February Horizon Scanning Research & 2017 Intelligence Centre

Dapagliflozin (Forxiga) for type 1 diabetes mellitus – add-on to insulin therapy

NIHR HSRIC ID: 7546

Lay summary

Dapagliflozin is a drug used to treat type 2 diabetes mellitus (DM) that is currently being studied to see if it would work in patients with type 1 DM, alongside the insulin injections that they already take. Type 1 DM occurs when the person’s own immune system attacks the pancreas and destroys the cells that produce insulin. Insulin is needed to regulate the body's sugar levels. Dapagliflozin is taken as a tablet once a day. If licensed, dapagliflozin may offer patients with type 1 DM an additional treatment option alongside insulin to maintain stable sugar levels.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

Type 1 diabetes mellitus (DM): adults; add-on to insulin therapy in patients with inadequately controlled blood sugar.

TECHNOLOGY

DESCRIPTION

Dapagliflozin (Forxiga; BMS-512148) is an oral, once-daily, sodium glucose co-transporter type 2 (SGLT2) inhibitor. SGLT2 is a low affinity, high-capacity transporter that is responsible for 90% of the glucose reabsorbed by the kidneys. SGLT2 inhibitors help maintain blood glucose levels by regulating the reabsorption of filtered glucose.

In the phase III clinical trial, dapagliflozin is administered orally at either 5mg or 10mg once daily in combination with insulin1.

Forxiga is currently licensed in the EU for the treatment of adults with type 2 DM to improve glycaemic control as a monotherapy in patients where metformin is inappropriate or as an add-on therapy when glycaemic control is inadequate with other glucose-lowering products2. Very common adverse events (AEs) (>10%) include hypoglycaemia, when used with sulphonyurea or insulin. Common AEs include vulvovaginitis, balanitis and related genital infections, urinary tract infection, dizziness, back pain, dysuria, polyuria, increased haematocrit, decreased creatinine renal clearance, and dyslipidaemia2.

Dapagliflozin is currently in phase III clinical trials for chronic renal failure, chronic heart failure, and in a cardiovascular outcome study in patients with type 2 DM. It is also in phase II trials for type 2 DM in patients with non-alcoholic fatty liver disease and obesity.

INNOVATION and/or ADVANTAGES

If licensed, dapagliflozin may offer an additional oral treatment option for patients with type 1 DM who require an additional therapy alongside insulin.

DEVELOPER

AstraZeneca UK Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Type 1 DM is a chronic autoimmune disorder that may be precipitated by environmental factors in genetically susceptible individuals3. The immune system attacks the beta-cells in the islets of Langerhans of the pancreas, destroying or damaging them sufficiently to reduce Horizon Scanning Research & Intelligence Centre

and eventually eliminate insulin production3. The disease is most often diagnosed in children and adolescents, but it can also develop in adults in their late 30s and early 40s4.

Type 1 DM usually presents with polydipsia (increased thirst and fluid intake), polyphagia (increased appetite) and polyuria (increased frequency of urination) alongside hyper- glycaemia4,5. These symptoms are a consequence of hepatic overproduction of glucose via glycogenolysis and gluconeogenesis pathways and decreased cellular uptake of glucose by peripheral tissues such as muscle and adipose tissue. In addition, excessive fat breakdown and fatty acid oxidation may lead to hyperlipidaemia and ketosis6. Patients with type 1 DM have an immediate need for exogenous insulin replacement, which will be required for life5. Over the years, type 1 DM causes tissue damage which, if not detected and managed early, can result in blindness, kidney failure and foot ulceration leading to amputation, as well as premature heart disease, stroke and death7.

CLINICAL NEED and BURDEN OF DISEASE

It is estimated that more than 1 in 16 people in the UK has diabetes (diagnosed or undiagnosed)8, with almost 3.5 million people having diagnosed diabetes and over 370,000 having type 1 DM7,8. Diabetes care is estimated to account for up to 10% of NHS expenditure9.

In 2014-15, there were 25,800 hospital admissions for type 1 DM (ICD-10 E10) in England, resulting in 91,803 bed days and 37,534 finished consultant episodes10. In the same year in England and Wales, 344 deaths were registered for type 1 DM (ICD-10 E10)11.

Expert opinion stated that patients with type 1 DM who are above the target HbA1c of 58mmol/mol are potentially eligible for adjunctive therapya. In 2014/15 approximately 83% of people with type 1 DM in England and Wales had received the NICE recommended HbA1c blood test12.The population likely to be eligible to receive dapagliflozin is estimated to be 307,100.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus (TA151). July 2008. • NICE guideline. Diabetes (type 1 and type 2) in children and young people: diagnosis and management (NG18). Updated November 2016. • NICE guideline. Type 1 diabetes in adults: diagnosis and management (NG17). Updated July 2016. • NICE guideline. Diabetes in pregnancy: management from pre-conception to the postnatal period (NG3). Updated August 2015. • NICE quality standard. Diabetes in adults (QS6). Updated August 2016. • NICE quality standard. Diabetes in children and young people (QS125). July 2016. • NICE quality standard. Diabetes in pregnancy (QS109). January 2016. • NICE interventional procedure guidance. Allogeneic pancreatic islet cell transplantation for type 1 diabetes mellitus (IPG257). April 2008.

a Expert personal communication.

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• NICE evidence summary. Type 1 diabetes mellitus in adults: high-strength insulin glargine 300 units/ml (Toujeo) (ESNM62). October 2015. • NICE evidence summary. Type 1 diabetes: insulin degludec (ESNM24). September 2013. • NICE diagnostic guidance. Integrated sensor-augmented pump therapy systems for managing blood glucose levels in type 1 diabetes (the MiniMed Paradigm Veo system and the Vibe and G4 platinum CGM system) (DG21). February 2016.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for insulin-resistant diabetes services (All Ages). A03/S(HSS)/b. • NHS England. 2013/14 NHS Standard Contract for specialised endocrinology services (Adult) A03/S/a.

Other Guidance

• British Medical Journal. Diagnosis and management of type 1 diabetes in adults: summary of updated NICE guidance. 201513. • Joint British Diabetes Societies for Inpatient Care. Management of adults with diabetes undergoing surgery and elective procedures: improving standards. 201514. • Scottish Intercollegiate Guidelines Network. Management of diabetes (SIGN116). 201315.

CURRENT TREATMENT OPTIONS

Type 1 DM is treated by insulin replacement, supported by the active management of other cardiovascular risk factors such as hypertension and high circulating lipids7. NICE recommends offering all adults with type I DM7,13: • A structured education programme in the self-management of flexible insulin therapy, for example the DAFNE (dose adjustment for normal eating programme) for 6 to 12 months as well as education about self-monitoring blood glucose levels. • Dietary advice about blood glucose control, weight control and cardiovascular risk management. • Insulin therapy: o Multiple daily injection basal-bolus insulin regimens. o Insulin detemir twice daily as basal insulin therapy, or insulin glargine if insulin detemir is not tolerated; with bolus rapid acting insulin injected before meals. o In flexible therapy, doses of basal insulin are based on fasting glucose readings and readings made five or more hours after eating; doses for pre-meal insulin are based on the current blood glucose test result and the amount of carbohydrate the patient plans to eat. o Twice daily mixed insulin may be offered if multiple daily injections are not possible. 16 o Continuous subcutaneous insulin infusion treatment is also available . • Metformin adjunct therapy alongside insulin can also be given for improvement of blood glucose control while minimising effective insulin dose. • Advise routine monitoring of blood glucose at least four times a day, before each meal and before bed. • Advise patients to aim for a fasting plasma glucose of 5-7 mmol/L before breakfast; 4-7 mmol/L before meals at other times of day, and if patients chose to test after meals, 5-9 mmol/L at least 90 minutes after eating.

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Expert opinion stated that continuous glucose monitoring and islet transplantation are also recommended as options for management of patients with type 1 DMb.

EFFICACY and SAFETY

Trial DEPICT 1, NCT02268214, MB102-229, NCT02582814, D1695C00001; EudraCT2013-004674-97; dapagliflozin in dapagliflozin in combination with insulin; combination with insulin; phase III. phase III. Sponsor Bristol-Myers Squibb. AstraZeneca. Status Ongoing. Ongoing. 1 17 Source of Trial registry . Trial registry . information Location EU (incl UK) USA, Canada, and other Japan. countries. Design Randomised, placebo-controlled. Randomised, parallel-group. Participants n=768 (planned); aged 18-75 yrs; type 1 n=170 (planned), aged 18-75 yrs; DM; insulin use for ≤12 mths prior; diagnosis of type 1 DM; C-peptide multiple daily injections (MDI) or <0.7ng/mL; insulin use for ≤12 mths prior; continuous subcutaneous insulin infusion MDI or CSII unchanged for ≤3 mths; total (CSII) unchanged for ≤3 months; total daily insulin dose ≥0.3 U/kg/day for ≤3 insulin dose of ≥0.3U/kg/day for ≤3 mths; mths; MDI insulin ≥3x injections per day; MDI insulin administration ≥3x injections; HbA1c ≥7.5% and ≤10.5%; body mass glycosylated haemoglobin (A1C) ≥7.7% index (BMI) ≥20.0kg/m² at visit 1; no type and ≤11.0%; no type 2 DM or maturity 2 DM or MODY; no antihyperglycaemic onset diabetes of the young (MODY), agent, other than α-GI or insulin ≤1mth pancreatic surgery, or chronic prior; no use of thiazolidinediones ≤6 pancreatitis; no antihyperglycaemic agent mths; no hospitalisation for poor other than metformin, or insulin ≤1 mth glycaemic control. prior; no frequent episodes of severe hypoglycaemia. Schedule Randomised to dapagliflozin 5mg or Randomised to dapagliflozin 5mg or dapagliflozin 10mg (both with insulin) dapagliflozin 10mg (both with insulin) administered orally, once daily for 52 wks; administered orally, once daily for 52 wks. or placebo (with insulin) daily for 52 wks. Follow-up 52 wks. 52 wks. Primary Adjusted mean change in haemoglobin Incidence of adverse events; safety and outcome/s A1C (HbA1c) at wk 24. tolerability assessed by physical examination; vital signs (blood pressure, heart rate); electrocardiogram (ECG); clinical laboratory measures, urine test results. Secondary Change in total daily insulin dose, body At 24 and 52 wks: change in HbA1c, outcome/s weight, mean 24hr glucose readings, and glycoalbumin, average glucose values mean amplitude of glucose excursion of measured by 6-point self-monitored blood 24hr glucose readings; proportion of 24hr glucose (SMBG); total daily insulin dose; glucose readings within range ≥70mg/dL body weight; proportion with HbA1c and ≤180mg/dL; proportion achieving reduction of ≤0.5% without severe HbA1c reduction ≥0.5% without severe hypoglycaemia; change in systolic and/or hypoglycaemia events. diastolic blood pressure; proportion with HbA1c reduction ≤0.5%; proportion with HbA1c <7.0% at 24 and 52 wks. Expected Study primary completion date reported Study primary completion date reported reporting as Jan 2017. as Oct 2017. date

b Expert personal communication.

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Trial Depict 2, NCT02460978, EudraCT2014- NCT01498185, MB102-072; dapagliflozin 004599-49, MB102-230; dapagliflozin in as an add-on to insulin therapy vs combination with insulin vs placebo; placebo, phase II. phase III. Sponsor Bristol-Myers Squibb. AstraZeneca. Status Ongoing. Completed. Source of Trial registry18. Trial registry19, publication20. information Location EU (incl UK) USA, Canada and other USA. countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=768 (planned); aged 18-75 yrs; type 1 n=70; aged 18-65 yrs; type 1 DM; A1C DM; C-peptide <0.7ng/ml; insulin use for ≥7.0% and ≤10.0%; insulin use for at ≤12 ≤12 mths; MDI or CSII unchanged for at mths; MDI or CSII stable ≥3 mths; stable ≤3 mths; total insulin dose of basal insulin dose ≥2 wks; C-peptide >0.3U/kg/day for ≤3 mths; MDI insulin value <0.7ng/mL; BMI 18.5 to 35.0kg/m2; administration >3x injections per day; no type 2 DM, MODY, pancreatic surgery HbA1c ≥7.7% and ≤11.0%; BMI or chronic pancreatitis; no oral ≥18.5kg/m2; no type 2 DM or MODY, hypoglycaemic agents; no diabetic pancreatic surgery, or chronic ketoacidosis ≤24 wks; no hospitalisation pancreatitis; no antidiabetic medication for glycemic control ≤6 mths; no frequent (other than insulin) ≤1 mth; no GLP-1 episodes of severe hypoglycaemia ≤1 receptor agonist, metformin and/or month prior. thiazolidinediones ≤2 mths prior; no frequent episodes of severe hypoglycaemia; no Addison's disease. Schedule Randomised to dapagliflozin 5mg or Randomised to dapagliflozin 1mg, 2.5mg, dapagliflozin 10mg (both with insulin) 5mg, or 10mg (all with insulin) administered orally, once daily for 52 wks; administered orally, once daily for 2 wks; or placebo (with insulin) administered or placebo (with insulin) administered orally, once daily for 52 wks. orally, once daily for 2 wks. Follow-up 52 wks. 2 wks.

Primary Change in hemoglobin A1C (HbA1c) at Safety and tolerability measured by outcome/s week 24. numbers with serious adverse events (SAEs), deaths or discontinuations due to AEs, events of hypoglycaemia, AEs of genitourinary infection or potentially clinically significant changes in vital signs. Secondary Change in: total daily insulin dose, body Mean change on day 7 in glucose; outcome/s weight, 24 hr glucose readings from maximum plasma concentration (Cmax); Continuous Glucose Monitoring (CGM); time of maximum plasma concentration amplitude of glucose excursion of 24-hr (Tmax); area under the concentration- glucose readings obtained from CGM and time curve in one dosing interval 24 hr glucose readings from CGM within [AUC(TAU)]; ratio of metabolite to parent >70mg/dL and ≤180mg/dL; proportion of area under the curve [AUC]. HbA1c reduction ≥0.5% and without severe hypoglycaemia events. Key results - Sixty-two patients (88.6%) completed the study; by day 7, no significant differences were noted in outcomes; for dapagliflozin 10mg vs placebo respectively: glycosuria increase of 88g/24 hr (95% CI 55 to121) vs decrease of -21.5g/24 hr (95% CI -53.9 to 11.0); 24 hr average blood glucose, -2.29mmol/L (95% CI - 3.71 to -0.87) vs. -1.13mmol/L (95% CI - 3.63 to 1.37); mean amplitude of

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glycaemic excursion: -3.77mmol/L (95% CI -6.09 to -1.45) vs -0.45mmol/L (95% CI -4.98 to 4.08); mean % change in total daily insulin dose -16.2% (95% CI -29.4 to -0.5) vs. +1.7% (95% CI -22.8 to 33.9). Adverse - AEs included urinary tract infections, effects (AEs) genital infections and hypoglycaemia, and were judged unrelated to treatment. There was one major case of hypoglycaemia in the dapagliflozin 10mg group, and one SAE of gastroparesis in the dapagliflozin 5mg group. Both AEs resulted in treatment discontinuation. Expected Study primary completion date reported Study primary completion date reported reporting as May 2017. as Oct 2012. date

ESTIMATED COST and IMPACT

COST

A pack of 28 x 5mg or 10mg tablets of dapagliflozin (Forxiga) costs £3721.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: Expert opinion stated that dapagliflozin  No impact identified may potentially play an important role in managing patients with type 1 DM because the majority do not achieve target HbA1c levels despite their best efforts and current available therapiesc.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs: Expert opinion stated  Other reduction in costs: that patients will require support for ketone testing. This will require more education, provision of ketone strips and meters, and may also require changes to current hospital diabetic ketoacidosis management protocolsc.

 Other  None identified

c Expert personal communication.

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Other Issues

 Clinical uncertainty or other research question  None identified identified: Expert opinion stated that dapagliflozin would be used as an adjunct to insulin therapy and would not replace the use of insulin; and the main safety concern with dapagliflozin is the risk of diabetic ketosis. Patients administered SGLT2 inhibitor therapy must be advised to measure blood ketones if they are feeling unwell and regardless of their blood glucose (some patients have developed ketoacidosis with a blood glucose level of under 10mmol per litre). This is an important safety issue as it can result in hospital admission and risk of mortalityc.

REFERENCES

1 ClinicalTrials.gov. A multicenter, randomised, double-blind, placebo-controlled, parallel group, phase 3 study to evaluate the efficacy and safety of dapagliflozin as an add-on to insulin therapy in subjects with type 1 diabetes mellitus. https://www.clinicaltrials.gov/ct2/show/NCT02268214?term=NCT02268214 Accessed 1 December 2016. 2 Electronic Medicines Compendium. Forxiga 5 mg & 10 mg film coated tablets. https://www.medicines.org.uk/emc/medicine/27188 Accessed 1 December 2016. 3 Van Belle TL, Coppieters KT, and Von Herrath M. Type 1 diabetes: etiology, immunology and therapeutic strategies. American Physiological Society 2011; 91:79-118. 4 MedScape. Type 1 diabetes mellitus. http://emedicine.medscape.com/article/117739-overview Accessed 1 December 2016. 5 Atkinson MA. The pathogenesis and natural history of type 1 diabetes. Cold Spring Harbor Perspectives in Medicine 2012;2:a007641. 6 Eiselein L, Schwartz HJ, and Rutledge JC. The challenge of type 1 diabetes mellitus. Oxford journals 2004; 45(3):231-236. 7 National Institute for Health and Care Excellence. Type 1 diabetes in adults: diagnosis and management. NICE guideline NG17. London: NICE; August 2015. 8 Diabetes UK. Facts and Stats November 2015. https://www.diabetes.org.uk/Documents/Position%20statements/Diabetes%20UK%20Facts%20a nd%20Stats_Dec%202015.pdf Accessed 1 December 2016. 9 National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline NG28. London: NICE; December 2015. 10 Health & Social Care Information Centre. Hospital Episode Statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk/hes 11 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2014. www.ons.gov.uk 12 Health and Social Care Information Centre. National Diabetes Audit 2013-2014 and 2014-2015 Report 1: Care Processes and Treatment Targets. Version 1, 28 January 2016. http://content.digital.nhs.uk/catalogue/PUB19900/nati-diab-rep1-audi-2013-15.pdf 13 Amiel SA, Lawrence RD, Pursey N et al. Diagnosis and management of type 1 diabetes in adults: summary of updated NICE guidance. British Medical Journal 2015;351:h4188. 14 Joint British Diabetes Societies for Inpatient Care. Management of adults with diabetes undergoing surgery and elective procedures: improving standards summary. Revised September 2015. http://www.diabetologistsabcd.org.uk/JBDS/JBDS_IP_Surgical_Guideline_2015_Summary.pdf 15 Scottish Intercollegiate Guidelines Network. Management of diabetes. National clinical guideline 116. Edinburgh: SIGN; September 2013.

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16 National Institute for Health and Care Excellence. Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus TA151. London: NICE; July 2008. 17 ClinicalTrials.gov. A clinical pharmacology and long term study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of dapagliflozin therapy in combination with insulin in Japanese subjects with type 1 diabetes who have inadequate glycaemic control. https://www.clinicaltrials.gov/ct2/show/NCT02582814?term=NCT02582814 Accessed 1 December 2016. 18 ClinicalTrials.gov. A multicenter, randomised, double-blind, placebo-controlled, parallel group, phase 3 study to evaluate the efficacy and safety of dapagliflozin as an add-on to insulin therapy in subjects with type 1 diabetes mellitus - Study two. https://www.clinicaltrials.gov/ct2/show/NCT02460978 Accessed 1 December 2016. 19 ClinicalTrials.gov. A randomised, double-blind, placebo-controlled, parallel group, phase 2 trial to explore the safety, pharmacokinetics and pharmacodynamics of dapagliflozin as an add-on to insulin therapy in subjects with type 1 diabetes mellitus. https://www.clinicaltrials.gov/ct2/show/NCT01498185 Accessed 1 December 2016. 20 Henry RR, Rosenstock J, Edelman S et al. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care. 2015;38(3):412-419. 21 Joint Formulary Committee. British National Formulary. BNF December 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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