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Targeting SGLT2 — a new prescribing option for patients with type 2 diabetes

Gareth Malson reports on dapagliflozin and its potential in diabetes treatment

By Gareth Malson

Who it is for

Historically, glucosuria has been a warning sign for patients with diabetes — a suggestion that blood glucose levels are higher than they should be. Now, a new treatment for type 2 diabetes is turning that logic on its head.

Inhibition of the sodium-glucose co-transporter 2 (SGLT2) — the latest target for an ever-expanding armoury of type 2 diabetes medicines — causes glucosuria, and dapagliflozin (Forxiga; Bristol-Myers-Squibb/Astra Zeneca) is the first inhibitor of this kind to reach the UK.

Endocrinologists will have welcomed the arrival of a new therapeutic option. “Type 2 diabetes is a big issue,” says Clifford Bailey, professor of clinical science and head of diabetes research at Aston University, Birmingham. “At the current count, it affects 5 per cent of adults and accounts for 10 per cent of all direct healthcare costs. The disease can emerge in many ways — impaired insulin secretion, impaired insulin action or inappropriate suppression of glucagon. Due to these many manifestations, clinicians need different approaches to tackle the disease — the more the better.”

Forxiga is licensed for monotherapy and combination therapy.

How it works

“Dapagliflozin inhibits the reuptake of glucose from the proximal tubule of the kidneys,” Professor Bailey explains. “This enables the elimination of excess glucose — via a mechanism that is completely independent of insulin.”

This mechanism has additional bonuses. “It’s possible to eliminate 70–80g of glucose per day. This equates to around 300 calories — meaning the drug can cause weight loss. It also, through an osmotic diuresis effect, generates a mild reduction in blood pressure — around 3–4mmHg.”

Owing to its selectivity for the SGLT2 receptor, dapagliflozin can also avoid the risk of hypoglycaemia: “As glucose drops towards normal with this agent, SGLT1, which is not blocked by dapagliflozin, acts as a safety mechanism for preventing ‘hypos’,” Professor Bailey explains. SGLT1 is also responsible for the uptake of glucose in the intestine — so specificity for SGLT2 is beneficial.

However, the summary of product characteristics notes that hypoglycaemia is “very common” if taken with a sulfonylurea or insulin.

Research

A summary of the key phase III clinical trials has been produced by the Regional Drug & Therapeutics Centre.1 It confirms that dapagliflozin generated a significantly greater reduction in HbA1c when compared with placebo in patients taking metformin or insulin and with placebo alone.

It also concludes that the drug has been “shown to be non-inferior to metformin alone, as well as giving a significantly greater reduction in weight, in treatment-naive patients.”

The centre warns, however, that HbA1c  is a surrogate outcome, not a patient-orientated outcome. Consequently, it concludes: “While the differences in HbA1c  reported with dapagliflozin were statistically significant, their clinical significance is unclear.”

Victoria Ruszala, lead pharmacist for diabetes at North Bristol NHS Trust, is also concerned that the drug’s long-term safety is not yet assured, due to a lack of long-term clinical studies. “The extension trials were 78 weeks on top of the standard 24-week trial,” she highlights, “so the longest duration of trial data we have is 102 weeks. That’s not long for patients with diabetes.”

Administration

The standard dose for dapagliflozin is 10mg once daily — taken orally at any time of day, before or after food. A 5mg tablet is available but this is only recommended for patients with severe hepatic impairment.

The drug is not recommended for patients with moderate-to-severe renal impairment (a creatinine clearance below 60ml/min).

Safety

In clinical trials, patients taking dapagliflozin have shown an increased tendency to develop urinary tract infections and genital thrush. This is probably not surprising, given that their urine will have a high sugar content.

“There is a need for extra cleanliness generally,” Professor Bailey confirms for those prescribed the drug. “If an infection does develop, trial patients responded to standard treatment.”

Mrs Ruszala, however, points out: “During trials these infections did respond to standard treatment. However, we don’t know whether, long term, resistance will develop among the infecting organisms. The trials so far have not been long enough to provide that assurance.”

Cost

Both strengths of dapagliflozin cost £36.59 for a 28-day supply — comparable to that for dipeptidyl peptidase 4 (DPP-4) inhibitors.

For comparison, equivalent supplies of selected treatments for type 2 diabetes, according to the electronic Drug Tariff (accessed in May 2013), are as follows:

•    Gliclazide 80mg bd — £2.12
•    Pioglitazone 30mg od — £3.88
•    Linagliptin 5mg od — £33.26
•    Sitagliptin 100mg od — £33.36
•    Vildagliptin 50mg bd — £31.76
•    Saxagliptin 5mg od — £31.60
•    Exenatide 10µg bd — £68.24

Place in therapy

“Because its action is independent of insulin, dapagliflozin can be used at any stage of the disease — provided the patient has adequate renal function,” Professor Bailey believes. “The kidneys aren’t damaged by the drug — but they need to be functioning in order to clear the glucose in the first place.

“Dapagliflozin is a similar price to DPP-4 inhibitors, offers the added benefits of potential weight loss and blood pressure control, and has a long duration of action. It is also very easy to test patients for compliance to treatment using a urine dipstick (if an SGLT2 inhibitor was in use, the urine glucose should be off the top of the scale). The drug should be available on formularies for clinicians to prescribe and will be of particular benefit to patients who are overweight.”

Mrs Ruszala’s opinion on dapagliflozin is more reserved. “The manufacturer appears to be marketing the drug as a second-line agent, which would mean it is competing with sulfonylureas,” says Mrs Ruszala. “This makes sense as the drug requires good renal function; if you wait until third line, your patients’ kidneys may have deteriorated too much to be able to use it. However, using dapagliflozin second line would go against current National Institute for Health and Care Excellence guidance.

“Realistically, I can only see it being used in the small subgroup of patients that cannot have a sulfonylurea. As an alternative second-line agent, DPP-4 inhibitors have more experience in practice and the same benefits.

“Dapagliflozin does allow individualisation of treatment so it could be considered by formulary committees. However, with a NICE technology appraisal available shortly, many committees may well wait until then — at which point the decision may be taken out of their hands.”

NICE’s decision is due to be published this month. The Scottish Medicines Consortium has restricted use of the drug to patients who do not achieve adequate glycaemic control with metformin and for whom a sulfonylurea is inappropriate.

 

Key points

•    Dapagliflozin is an SGLT2 (sodium-glucose co-transporter 2) inhibitor, which means it blocks the reuptake of glucose and promotes glucose excretion in urine.

•    Added potential benefits of dapagliflozin are weight loss and a mild reduction in blood pressure but common side effects include genital thrush and urinary tract infections.

•    The normal dose is 10mg daily.

•    Forxiga is licensed for mono- and combination therapy but in practice prescribing may be restricted to patients who cannot use sulfonylureas.

 

DISCLOSURE Professor Bailey has received research support from and attended advisory board meetings for Astra Zeneca.

Reference

1    Regional Drug & Therapeutics Centre. New Drug Evaluation no 121: Dapagliflozin. December 2012. Available at: www.nelm.nhs.uk (accessed 21 May 2013).

 

The author

Gareth Malsonis a pharmacist and freelance writer.

 

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11121765

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Supplementary images

  • Excretion of glucose in urine is the result of inhibiting SGLT2 co-transporters (Robert Byron/Dreamstime.com)

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