Prescribing pearls: A guide to sulfonylureas

What is a sulfonylurea?

Sulfonylureas (SUs), structural variants of the earlier sulfonamide antibacterial drugs found to induce hypoglycaemia, have been used since the 1960s.¹ First-generation SUs (e.g. tolbutamide) have been superseded by more potent second-generation SUs (e.g. gliclazide, glipizide and glimepiride).

Historically, SUs have been common add-on therapy to metformin, owing to effectiveness and low cost.² Although practice now favours earlier use of newer agents shown to have cardiorenal benefits, SUs are still used extensively across the UK, despite causing weight gain and hypoglycaemia.³

Mechanisms of action

SUs act directly on the beta-cells of the islets of Langerhans to stimulate insulin secretion, stimulating insulin release even when glucose concentrations are below the normal threshold for insulin release (<5 mmol/L), which is why they can cause hypoglycaemia.⁴ The insulin release also leads to insulin-induced suppression of hepatic glucose production.⁵

SUs vary in their pharmacokinetic properties; consider duration of action when individualising treatment.

Indications

• First-line treatment as “rescue therapy” for patients with symptomatic hyperglycaemia; review once better glycaemic control achieved.

• First-line treatment in steroid-induced diabetes.³

• Add-on therapy in type 2 diabetes.

• First-line treatment of HNF1-alpha MODY (maturity-onset diabetes of the young).⁶

Positioning in guidelines

In NICE’s guideline on the management of type 2 diabetes in adults (NG28), SUs may be used first-line for rescue therapy in symptomatic hyperglycaemia, or if low cardiovascular risk and metformin intolerance/contraindication.⁷ They are also recommended as the first line for steroid-induced diabetes.⁸

Otherwise, SUs are a third-line option alongside DPP-4 inhibitors and pioglitazone. Drug choice should be based on patient preferences; the individual’s clinical, social and occupational circumstances; safety; and, where possible, cost (in terms of person outcomes and NHS costs).⁷

Glycaemic effects

SUs reduce fasting glucose by 2–4 mmol/L, decreasing HbA_1c by 11–22 mmol/mol when added to lifestyle measures.⁹

The glucose-lowering effect is immediate, provided there are functioning beta-cells. Beta-cell mass in type 2 diabetes declines over time, so the dose may need to be increased and, in a proportion of people, there may be more rapid progression to “treatment failure”.⁹

Adverse effects

Weight gain

The anabolic effects of increased insulin production and reduced glucose excretion can lead to 1–4 kg weight gain, with stabilisation at around 6 months.⁹

However, in the ADVANCE study, minimal weight gain was seen with gliclazide modified-release (MR) over a 5-year period.¹⁰

Hypoglycaemia

Due to the increased risk of hypoglycaemia, glucose monitoring is recommended. Hypoglycaemia occurs annually in ~20% of people treated with SUs⁸ and severe hypoglycaemia in ~1%. This can be life-threatening. This may not be caused directly by the SU, but may be a marker of severity of comorbidity.^10,11 The risk of hypoglycaemia increases with age, severity of comorbidity, in people with high cardiovascular risk or established CVD, and in people with significantly impaired renal function (stage 3 CKD or above).¹² Use a shorter-acting SU at a lower dose, or avoid SU use.

SU-induced hypoglycaemia may need to be treated in hospital owing to the recurrence of hypoglycaemia, particularly for the longer-acting SUs. Glucagon in type 2 diabetes can be less effective, as it is an insulin secretagogue itself.

Sensitivity reactions and rarer side-effects

Transient cutaneous rashes and, rarely, erythema multiforme, fevers, jaundice, acute porphyria, photosensitivity and blood dyscrasias.

Contraindications

• All SUs contraindicated in those with a history of ketoacidosis or severe hepatic impairment.

• Avoid gliclazide and tolbutamide in acute porphyria.

Cautions

Use with caution in:

• G6PD deficiency.

• Older people (prescribe lower doses and shorter-acting SUs to avoid prolonged hypoglycaemia).

• Renal or mild/moderate hepatic dysfunction (dose reductions and shorter-acting SUs may be indicated).

• Obesity (these medications contribute to weight gain).

Drug interactions

SUs are hepatically metabolised, highly plasma protein-bound drugs. This can lead to interactions with drugs that inhibit hepatic metabolism (e.g. amiodarone, chloramphenicol, clarithromycin, azole antifungal agents and monoamine oxidase inhibitors), drugs that induce hepatic metabolism (e.g. rifampicin) and other protein-bound drugs (e.g. sulfonamides, warfarin and NSAIDs). Displacement from proteins by competing drugs increases hypoglycaemia risk.

To reduce the risk of hypoglycaemia, reduce doses of SU and insulin initially when adding any other glucose-lowering drugs. Beta-blockers can reduce the warning signs of hypoglycaemia and should be used with caution alongside SUs.¹³

Available sulfonylureas¹⁴

Note: Glibenclamide is not readily available in the UK, but can be imported (some patients stabilised on this for HNF1-alpha MODY may need it).

Duration of action of SUs¹⁵

Initiating and monitoring gliclazide

• Consider the level of risk of hypoglycaemia and its consequences (e.g. age, frailty status, comorbidities including renal impairment, does the person drive (see Resources) or operate machinery as part of their job?

• To reduce risk of hypoglycaemia, start at low dose and titrate up, as indicated below.

• Ensure the person with diabetes and/or carers know what hypoglycaemia is, how to recognise it and how to treat it effectively (see Resources).

• Agree an individual blood glucose (BG) target, with particular attention to the person’s risk of hypoglycaemia (as above).

• Ensure drivers understand the DVLA requirement to test their glucose levels at times relevant to driving and follow DVLA guidance.

Note: Always consult the Summary of Product Characteristics before prescribing any drug. Visit: www.medicines.org.uk/emc

Using gliclazide for steroid-induced hyperglycaemia

If using gliclazide for steroid-related hyperglycaemia, refer to How to diagnose and manage steroid-induced diabetes.

Prescribing tips and special circumstances

Shorter-acting SUs (e.g. gliclazide, glipizide) reduce the risk of prolonged hypoglycaemia, and are generally preferred to longer-acting glimepiride.

Modified-release gliclazide allows for once-daily dosing and may be associated with the lowest risk of hypoglycaemia.¹⁶

Always provide access to home glucose testing and be alert to the risk of hypoglycaemia – if hypoglycaemia is suspected, consider a reduction in dose.

Deprescribing

• Stop gliclazide if “treatment failure” is suspected (see Glycaemic effects).

• If using for rescue therapy, monitor SMBG and decrease gliclazide dose as other medication becomes effective (decrease in same way as titration).

• If using for steroid-related hyperglycaemia, decrease the gliclazide dose if steroid dose decreased (see How to guide).

• Stop gliclazide if eGFR <30 mL/min/1.73 m².

Sulfonylureas and fasting

There is a risk of hypoglycaemia with sulfonylureas any time fasting occurs (e.g. for surgery, investigations or during Ramadan). Less risk of hypoglycaemia if on stable SU dose at least 3 months prior to Ramadan, and with glipizide, glimepiride and gliclazide.^17,18 Take once-daily dose at iftar (sunset); if twice daily, then usual dose at iftar and consider reduced dose at suhoor (sunrise).¹⁹

See our How to series for further guidance:

Surgery  |  Ramadan

Resources

• Diabetes UK:
What is a hypo?

• Fitness to drive:
– How to assess fitness to drive
– Assessing fitness to drive: a guide for medical professionals

Acknowledgement: Pam Brown for her help in the development of this series.