exenatide to metformin and a sulfonylurea if BMI ≥35 kg/m2 in people of European descent and with problems associated with high weight, or BMI <35 kg/m2 and insulin is unacceptable because of occupational implications or weight loss would benefit other comorbidities.
- Treatment with standard-release exenatide should only be continued if HbA1c concentration is reduced by at least 1% and a weight loss of at least 3% is achieved within six months of starting treatment.
- Consider pioglitazone with insulin if a TDZ has previously had a marked glucose-lowering effect, or blood glucose control is inadequate with high-dose insulin.
NICE recommendations regarding the appropriate use of modified-release exenatide and liraglutide
NICE recommends that modified-release exenatide or liraglutide may be used in triple therapy regimens (in combination with metformin and a sulphonylurea, or metformin and a TDZ) only when glycaemic control is inadequate and the patient has:
- A BMI ≥35 kg/m² (in those of European descent, with appropriate adjustment for other ethnic groups) and weight-related psychological or medical problems, or
- A BMI <35 kg/m², and insulin would be unacceptable for occupational reasons, or weight loss would benefit other significant obesity-related comorbidities.
Treatment with modified-release exenatide or liraglutide in a triple therapy regimen should be continued only if HbA1c concentration is reduced by at least 1 percentage point and a weight loss of at least 3% is achieved within six months of starting treatment.
Modified-release exenatide or liraglutide in dual therapy regimens (in combination with metformin or a sulphonylurea) is recommended by NICE only if:
- treatment with metformin or a sulphonylurea is contra-indicated or not tolerated, and
- treatment with TDZs and DPP-4 inhibitors is contra-indicated or not tolerated.
Modified-release exenatide or liraglutide in a dual therapy regimen should be continued only if HbA1c concentration is reduced by at least 1 percentage point within six months of starting treatment.
Metformin is the only drug licensed in this group. The dose of metformin should be stepped up over several weeks to minimise the risk of gastrointestinal side-effects. A trial of extended-absorption metformin may be used if gastrointestinal tolerability prevents the person from continuing with metformin. The dose should be reviewed if serum creatinine rises to above 130 μmol/L or estimated glomerular filtration rate (eGFR) drops to less than 45 ml/minute/1.73 m2. Metformin should be stopped if serum creatinine rises to above 150 μmol/L or the eGFR drops to below 30 ml/minute/1.73 m2.
- Benefits and indications:
- Metformin is the only oral hypoglycaemic shown to reduce macrovascular complications and death.
- It is associated with fewer hypoglycaemic attacks than sulphonylureas and does not cause weight gain.
- It is more effective than sulphonylureas in reducing any diabetes endpoint, all-cause mortality, and stroke. These improvements have not been explained entirely on the basis of glycaemic control.
- There is no evidence that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other antihyperglycemic treatments.
- Gastrointestinal side-effects occur commonly with metformin at higher doses, and may necessitate a change of drug.
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Sulphonylureas are thought to act by enhancing pancreatic islet cell function. They are also thought to act on the liver, stimulating the glycolytic pathway and inhibiting the production of glucose. They generally have a duration of action of 12-24 hours.
- Benefits and indications:
- Sulphonylureas may be used as a first-line drug where oral hypoglycaemic medication is required, particularly in patients who cannot tolerate metformin or in whom it is contra-indicated.
- Newer drugs in this group, such as glipizide and glimipramide, appear to afford similar efficacy as the older drugs such as gliclazide.
- Chlorpropamide is no longer recommended, as it has more side-effects than other members of this group.
- The main risk with sulphonylureas is hypoglycaemia. This is increased in older age groups, mild-to-moderate hepatic impairment, and renal impairment.
- Glibenclamide, a long-acting sulfonylurea, is associated with a greater risk of hypoglycaemia and therefore should be avoided in the elderly, and shorter-acting alternatives, such as gliclazide or tolbutamide, should be used instead.
- Other problems can include weight gain, liver dysfunction and gastrointestinal disturbance.
Rapid-acting insulin secretagogues - postprandial glucose regulators
The two meglitinides licensed for use in the UK are repaglinide and nateglinide. They are relatively short-acting stimulators of insulin secretion (<6 hours). They act by binding to various sites on pancreatic beta cells.
- Benefits and indications:
- Meglitinides are characterised by short duration and rapid onset of action, which requires them to be taken before a main meal.
- Repaglinide may be suitable as monotherapy for non-obese patients in whom metformin is contra-indicated or not tolerated, or in combination with metformin.
- Nateglinide is licensed only for use in combination with metformin.
- Risks: as with the sulfonylureas, the main risk with meglitinides is hypoglycaemia.
Thiazolidinediones (TDZs) or 'glitazones' - pioglitazone is the only one currently licensed in the UK. Its mechanism of action is still subject to debate but is thought to act in a similar manner to metformin, increasing hepatic sensitivity to insulin, and enhancing glucose clearance. Unlike metformin, it appears to have an effect on insulin-mediated glucose uptake at all insulin levels, making it effective in patients with insulin resistance. A TDZ may be preferable to a DPP-4 inhibitor if the patient has marked insulin insensitivity.
- Benefits and indications:
- TDZs are usually used in combination with a sulphonylurea or metformin. It has also been licensed as monotherapy.
- The combination with metformin or a sulphonylurea should only be used in patients unable to tolerate metformin and sulphonylurea in combination therapy, or in whom either metformin or a sulphonylurea is contra-indicated.
- In such cases, the TDZ should replace whichever drug in the combination is poorly tolerated or contra-indicated.
- A TDZ plus metformin is a useful combination for obese patients. The introduction of a TDZ may cause a deterioration of blood glucose control temporarily when used in combination therapy.
- Pioglitazone may be considered with insulin therapy in patients who have previously had a marked glucose-lowering response to TDZ therapy or in those on high-dose insulin therapy and whose blood glucose is inadequately controlled.
Do not commence or continue a TDZ in patients who have heart failure, or who are at higher risk of fracture:
- Cardiovascular: the risk of heart failure is increased when pioglitazone is combined with insulin and in patients with a history of cardiovascular disease. Patients who take pioglitazone should be closely monitored for signs of heart failure, and treatment should be stopped immediately if any deterioration in cardiac status occurs. Pioglitazone should not be used in patients with heart failure or a history of heart failure.
- Risk of bladder cancer: there is a small increased risk of bladder cancer associated with pioglitazone use. Pioglitazone should not be used in patients with active bladder cancer, a past history of bladder cancer or for patients with uninvestigated macroscopic haematuria. .
- There have been rare reports of liver failure, but large-scale trials have shown no difference in incidence between TDZs and other oral hypoglycaemics. Baseline LFTs and periodic monitoring are recommended.
- There is an increased risk of fractures, especially in women.
Only continue with a TDZ if there has been a beneficial metabolic response (HbA1c falling 0.5% in 6 months).
- Acarbose acts by inhibiting intestinal alpha glucosidases, which delays the absorption and digestion of sucrose and starch.
- Acarbose is usually only used when other oral glucose-lowering medications cannot be used.
- The use of acarbose is limited by its gastrointestinal adverse effects but these do decrease with time.
Dipeptidylpeptidase-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin)
- Linagliptin, saxagliptin, sitagliptin, and vildagliptin inhibit dipeptidylpeptidase-4 to increase insulin secretion and lower glucagon secretion.
- Linagliptin is licensed for use in type 2 diabetes as monotherapy (if metformin is inappropriate), or in combination with metformin when metformin alone provides inadequate glucose control), or with both metformin and a sulfonylurea (when additional treatment is required).
- Saxagliptin, sitagliptin, and vildagliptin are licensed for use in combination with metformin, a sulfonylurea (if metformin is inappropriate) or pioglitazone when additional treatment is required.
- Sitagliptin and vildagliptin are licensed for use as monotherapy (if metformin is inappropriate). Sitagliptin is licensed for use in combination with both metformin and a sulfonylurea, or both metformin and pioglitazone when dual therapy with fails to achieve adequate glycaemic control.
- Sitagliptin or saxagliptin in combination with insulin (with or without metformin) is licensed for use when insulin has not provided adequate glycaemic control.
- Benefits and indications:
- They may be appropriate ahead of a TDZ when the latter is contra-indicated, or if further weight gain would cause or exacerbate significant problems associated with a high body weight. In these circumstances, they are considered as a third-line therapy in combination with metformin and sulfonylurea when glycaemic control is still inadequate.
- They can be considered second-line with metformin in patients at particular risk of hypoglycaemia (elderly patients living alone; other patients working at heights or with heavy machinery), or second-line in combination with a sulfonylurea in patients intolerant of metformin.
- Hypersensitivity reactions may occur (anaphylaxis, angioedema and Stevens-Johnson syndrome).
Only continue DPP-4 inhibitor therapy if there has been a beneficial metabolic response (HbA1c falling 0.5% in 6 months).
Glucagon-like peptide-1 mimetics (exenatide and liraglutide)
Exenatide and liraglutide are both given by subcutaneous injection. They activate the glucagon-like peptide-1 (GLP-1) receptor to increase insulin secretion, suppress glucagon secretion, and slow gastric emptying. Treatment is associated with the prevention of weight gain and possibly even with weight loss.
- Benefits and indications:
- It may be a particularly useful step in patients who hold LGV or PCV driving licences, who would lose them if converted to insulin.
- Can cause significant weight loss (rather than gain). Hence, it is most appropriate in patients with BMI ≥35.0 kg/m2.
- May cause significant gastrointestinal disturbance and there are reports of associated severe acute pancreatitis.
- There is an interaction with warfarin (monitor INR carefully).
- The long-term safety is not yet established.
Only continue GLP-1 mimetic treatment if there has been a beneficial response (HbA1c fall of 1% and a weight loss of at least 3% of initial body weight at six months).
Further help & information
Further reading & references
- Management of diabetes, Scottish Intercollegiate Guidelines Network - SIGN (March 2010)
- Khardori R; Type 2 Diabetes Mellitus, Medscape, Sept 2012
- NHS Diabetes website
- Diagnosis and management of type 1 diabetes in children, young people and adults; NICE Clinical Guideline (July 2004)
- Moon RJ, Bascombe LA, Holt RI; The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Diabetes Obes Metab. 2007 Jan;9(1):143-5.
- Type 2 diabetes - newer agents (partial update); NICE Clinical Guideline (May 2009)
- Diabetes (type 2) - exenatide (prolonged release); NICE Technology Appraisal Guideline (February 2012)
- Diabetes (type 2) - liraglutide for the treatment of type 2 diabetes mellitus; NICE Technology Appraisal Guideline (October 2010)
- No authors listed; Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65.
- No authors listed; Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53.
- Salpeter SR, Greyber E, Pasternak GA, et al; Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD002967.
- British National Formulary; 64th Edition (Sep 2012) British Medical Association and Royal Pharmaceutical Society of Great Britain, London (links to current BNF)
- Rajagopalan R, Iyer S, Perez A; Comparison of pioglitazone with other antidiabetic drugs for associated incidence of liver failure: no evidence of increased risk of liver failure with pioglitazone. Diabetes Obes Metab. 2005 Mar;7(2):161-9.
|Original Author: Dr Laurence Knott||Current Version: Dr Colin Tidy||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 16/10/2012||Document ID: 521 Version: 8||© EMIS|
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