From 1 April 2015 dapagliflozin will be the first sodium–glucose co-transporter-2 (SGLT2) inhibitor to be PBS listed for type 2 diabetes add-on treatment in dual combination with insulin.1
Dapagliflozin is already PBS listed for dual combination therapy with metformin or a sulfonylurea, in patients with inadequate glycaemic control despite monotherapy with metformin or a sulfonylurea (see separate In Brief item in this issue on SGLT2 inhibitor listings).2
When to consider prescribing
Australian guidelines recommend an SGLT2 inhibitor for third-line therapy add-on treatment when blood glucose targets are not reached after 6 months of treatment with current therapies at the maximum tolerated doses.3
Patients are eligible for PBS-subsidised add-on dual combination of dapagliflozin with insulin when inadequate glycaemic control has been shown despite treatment with:1
- a combination of insulin and oral antidiabetic medicines, or
- insulin alone, when metformin is contraindicated.
While it is important to weigh up the benefits and risks of diabetes therapies based on individual patient needs, be aware that SGLT2 inhibitors are new and, as with all new medicines, long-term safety is unknown.3, 4
SGLT2 inhibitors have also not yet been shown to reduce the risk of macrovascular disease, diabetes-related complications or mortality.3, 4 Trials designed to confirm the long-term impact of SGLT2 inhibitors on cardiovascular outcomes are in progress.5, 6
Add-on dapagliflozin improves glycaemic control for patients with mild or no kidney disease
A 48-week randomised controlled trial assessed the effect of dapagliflozin add-on therapy in more than 800 patients inadequately controlled on basal and/or bolus insulin, with or without oral antidiabetic treatment. These patients had mild or no kidney disease, with eGFR > 70 mL/min.7
The primary outcome was mean HbA1c reduction from baseline at 24 weeks. HbA1c was significantly reduced by 0.96% in the dapagliflozin 10 mg/day group compared with 0.39% in the placebo group.7
A follow-up study at 104 weeks found dapagliflozin 10 mg/day improved glycaemic control, with mean HbA1c reduction from baseline of 0.78% compared with 0.43% in the placebo group.8
Avoid dapagliflozin in patients with eGFR < 60 mL/min
Efficacy of dapagliflozin depends on glomerular filtration of glucose.9
Dapagliflozin 10 mg/day did not improve glycaemic control in 252 patients with moderate renal impairment (eGFR 30–59 mL/min) in a 24-week RCT of patients inadequately controlled on oral antidiabetics or insulin.9 HbA1c reduction from baseline was 0.44% and not significantly different compared with placebo at 0.32%.9
Check kidney function
There is limited experience with dapagliflozin in patients with eGFR < 30 mL/min or with end-stage kidney disease; however, it is not expected to be effective based on the mechanism of action and results from patients with moderate renal impairment.9, 10
Reduced renal function is common in older people, who are also concurrently at risk of volume depletion exacerbated by other medicines such as loop diuretics.10 Dapagliflozin is not recommended for these patients due to the additional volume-depletion property of diuretics.10
Assess kidney function:
- before starting dapagliflozin and at least annually thereafter
- when starting other medicines known to reduce kidney function, and periodically thereafter
- at least 2–4 times a year in patients whose kidney function approaches eGFR < 60 mL/min.10
May be suitable in patients with longstanding diabetes treated with insulin
Beta-cell failure usually progresses in patients with hyperglycaemia, and an increase in daily insulin dose is often required.8, 11 Increasing insulin doses may result in further weight gain and hypoglycaemic events.12
SGLT2 inhibitors may be used in patients with advanced beta-cell failure, as they do not rely on insulin secretion or action to achieve glycaemic control,10 and when added to insulin have been shown to:
- reduce insulin requirements: studies have shown adding dapagliflozin (with oral background therapy with metformin and/or a glitazone) in combination with insulin improves glycaemic control at a reduced insulin dose (50% lower),13 and stabilises the insulin dose over 104 weeks of treatment8
- result in weight loss: when dapagliflozin 10 mg/day was added to insulin (with or without oral background therapy) a significant baseline-adjusted mean reduction in total body weight of 1.6 kg was shown at 24 weeks compared with an increase of 0.43 kg for placebo
added to insulin.
At 104 weeks the baseline-adjusted mean reduction in total body weight was 1.5 kg in the dapagliflozin 10 mg group compared with an increase of 1.8 kg for placebo added to insulin.8
- cause no increased incidence of hypoglycaemic episodes: the proportions of patients with at least one hypoglycaemic event were balanced across treatment groups seen after 104 weeks of treatment with dapagliflozin add-on therapy.8
Based on these studies, as long as kidney function is adequate, it may be appropriate to consider dapagliflozin add-on treatment for patients with longstanding diabetes treated with insulin.
To reduce the risk of hypoglycaemia, use a lower dose of insulin or an insulin secretagogue when adding dapagliflozin.10
Long-term safety still unknown
When choosing add-on therapy, consider that the long-term effects of this drug class are not yet known.3, 4
Given the mechanism of action of SGLT2 inhibitors, adverse effects such as genital infections and UTIs , volume depletion, kidney safety and hypoglycaemia have been a focus of safety and tolerability in clinical trials.7, 8
In the 104-week follow-up trial evaluating add-on therapy with dapagliflozin to insulin the main safety concerns related to:
- genital infection and UTIs: incidence for suggested genital infection and UTIs with dapagliflozin 10 mg were 14.3% and 13.8%, respectively, and 3% and 5.6%, respectively, in the placebo group.8
While most were single episodes that occurred in the first 24 weeks and responded to routine management, five people discontinued the study for this reason 8
- certain types of cancer: overall cancer was uncommon and the same rates were seen in the treatment and placebo groups.8 However, there were three cases of bladder cancer, three cases of breast cancer and one case
of prostate cancer in the dapagliflozin groups, and no forms of these cancers in the placebo group.
While these are not significant increases, a causal relationship cannot be ruled out and further investigation in postmarketing surveillance is being undertaken. 8
For further information
For more information on the use of SGLT2 inhibitors for the treatment of type 2 diabetes refer to the full NPS RADAR review dapagliflozin and canagliflozin (published December 2013).
- Australian Government Department of Health. Pharmaceutical Benefits Schedule. Summary of Pharmaceutical Benefits. Summary of Changes, Effective 1 April 2015 (accessed 12\u00a0March 2015).
- Australian Government Department of Health. Pharmaceutical Benefits Scheme. 2015. [PBS] (accessed 3 February 2015).
- The Royal Australian College of General Practitioners. General Practice Management of Type 2 Diabetes. 2014-2015. [RACGP (online PDF)] (accessed 3 December 2014).
- UpToDate. Management of persistent hyperglycemia in type 2 diabetes mellitus. 2015. [UpToDate] (accessed 28 January 2015).
- ClinicalTrials.gov U.S.National Institutes of Health. CANVAS \u2013 CANagliflozin cardioVascular Assessment Study. 2012. [ClinicalTrials.gov] (accessed 16 February 2015).
- ClinicalTrials.gov U.S. National Institutes of Health. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). 2012. [ClinicalTrials.gov] (accessed 16 February 2015).
- Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012;156:405\u201315. [PubMed]
- Wilding JP, Woo V, Rohwedder K, et al. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab 2014;16:124\u201336. [PubMed]
- Kohan DE, Fioretto P, Tang W, et al. Kohan DE, Fioretto P. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85:962\u201371. [PubMed]
- AstraZeneca Pty Ltd. Forxiga Product Information. April 2014. [TGA] (accessed 22 January 2015).
- Prentki M and Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006;116:1802-12. [PubMed] .
- Russell-Jones D, Khan R. Insulin-associated weight gain in diabetes \u2013 causes, effects and coping strategies. Diabetes Obes Metab 2007;9:799\u2013812. [PubMed]
- Wilding JP, Norwood P, T'Joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 2009;32:1656\u201362. [PubMed]