Antihyperglycaemic agents used for type 2 diabetes

See also the separate Management of Type 2 Diabetes article.

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 people with type 1 diabetes.¹

Blood glucose-lowering therapy²

HbA1c measurement

In adults with type 2 diabetes, measure HbA1c levels at:

• 3- to 6-monthly intervals (tailored to individual needs), until the HbA1c is stable on unchanging therapy

• 6-monthly intervals once the HbA1c level and blood glucose-lowering therapy are stable.

If HbA1c monitoring is invalid because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose control using one of the following:

• Quality-controlled plasma glucose profiles.

• Total glycated haemoglobin estimation (if abnormal haemoglobins).

• Fructosamine estimation.

HbA1c targets

For adults with type 2 diabetes managed either by lifestyle and diet, or by lifestyle and diet combined with a single drug not associated with hypoglycaemia, support the person to aim for an HbA1c level of 48 mmol/mol (6.5%). For adults on a drug associated with hypoglycaemia, support the person to aim for an HbA1c level of 53 mmol/mol (7.0%).

In adults with type 2 diabetes, if HbA1c levels are not adequately controlled by a single drug and rise to 58 mmol/mol (7.5%) or higher: reinforce advice about diet, lifestyle and adherence to drug treatment, support the person to aim for an HbA1c level of 53 mmol/mol (7.0%) and intensify drug treatment.

Consider relaxing the target HbA1c level on a case-by-case basis, with particular consideration for people who are older or frail, for adults with type 2 diabetes:

• Who are unlikely to achieve longer-term risk-reduction benefits - for example, people with a reduced life expectancy.

• For whom tight blood glucose control poses a high risk of the consequences of hypoglycaemia - for example:

  • People who are at risk of falling.

  • People who have impaired awareness of hypoglycaemia.

  • People who drive or operate machinery as part of their job.

• For whom intensive management would not necessarily be appropriate - for example, people with significant comorbidities.

If adults with type 2 diabetes achieve an HbA1c level that is lower than their target and they are not experiencing hypoglycaemia, encourage them to maintain it. Be aware that there are other possible reasons for a low HbA1c level - for example, deteriorating renal function or sudden weight loss.

Rescue therapy at any phase of treatment

If an adult with type 2 diabetes is symptomatically hyperglycaemic, consider insulin or a sulfonylurea and review treatment when blood glucose control has been achieved.

First-line drug treatment

Offer standard-release metformin as the initial drug treatment for adults with type 2 diabetes. Gradually increase the dose over several weeks to minimise the risk of gastrointestinal side-effects. If an adult with type 2 diabetes experiences gastrointestinal side-effects with standard-release metformin, consider a trial of modified-release metformin.

In adults with type 2 diabetes, review the dose of metformin if the eGFR is below 45 ml/minute/1.73 m². Stop metformin if the eGFR is below 30 ml/minute/1.73 m². Prescribe metformin with caution for those at risk of a sudden deterioration in kidney function and those at risk of eGFR falling below 45 ml/minute/1.73 m².

In adults with type 2 diabetes, if metformin is contra-indicated or not tolerated, assess the cardiovascular risk using a recognised risk scoring system such as QRISK®3.

Based on the cardiovascular risk assessment for the person with type 2 diabetes:

• If they have chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin. If they are at high risk of developing cardiovascular disease, consider an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin.When starting an adult with type 2 diabetes on dual therapy with metformin and an SGLT2 inhibitor as first-line therapy, introduce the drugs sequentially, starting with metformin and checking tolerability. Start the SGLT2 inhibitor as soon as metformin tolerability is confirmed.

• For first-line drug treatment in adults with type 2 diabetes, if metformin is contra-indicated or not tolerated and if they do not have chronic heart failure, or established atherosclerotic cardiovascular disease or are at high risk for developing cardiovascular disease, consider:

  • A DPP‑4 inhibitor; or

  • Pioglitazone; or

  • A sulfonylurea; or

  • An SGLT2 inhibitor for people who meet the criteria in the National Institute for Health and Care Excellence (NICE's) technology appraisal guidance on canagliflozin, dapagliflozin and empagliflozin as monotherapies or ertugliflozin as monotherapy or with metformin for treating type 2 diabetes.³

• Before starting an SGLT2 inhibitor, check whether the person may be at increased risk of diabetic ketoacidosis (DKA) - for example if:

  • They have had a previous episode of DKA.

  • They are unwell with intercurrent illness.

  • They are following a very low-carbohydrate or ketogenic diet.

Further intervention

Introduce drugs used in combination therapy in a stepwise manner, checking for tolerability and effectiveness of each drug.

For adults with type 2 diabetes, if monotherapy has not continued to control HbA1c to below the person's individually agreed threshold for further intervention, consider adding:

• A DPP‑4 inhibitor; or

• Pioglitazone; or

• A sulfonylurea; or

• An SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin in combination therapy, ertugliflozin as monotherapy or with metformin, or dapagliflozin or empagliflozin in combination therapy.³

For adults with type 2 diabetes, if dual therapy with metformin and another oral drug has not continued to control HbA1c to below the person's individually agreed threshold for further intervention consider either:

• Triple therapy by adding a DPP‑4 inhibitor, pioglitazone or a sulfonylurea or an SGLT2 inhibitor for people who meet the criteria in NICE's technology appraisal guidance on canagliflozin in combination therapy, dapagliflozin in triple therapy, empagliflozin in combination therapy, or ertugliflozin with metformin and a dipeptidyl peptidase-4 inhibitor;³ or

• Starting insulin-based treatment (see the section on insulin-based treatments).

See the separate article on Insulin Regimens for further information.

If triple therapy with metformin and two other oral drugs is not effective, is not tolerated or is contra-indicated, consider triple therapy by switching one drug for a GLP‑1 mimetic for adults with type 2 diabetes who:

• Have a body mass index (BMI) of 35 kg/m² or higher (adjust accordingly for people from Black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity; or

• Have a BMI lower than 35 kg/m²; and:

  • For whom insulin therapy would have significant occupational implications; or

  • Weight loss would benefit other significant obesity-related comorbidities.

• Only continue GLP‑1 mimetic therapy if the adult with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and weight loss of at least 3% of initial body weight in sixmonths).

• For adults with type 2 diabetes, only offer combination therapy with a GLP‑1 mimetic and insulin along with specialist care advice and ongoing support from a consultant-led multidisciplinary team.

• Dipeptidylpeptidase-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin)