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Dapagliflozin: first SGLT2 inhibitor for type 2

Steve Chaplin BPharm, MSc and John Wilding DM, FRCP

Dapagliflozin (Forxiga) is the KEY POINTS first SGLT2 inhibitor licensed for the treatment of type 2 n dapagliflozin is a reversible inhibitor of sodium- co- transporter 2 (SGLT2), the main transporter for reabsorption of diabetes. In our New prod - glucose in the proximal tubule ucts review, Steve Chaplin n it is licensed to improve glycaemic control in adults with as presents the clinical data monotherapy when is not tolerated and as add-on therapy with glucose-lowering agents (including ) relating to its efficacy and n a month’s treatment at the recommended dose of 10mg once daily costs adverse events, and £36.59 Professor John Wilding dis - n in placebo-controlled clinical trials, dapagliflozin improved glycaemic control and caused weight loss when given as monotherapy or in combination with cusses its potential role in metformin, a or insulin plus oral glucose-lowering agents treatment. n dapagliflozin/metformin is noninferior to /metformin for improving glycaemic control ICE guidance on the treatment of n the risk of hypoglycaemia is low but slightly increased when dapagliflozin is Ntype 2 diabetes with glucose-lowering combined with insulin or a sulfonylurea; in combination with metformin, the therapies recommends, after lifestyle risk is lower than with glipizide/metformin modification, metformin as the agent of n adverse effects include polyuria and genital fungal infection first choice (or a sulfonylurea when appro - priate, or acarbose if other agents not tol - n dapagliflozin offers the benefits of weight loss and lower incidence of hypo- erated). 1 glycaemia when used early in treatment when metformin is not tolerated or as If glycaemic control is not achieved add-on to metformin; added to insulin, it can break the cycle of insulin dose with monotherapy, dual therapy is recom - escalation and weight gain mended with addition of a sulfonylurea if metformin was first line, a DPP-4 inhibitor, formin is not tolerated and as add-on ther - or a rapid-acting insulin sec - apy with glucose-lowering agents (includ - retagogue. ing insulin) when glycaemic control is not adequate. The technology In its final draft guidance, NICE has Dapagliflozin (Forxiga) is a reversible recommended dapagliflozin in dual treat - inhibitor of sodium-glucose co-transporter ment of type 2 diabetes in combination 2 (SGLT2), the main transporter for reab - with metformin and with insulin. It is not sorption of glucose from the glomerular recommended in a triple-therapy regimen filtrate (see Figure 1). It increases renal in combination with metformin and a sul - excretion of glucose to an extent that fonylurea. depends on the blood glucose level and The recommended dose is 10mg glomerular filtration rate. During treat - once daily. The dose of concomitant ment with 10mg per day, this averages insulin or insulin secretagogue may need 70g per day of glucose, equivalent to an to be reduced to lower the risk of hypo - energy loss of 280kcal per day. 2 glycaemia. Dapagliflozin is licensed to improve No dose adjustment is recommended glycaemic control in adults with type 2 for patients with mild renal impairment diabetes when diet and exercise are not but dapagliflozin is contraindicated when sufficient, as monotherapy when met - renal impairment is moderate or severe. prescriber.co.uk Prescriber 19 June 2013 z 13 n NEW PRODUCTS l Dapagliflozin

of 64–69mmol per litre (8–8.5 per cent) Proximal Blood despite current treatment. 10 tubule The primary end-point of the main clinical trials was improvement in gly - Na + caemic control as measured by change in HbA from baseline. After 24 weeks, SGLT2 1c dapagliflozin reduced HbA 1c by about 0.8 per cent in all combinations of other glu - cose-lowering treatments compared with glucose glucose 0.13–0.30 per cent for placebo (see Table 1). 10 The reduction in HbA was Na + 1c dapagliflozin smaller compared to glipizide as add-on to metformin but dapagliflozin was non - SGLT2 inferior. Several trials also reported that dapagliflozin increased the proportion of K+ patients achieving a target HbA 1c of + <53mmol per litre (<7 per cent). 3,5,6 K Na +/K + Extension studies have found a slow pump increase in HbA 1c during prolonged treat - ment, but the efficacy of dapagliflozin in Figure 1. Sodium-glucose co-transporter 2 (SGLT2) is the main transporter for reabsorption combination with metformin and its com - of glucose in the proximal tubule. Dapagliflozin inhibits SGLT2, thereby reducing glucose parability with glipizide are maintained for 5,9 reabsorption and thus HbA one to two years. 1c Dapagliflozin was associated with No dose change is required in mild or link is considered unlikely but as a pre - weight loss of 1–2kg over six months moderate hepatic impairment but the cautionary measure dapagliflozin should regardless of which glucose-lowering starting dose should be 5mg per day in not be prescribed with pioglitazone. 2 drug it was combined with, and greater those with severe hepatic impairment. No weight loss compared with glipizide in dose adjustment is recommended for Clinical trials combination with metformin (see Table older people though experience in the The effect of dapagliflozin on glycaemic 1). 10 These differences are maintained over-75s is limited. control has been compared with placebo after two years’ treatment. 5,7,9 Weight Renal function should be measured as monotherapy 3 and in combination with loss during treatment with dapagliflozin before and at least annually during treat - metformin, 4,5 a sulfonylurea 6 and insulin, 7 is mainly due to a reduction in body fat, ment. Caution is required in patients at and compared with glipizide as add-on not fluid loss. 11 risk of volume depletion or a raised therapy to metformin in a noninferiority haematocrit, and dapagliflozin is not rec - study. 8,9 Adverse effects ommended in those taking a loop These trials lasted for 24–104 weeks The common adverse events reported in diuretic. and included patients with type 2 dia - clinical trials are listed in Table 2. 10 Meta- An excess of cases of bladder cancer betes of five to seven years’ duration who analysis showed no increase in the risk 10 was reported in clinical trials: a causal were in their mid-50s and had an HbA 1c of cardiovascular events.

Per cent HbA 1c change Body weight change (kg) dapagliflozin comparator dapagliflozin comparator differ ence 10mg/day a 10mg/day b

monotherapy vs placebo 3 -0.89 -0.23 -3.16 -2.19 -0.97 metformin vs dapa/metformin 4 -0.84 -0.30 -2.86 -0.89 -1.97 vs dapa/glimepiride 6 -0.82 -0.13 -2.26 -0.72 -1.54 insulin vs dapa/insulin 7c -0.90 -0.30 -1.67 +0.02 -1.69 metformin/glipizide vs metformin/dapa 8 -0.52 -0.52 -3.22 +1.44 -4.65

a all differences in HbA 1c from comparator p<0.0001 except noninferior vs glipizide b all differences in HbA 1c from comparator p<0.0001 cboth +/- oral glucose-lowering agents

10 Table 1. Change in per cent HbA 1c and body weight from baseline in the main clinical trials

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6. Strojek K, et al . Diab Obes Metab 2011; Dapagliflozin (%) Placebo (%) 13:928–38. 7. Rohwedder K, et al . Long-term effectiveness hypoglycaemia 10.2 7.0 of dapagliflozin over 104 weeks in patients genital infection 4.8 0.9 with type 2 diabetes poorly controlled with back pain 4.2 3.2 insulin . European Association for Diabetes polyuria 3.8 1.7 annual meeting, Berlin, 2012. Poster 753. 8. Nauck MA, et al . Diabetes Care 2011; dyslipidaemia 2.5 1.5 34:2015–22. dysuria 2.1 0.7 9. Nauck M, et al . Long term efficacy and safety of add-on dapagliflozin vs add-on glip - Table 2. Common adverse events in clinical trials 1 izide in patients with T2DM inadequately con - The incidence of hypoglycaemic References trolled with metformin 2-year results . events increased with the addition of 1. NICE Pathways. Blood-glucose-lowering ther - American Diabetes Association 71st Scientific dapagliflozin to insulin plus oral glucose- apy for type 2 diabetes. October 2012 Sessions, San Diego, California, June 2011. Poster 40 LB. lowering agents (all: 57 vs 52 per cent with (http://pathways.nice.org.uk/pathways/dia - 10. European Medicines Agency. Forxiga 7 betes#path=view%3A/pathways/diabetes/blo placebo; major: 1.5 vs 1.0 per cent) and European public assessment report . 6 od-glucose-lowering-therapy-for-type-2-dia - to glimepiride (all: 7.9 vs 4.8 per cent). betes.xml&content=view-node%3Anodes-con - September 2012 ( www.ema.europa.eu/ Conversely, the combination of sidering-triple-therapy ; accessed 7.1.13). docs/en_GB/document_library/EPAR_- dapagliflozin/metformin was associated 2. AstraZeneca. Forxiga summary of product _Public_assessment_report/human/002322/ with a lower incidence of hypoglycaemic characteristics . November 2012. WC500136024.pdf ). events than glipizide/metformin (all: 3.4 3. Ferrannini E, et al . Diabetes Care 2010; 11. Bolinder J, et al . J Clin Endocrinol Metab vs 40 per cent; major: 0 vs 0.7 per cent). 8 33:2217–24. 2012;97:1020–31. Genital infections (vulvovaginal 4. Bailey CJ, et al . Lancet 2010;375:2223–33. mycotic infection, vaginal infection and 5. Bailey CJ, et al . Long-term efficacy of Declaration of interests dapagliflozin as add-on to metformin in T2DM None to declare. vulvovaginal pruritus in women; balanitis, inadequately controlled with metformin alone . genital pruritus and fungal infection in American Diabetes Association 71st Scientific men) were rated mild to moderate in Sessions, San Diego, California, 24–28 June Steve Chaplin is a pharmacist who severity in 97 per cent of cases. 10 2011. Poster 988-P. specialises in writing on therapeutics

that addition of dapagliflozin can break intolerant of metformin) or as an add-on Place in therapy this cycle, reducing insulin requirements to metformin, particularly when weight Causing glycosuria to treat diabetes may and stabilising body weight. loss and avoidance of hypoglycaemia are at first seem counterintuitive, but the clin - An additional benefit from the mode important to the patient. ical trial data with the SGLT2 inhibitor of action is reduction in blood pressure There is also potential value in dapagliflozin show that this approach can (about 4mmHg systolic, 2mmHg dias - patients who have progressed to insulin have significant benefits for patients with tolic). treatment, where it has the potential to type 2 diabetes. Side-effects seem to be mostly man - break the cycle of insulin dose escalation Diabetes is strongly associated with ageable, with about 1 in 20 experiencing and weight gain. obesity, yet many treatments (for example symptoms of genital infection over six , pioglitazone and insulin) months’ treatment; it is reassuring that Declaration of interests result in weight gain. The difference in most respond to standard therapy and Professor Wilding has been a clinical inves - body weight between dapagliflozin and few cases are recurrent, although tigator for clinical trials of dapagliflozin, glipizide in a head-to-head study was over patients with a history of recurrent genital and has received honoraria for consulting 4kg after two years’ treatment, and fur - infections such as thrush and balanitis and speaker fees from Bristol-Myers thermore this was associated with much might not be suited to this treatment. Squibb and AstraZeneca, and also from less hypoglycaemia. Dapagliflozin depends on glomerular Janssen, Boehringer Ingelheim and The group of patients on high doses filtration of glucose for its mode of action Astellas, companies that also have SGLT2 of insulin (often also taking other drugs so is not suited to patients with moderate inhibitors in development. such as metformin and sulfonylureas) are or severe renal impairment due to a particular challenge, as increasing reduced efficacy. John Wilding is professor of medicine insulin doses tends to result in further and honorary consultant physician, weight gain, creating a vicious cycle of Conclusion Department of Obesity & Endocrin- worsening insulin resistance and increas - Dapagliflozin can potentially be used ology, Institute of and Chronic ing insulin requirements, often without early in the treatment of type 2 diabetes Disease, University Hospital Aintree, improvement in control. Trial data show (for example as monotherapy in patients Liverpool

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