Ertugliflozin as monotherapy or with metformin for treating type 2 diabetes

Evidence-based recommendations on ertugliflozin (Steglatro) as monotherapy or with metformin for treating type 2 diabetes in adults.

# Recommendations
Ertugliflozin as monotherapy is recommended as an option for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if:
a dipeptidyl peptidase 4 (DPP4) inhibitor would otherwise be prescribed and
a sulfonylurea or pioglitazone is not appropriate.
Ertugliflozin in a dual-therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if:
a sulfonylurea is contraindicated or not tolerated or
the person is at significant risk of hypoglycaemia or its consequences.
If patients and their clinicians consider ertugliflozin to be 1 of a range of suitable treatments including canagliflozin, dapagliflozin and empagliflozin, the least expensive should be chosen.
These recommendations are not intended to affect treatment with ertugliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Canagliflozin, dapagliflozin and empagliflozin are options for treating type 2 diabetes in adults. They are taken with metformin or on their own (that is, as monotherapy) if metformin is not appropriate. They are sodium-glucose cotransporter 2 (SGLT2) inhibitors, as is ertugliflozin.
Indirect comparisons show that ertugliflozin has similar overall health benefits to canagliflozin, dapagliflozin and empagliflozin. The acquisition cost of ertugliflozin is lower than the acquisition costs of these other drugs. Ertugliflozin is therefore recommended as an option for treating type 2 diabetes as monotherapy or with metformin in line with the previous recommendations for SGLT2 inhibitors.# Information about ertugliflozin
Marketing authorisation
Ertugliflozin (Steglatro, Merck Sharp & Dohme) is indicated 'in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications
in addition to other medicinal products for the treatment of diabetes'.
Dosage in the marketing authorisation
'The recommended starting dose of ertugliflozin is 5 mg once daily. In patients tolerating ertugliflozin 5 mg once daily, the dose can be increased to 15 mg once daily if additional glycaemic control is needed.'
Price
mg (28 tablets) or 15 mg (28 tablets): 29.40 per pack (excluding VAT; company submission). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.

# Comparators

## Canagliflozin, dapagliflozin or empagliflozin are appropriate comparators
Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. NICE has already produced technology appraisal guidance on 3 other SGLT2 inhibitors for treating type 2 diabetes (canagliflozin, dapagliflozin and empagliflozin). These treatments are recommended:
as monotherapy when metformin is contraindicated or not tolerated, diet and exercise alone do not provide adequate glycaemic control, a dipeptidyl peptidase 4 (DPP4) inhibitor would otherwise be prescribed, and a sulfonylurea or pioglitazone is not appropriate
with metformin (dual therapy) when a sulfonylurea is contraindicated or not tolerated, or the person is at significant risk of hypoglycaemia or its consequences.The company presented a cost-comparison case in which it proposed that:
the overall health benefits associated with ertugliflozin are similar to or greater than those associated with canagliflozin, dapagliflozin and empagliflozin for monotherapy and dual therapy
the acquisition cost of ertugliflozin is similar to or lower than the costs associated with canagliflozin, dapagliflozin and empagliflozin.The committee understood that canagliflozin, dapagliflozin and empagliflozin are standard treatments for type 2 diabetes in the NHS. It concluded that canagliflozin, dapagliflozin and empagliflozin are appropriate comparators for this appraisal.

# Clinical effectiveness

## Ertugliflozin monotherapy is clinically effective compared with placebo
The company presented the results of the VERTISMONO trial. This compared ertugliflozin monotherapy at the licensed dosages (5 mg and 15 mg) against placebo in 461 people aged 18 years or older with inadequate glycaemic control (defined as HbA1c 7.0% to 10.5% ) despite diet and exercise. The primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week 26). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo in the full analysis set, which included all randomised patients who took at least 1 dose of study medication and had at least 1 measurement of the outcome variable (at baseline or after baseline). The results for secondary outcomes (percentage of patients with HbA1c less than 7%  at week 26, and changes in body weight and systolic and diastolic blood pressure from baseline to week 26) were favourable for both doses, although not all findings were statistically significant. The committee concluded that ertugliflozin monotherapy is a clinically effective treatment compared with placebo.

## Ertugliflozin in a dual-therapy regimen with metformin is clinically effective compared with placebo
The company presented the results of 2 clinical trials that provided evidence on the efficacy of ertugliflozin as dual therapy with metformin:
VERTISMET, which compared ertugliflozin 5 mg and 15 mg with placebo in 621 people aged 18 years or older with inadequate glycaemic control (defined as HbA1c 7.0% to 10.5% ) despite diet and exercise.
VERTISFACTORIAL, which was a 5arm study of 1,232 people aged 18 years or older with inadequate glycaemic control (defined as HbA1c 7.5% to 11.0% ). The study had 2 arms with ertugliflozin in dual therapy, and 3 arms that looked at its use in combination with 2 other glucose-lowering medicinal products (triple therapy). Only the evidence from the dual-therapy arms was considered relevant by the company and presented in the submission.In both studies, the primary outcome was change in HbA1c (measured as change in least-squared means from baseline to week 26). Both doses of ertugliflozin showed a statistically significant improvement compared with placebo for all outcomes in VERTISMET. The results for VERTISFACTORIAL showed that patients having ertugliflozin had lower mean HbA1c, body weight and blood pressure at week 26 compared with baseline. The committee concluded that ertugliflozin with metformin is a clinically effective treatment compared with placebo.

## Ertugliflozin has similar clinical effectiveness to canagliflozin, dapagliflozin and empagliflozin in both monotherapy and dual therapy
The company presented 2 network meta-analyses (NMAs) comparing the clinical effectiveness of ertugliflozin as monotherapy and dual therapy against canagliflozin, dapagliflozin and empagliflozin (all outcomes were assessed at 24 to 26 weeks). The NMAs included the pivotal trials for ertugliflozin (VERTISMONO, VERTISMET and VERTISFACTORIAL). The results showed that ertugliflozin, canagliflozin, dapagliflozin and empagliflozin had similar efficacy and safety. The trials included in the NMAs were generally the same as the trials that were assessed for the previous NICE technology appraisals of canagliflozin, dapagliflozin and empagliflozin. The ERG commented that differences between the studies included in the company's NMAs and the NMAs in the previous appraisals were either well-justified by the company or had little impact on the overall results of the analyses. However, the ERG also took the view that it was unnecessary, under the fast track appraisal cost-comparison process, for the company to have conducted the NMAs at all because they only needed to show that ertugliflozin has similar health benefits compared with 1 previously recommended product. In its own analysis, the ERG compared the results from each of the placebo-controlled trials for ertugliflozin against the results of another well-matched study; VERTISMONO was compared with the CANTATAM trial of canagliflozin by Stenlof et al. 2013 and VERTISMET was compared with a dapagliflozin trial by Bailey et al. 2010. The ERG did not do any statistical analysis but presented the results of the selected trials alongside the results of the VERTIS studies for the committee to compare visually. The ERG's interpretation of its additional analysis aligned with the company's conclusion that ertugliflozin and its comparators have similar efficacy and safety. The committee concluded that the clinical effectiveness of ertugliflozin, both as monotherapy and in dual therapy, is likely to be similar to that of the comparator treatments.

## Adverse events with ertugliflozin are likely to be similar to those with canagliflozin, dapagliflozin and empagliflozin in monotherapy and dual therapy
The company's NMAs showed no statistically significant differences in adverse-event rates between ertugliflozin and its comparators (canagliflozin, dapagliflozin and empagliflozin). The committee noted that women taking ertugliflozin monotherapy (5 mg and 15 mg) in VERTISMONO had a statistically significantly higher rate of genital mycotic infections than women in the placebo group. Similarly, women taking the 15mg dose in VERTISMET had a statistically significantly higher rate of genital mycotic infections than women in the placebo group. However, the committee noted the ERG's comment that the event rate observed in VERTISMONO seemed high compared with the rates observed in other ertugliflozin trials, and it considered this to be reassuring. The committee concluded that the adverse events associated with ertugliflozin are likely to be similar to those for canagliflozin, dapagliflozin or empagliflozin.

# Resource use

## It is appropriate to assume that all resource use and costs, other than drug acquisition costs, are identical for ertugliflozin and its comparators
The company assumed that, apart from direct drug acquisition costs, resource use and costs would be identical for ertugliflozin and its comparators. These costs included starting and administering treatment, treatment monitoring, managing adverse events and long-term disease management. The committee agreed with this assumption.

# Cost-comparison results

## Ertugliflozin meets the criteria for recommendation on the basis of similar health benefits and similar or lower cost
The company presented the results of a cost-comparison analysis for 1 year of treatment. It showed that, at list price, the acquisition cost of ertugliflozin is lower than that of canagliflozin, dapagliflozin and empagliflozin. The committee concluded that ertugliflozin, both as monotherapy and in dual therapy, meets the criteria for recommendation on the basis of a cost comparison, because:
the overall health benefits are similar to those of its comparators
the acquisition costs are similar to or lower than those of its comparators.Ertugliflozin is therefore recommended as monotherapy or dual therapy with metformin, as an option for treating type 2 diabetes in adults.