Ertugliflozin for type 2 diabetes mellitus

Transcription

1 October 2016 Horizon Scanning Research & Intelligence Centre Ertugliflozin for type 2 diabetes mellitus NIHR HSRIC ID: 7712; 11910; 12223; Lay summary Ertugliflozin is a new drug to treat type 2 diabetes. Type 2 diabetes is a disease that results when the level of sugar in the blood is too high. This can cause damage to the eyes, nerves, kidneys and other tissues. It also greatly increases the chance of heart attacks and strokes. Ertugliflozin is taken as a tablet once a day and works by increasing the amount of sugar that passes out of the body in urine. 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 nihrhsric@contacts.bham.ac.uk

2 TARGET GROUP Diabetes mellitus: type 2; in adults aged 18 years and older; in patients for whom diet and exercise do not provide adequate glycaemic control As monotherapy, in patients for whom use of metformin is considered inappropriate due to intolerance or contraindications. As add-on combination therapy, with other glucose-lowering medicinal products, including insulin. TECHNOLOGY DESCRIPTION Ertugliflozin (MK-8835; PF ) is an orally active inhibitor of the sodium glucose cotransporter type 2 (SGLT2). SGLT2 is responsible for 80-90% of renal glucose re-absorption and is often overexpressed and over activated in patients with type 2 diabetes. SGLT2 inhibitors reduce renal glucose reabsorption in the proximal convoluted tubule, leading to increased urinary glucose excretion 1. In phase III clinical trials, ertugliflozin is administered orally at 5mg or 15mg once daily 2. Ertugliflozin does not currently have Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, ertugliflozin will offer an additional treatment option for patients with type 2 diabetes mellitus. DEVELOPER Merck Sharp and Dohme AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND Type 2 diabetes mellitus is a chronic metabolic disorder, the prevalence of which has been increasing steadily in all parts of the world 3. Type 2 diabetes mellitus consists of an array of dysfunctions characterised by hyperglycaemia (glycosylated haemoglobin [HbA1c] >48mmol/mol or random plasma glucose >11mmol/L), resulting from the combination of resistance to insulin action, inadequate insulin secretion, and excessive or inappropriate glucagon secretion 4,5. Type 2 diabetes is the most common form of diabetes, accounting for about 90% of cases 5. Symptoms of type 2 diabetes include polyuria, polydipsia, polyphagia, weight loss, blurred vision, paraesthesia of the lower extremities and yeast infections 4,6.

3 Complications of type 2 diabetes include 5a : Microvascular complications retinopathy, nephropathy and neuropathy. Macrovascular complications cardiovascular disease, cerebrovascular disease, and peripheral arterial disease. Metabolic complications dyslipidaemia, hyperosmolar state, and diabetic ketoacidosis. Psychological complications including anxiety and depression. Type 2 diabetes is due primarily to lifestyle and genetic factors. A number of lifestyle factors are known to be important to the development of this condition, such as physical inactivity, poor diet, cigarette smoking and excessive consumption of alcohol 3,a. Obesity has been found to contribute to approximately 55% of cases of type 2 diabetes 3. There is a strong heritable genetic predisposition; having relatives with type 2 diabetes increases the risks substantially. The risk of developing type 2 diabetes is about 15% if one parent has type 2 diabetes and 75% if both parents have type 2 diabetes 5. However, individually these account for only a small proportion of cases. Lifestyle interventions (such as diet and physical activity) are recommended initially to manage type 2 diabetes and reduce the risk of complications. However, over time, many people will require antidiabetic drug treatments 5. CLINICAL NEED and BURDEN OF DISEASE It is estimated that more than 1 in 16 people in the UK has diabetes (diagnosed or undiagnosed), which equates to approximately 4 million people aged 16 years and over in England, of whom around 90% have type 2 diabetes 7,8. By 2035, it is estimated that 4.9 million people will have diabetes in England 8. People from South Asian and Black communities are two to four times more likely to develop type 2 diabetes than those from White ethnic groups 7. In , there were 20,971 hospital admissions for type 2 diabetes (ICD-10 E11) in England, resulting in 153,939 bed days and 34,028 finished consultant episodes 9. In the same year in England and Wales, 2,435 deaths were registered for type 2 diabetes (ICD-10 E11) 10. Diabetes is costly to the NHS, with a recent study estimating that 10% of all NHS expenditure is for diabetes 11. In , it was estimated that 9.5% of prescribing costs were for diabetes, including pharmaceutical treatment and blood glucose testing strips 12. Cardiovascular disease is a major cause of death and disability in people with diabetes, accounting for 52% of deaths in people with type 2 diabetes 7. There is a 139% increased risk of angina, a 94% increased risk of myocardial infarction, a 126% increased risk of heart failure, and a 63% increased risk of stroke among people with diabetes 7. People with type 2 diabetes have a two-fold increased risk of stroke within the first five years of diagnosis compared with the general population 7. Around one fifth of hospital admissions for heart failure, heart attack and stroke are in people with diabetes 7. It is estimated that 56% of patients receiving pharmacological treatment for type 2 diabetes are receiving first-line treatment, which equates to approximately 1.2 million people in England. It is also estimated that 25% of patients receiving pharmacological treatment for type 2 diabetes are receiving second-line treatment, which equates to approximately 517,000 people in England 13. a Expert personal communication. 3

4 PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Diabetes (type 2) dapagliflozin (with metformin and a sulfonylurea) (ID962). Expected January NICE technology appraisal in development. Diabetes (type 2) - canagliflozin, dapagliflozin and empagliflozin (monotherapy) (ID756). Expected May NICE technology appraisal. Empagliflozin in combination therapy for treating type 2 diabetes (TA336). March NICE technology appraisal. Canagliflozin in combination therapy for treating type 2 diabetes (TA315). June NICE technology appraisal. Dapagliflozin in combination therapy for treating type 2 diabetes (TA288). June NICE technology appraisal. Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus (TA151). July NICE guidelines. Type 2 diabetes: management (NG28). December NICE guidelines. Diabetes (type 1 and type 2) in children and young people: diagnosis and management (NG18). August NICE clinical guideline. Cardiovascular disease: risk assessment and reduction, including lipid modification (CG181). July NICE public health guidance. Type 2 diabetes: prevention in people at high risk (PH38). July NICE public health guidance. Type 2 diabetes prevention: population and communitylevel interventions (PH35). May NICE quality standard. Diabetes in adults (QS6). March NHS England Policies and Guidance NHS England. 2013/14 NHS Standard Contract for Insulin-Resistant Diabetes Services (All Ages). A17/S(HSS)/b. Other Guidance British Medical Journal. Management of type 2 diabetes in adults: summary of updated NICE guidance International Diabetes Federation. Diabetes eye health: a guide for health care professionals Joint British Diabetes Societies Inpatient Care Group. Management of adults with diabetes undergoing surgery and elective procedures: improving standards Scottish Intercollegiate Guidelines Network. Management of diabetes (116) NHS University Hospitals Leicester. Diabetes mellitus guidelines Trend UK. Diabetes and Dementia Guidance on Practical Management International Diabetes Federation. Managing older people with type 2 diabetes The Royal College of Ophthalmologists. Diabetic Retinopathy Guidelines Royal College of Nursing. Starting injectable treatment in adults with Type 2 diabetes

5 International Diabetes Federation. Global guideline for type 2 diabetes Diabetic Medicine. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis CURRENT TREATMENT OPTIONS Treatments for type 2 diabetes should adopt an individualised approach that is tailored to the needs and circumstances of the patient, taking into account their personal preferences, comorbidities, risks from polypharmacy, and ability to benefit from long-term interventions because of reduced life expectancy 25. Educating the patient in managing their diabetes, alongside dietary advice, and weight loss targets for patients who are overweight is often the first approach in managing this condition 14,25. Pharmacological treatment options include 14,25 : Standard-release metformin is the initial drug offered. The dose is gradually increased over several weeks to minimise the risk of gastrointestinal side effects. If gastrointestinal effects do occur, a modified-release formulation of metformin can be trialled. If metformin is contraindicated or not tolerated, the initial recommended treatment options are dipeptidyl peptidase-4 inhibitor (DPP-4, or gliptin ), pioglitazone or sulfonylurea. Pioglitazone should not be offered to diabetic patients with a history of heart failure, hepatic impairment, diabetic ketoacidosis, bladder cancer, or macroscopic haematuria. Drug treatment intensification with metformin in combination with either a DPP-4 inhibitor, pioglitazone, sulfonylurea or SGLT2 inhibitor (such as canagliflozin, dapagliflozin and empagliflozin), is recommended for patients whose HbA1c has not been controlled by metformin alone. For patients who are not taking metformin as the initial drug treatment, combinations of either a DPP-4 inhibitor, pioglitazone or sulfonylurea, or SGLT2 inhibitor can be used. If dual therapy with metformin and other oral drugs is insufficient, triple therapy with a combination of metformin, DPP-4 inhibitor, pioglitazone, sulfonylurea, or SGLT2 inhibitor may be used. A structured programme of insulin therapy may be offered in combination with continuing support and self-monitoring if triple therapy has not been effective. Insulin based therapy may be used in combination with any of the aforementioned drugs. EFFICACY and SAFETY Trial NCT , , , B ; ertugliflozin vs placebo; phase III. NCT , , , B ; ertuglizflozin in combination with sitagliptin vs placebo; phase III. Merck Sharp & Dohme NCT , , , B ; ertugliflozin vs glimepiride; phase III. Sponsor Merck Sharp & Dohme Merck Sharp & Dohme Status Complete but unpublished. Complete but unpublished. Ongoing. Source of Trial registry 2, Trial registry 26, Trial registry 27, information manufacturer. manufacturer. manufacturer. Location EU (incl UK), USA, Canada EU (incl UK), USA and EU (not UK), USA, Canada and other countries. other countries. and other countries. Design Randomised, placebocontrolledcontrolled. Randomised, placebo- Randomised, activecontrolled. 5

6 Participants n=464; aged 18 yrs and older; type 2 diabetes mellitus; no oral antihyperglycaemic agents for at least 8 wks prior to study participation. n=292; aged 18 yrs and older; type 2 diabetes mellitus; no oral antihyperglycaemic agents for at least 8 wks prior to study participation and HbA1c 8% and 10.5%; or on a single allowable antihyperglycaemic agent (metformin, α-glucosidase inhibitors, sulfonylureas and glinides) and HbA1c 7.5% and 10%; or on low dose dual combination therapy with allowable antihyperglycaemic agents and HbA1c 7.5% and 10%. n=1,230 (planned); aged 18 yrs and older; type 2 diabetes mellitus; on metformin monotherapy or metformin in combination with a single allowable antihyperglycaemic agent (dipeptidyl peptidase-4 inhibitor, glinides and α- glucosidase inhibitors). Schedule Part A: Randomised to ertugliflozin 5mg oral once daily for 26 wks; or ertugliflozin 15mg oral once daily; or placebo once daily for 26 Part B: Pts requiring rescue with metformin in part A continue to receive metformin in addition to their original randomised treatment, once daily for 26 Pts not requiring rescue with metformin in part A receive metformin placebo in addition to their original randomised treatment, once daily for 26 Follow-up Active treatment for 52 Primary HbA1c; adverse effects outcomes (AEs). Secondary Fasting plasma glucose, outcomes body weight, 2-hrs postprandial plasma glucose, and blood pressure; number of pts with HbA1c <7%. Randomised to ertugliflozin 5mg oral once daily for 26 wks; or ertugliflozin 15mg oral once daily; both in combination with sitagliptin 100mg oral once daily; or ertugliflozin placebo and sitagliptin placebo oral once daily for 26 Active treatment for 26 HbA1c; AEs. Fasting plasma glucose, body weight, 2-hrs postmeal glucose, body weight, and blood pressure; number of pts with HbA1c <7%. Randomised to ertugliflozin 5mg oral once daily; or ertugliflozin 15mg oral once daily; or glimepiride 8mg oral once daily. Active treatment for 26 HbA1c; AEs. Body weight; systolic blood pressure; number of pts with symptomatic hypoglycaemia. Key results Not reported. Not reported. - Adverse Not reported. Not reported. - effects (AEs) Expected reporting date Previously reported as July Previously reported as Feb Study completion date reported as April

7 Trial NCT , , , B ; ertugliflozin vs placebo; phase III. Sponsor Merck Sharp & Dohme NCT , ; ertugliflozin vs sitagliptin; phase III. NCT , , , B ; ertugliflozin vs placebo; phase III. Merck Sharp & Dohme Merck Sharp & Dohme Status Ongoing. Complete but unpublished. Complete but unpublished. Source of Trial registry 28, Trial registry 29, Trial registry 30, information manufacturer. manufacturer. manufacturer. Location EU (incl UK), USA and EU (incl UK), USA, EU (not UK), USA and other countries. Canada and other other countries. Design Randomised, placebocontrolled. Participants n=600 (planned); aged 18 yrs and older; type 2 diabetes mellitus; on metformin monotherapy for <8 wks prior to study participation; HbA1c 7% and 10.5%. Schedule Randomised to ertugliflozin 5mg oral once daily; or ertugliflozin 15mg once daily; or placebo oral once daily; all in combination with metformin 1,500mg oral once daily. countries. Randomised, activecontrolled. n=1,291; aged 18 yrs and older; type 2 diabetes mellitus; on metformin monotherapy ( 1,500mg/day) with HbA1c 7.5% and 11%; or on metformin monotherapy (<1,500mg/day) with HbA1c 8% and 11.5%. Randomised to ertugliflozin 5mg oral once daily; or ertugliflozin 15mg oral once daily; or ertugliflozin 5mg once daily in combination with sitagliptin 100mg oral once daily; or ertugliflozin 15 mg once daily in combination with sitagliptin 100mg oral once daily; or sitagliptin 100mg oral once daily; all in combination with metformin 1,500mg oral once daily. Randomised, placebocontrolled. n=462; aged 18 yrs and older; type 2 diabetes; on stable dose of metformin with either sitagliptin or another dipeptidyl peptidase-4 inhibitor or a sulfonylurea. Randomised to ertugliflozin 5mg oral once daily; or ertugliflozin 15mg oral once daily; or placebo oral once daily. Pts are to remain on their stable doses of metformin and sitagliptin, and receive glimepiride and insulin glargine rescue medication as required. Follow-up Active treatment for 104 Active treatment for 52 Active treatment for 52 Primary HbA1c; AEs. HbA1c; AEs. HbA1c; AEs. outcomes Secondary outcomes Fasting plasma glucose, body weight, blood pressure, bone mineral density, and bone biomarkers; number of pts with HbA1c <7%; number of pts with HbA1c <6.5%; number of pts requiring glycaemic rescue therapy. Fasting plasma glucose, body weight, blood pressure and beta-cell function; number of pts with HbA1c <7%. Fasting plasma glucose, body weight, and blood pressure; number of pts with HbA1c <7%. Key results - Not reported. Not reported. AEs - Not reported. Not reported. Expected reporting date Study completion date reported as Aug Previously reported as May Previously reported as June

8 ESTIMATED COST and IMPACT COST The cost of ertugliflozin is not yet known. The cost of other selected treatments for type 2 diabetes include 31 : Drug Dose Annual cost Metformin 1,500mg oral once daily Sitagliptin 100mg oral once daily Glimepiride 4mg oral once daily Empagliflozin 10mg oral once daily IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other Reduced symptoms or disability No impact identified Impact on Health and Social Care Services Increased use of existing services Re-organisation of existing services Other Decreased use of existing services Need for new services None identified Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs Other: uncertain unit cost compared to existing alternative treatment options. Reduced drug treatment costs Other reduction in costs None identified Other Issues Clinical uncertainty or other research question identified: expert opinion states that they believe ertugliflozin will add little to an already crowded field of SGLT2 inhibitors. Recent data suggest empagliflozin has a strong link with reduced cardiovascular events and mortality in patients with diabetes and high risk cardiovascular disease. Ertugliflozin will therefore have to demonstrate very significant benefits to be prescribed before other SGLT2 inhibitors b. None identified b Expert personal communication. 8

9 REFERENCES 1 Vasilakou D, Karagiasnnis T, Athanasiadou E et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Annals of Internal Medicine 2013;159(4): ClinicalTrials.gov. A phase 3, randomised, double-blind, placebo-controlled, 26-week multicentre study with a 26-week extension to evaluate the efficacy and safety of ertugliflozin monotherapy in the treatment of subjects with type 2 diabetes mellitus and inadequate glycaemic control despite diet and exercise. Accessed 14 October Olokoba AB, Obateru OA and Olokoba LB. Type 2 diabetes mellitus: a review of current trends. Oman Medical Journal 2012; 27(4): MedScape. Type 2 diabetes Mellitus. Accessed 14 October National Institute for Health and Care Excellence. Clinical knowledge summaries: diabetes type 2. Accessed 14 October NHS Choices. Type 2 diabetes. Accessed 14 October Diabetes UK. Facts and Stats November Stats_Dec% pdf Accessed 14 October Public Health England. Diabetes prevalence model. Accessed 14 October Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR Hex N, Bartlett C. Wright D et al. Estimating the current and future costs of type 1 and type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabetic Medicine 2012;29(7): Health & Social Care Information Centre. Prescribing for diabetes: England to Accessed 14 October National Institute for Health and Care Excellence. Dapagliflozin in combination therapy for treating type 2 diabetes. NICE technology appraisal costing template TA288. London: NICE; June McGuire H, Longson D, Adler A et al. Management of type 2 diabetes in adults: summary of updated NICE guidance. British Medical Journal 2016;353:i International Diabetes Federation. Diabetes eye health: a guide for health care professionals. Accessed 14 October Joint British Diabetes Societies for inpatient care. Management of adults with diabetes undergoing surgery and elective procedures: improving standards summary. Revised September Accessed 14 October Scottish Intercollegiate Guidelines Network. Management of diabetes. National clinical guideline 116. Edinburgh: SIGN; September Leicestershire diabetes. Leicestershire Diabetes Guidelines Accessed 14 October Trend UK. Diabetes and Dementia. Guidance on Practical Management Accessed 14 October International Diabetes Federation. Guideline for managing older people with type 2 diabetes. Accessed 14 October The Royal College of Ophthalmologists. Diabetic retinopathy guidelines; December updated-July-2013.pdf Accessed 14 October Royal College of Nursing. Staring injectable treatment in adults with Type 2 diabetes www2.rcn.org.uk/ data/assets/pdf_file/0009/78606/ pdf Accessed 14 October International Diabetes Federation. Global guideline for type 2 diabetes Accessed 14 October Savage MW, Dhatariya KK, Kilvert A et al. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabetic Medicine 2011;38:

10 25 National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guidelines NG28. London: NICE; December ClinicalTrials.gov. A phase 3, randomised, double-blind, placebo-controlled, parallel-group, multicentre clinical trial to evaluate the efficacy and safety of the initial combination of ertugliflozin with sitagliptin in the treatment of subjects with type 2 diabetes mellitus with inadequate glycaemic control on diet and exercise. Accessed 14 October ClinicalTrials.gov. A phase 3, multicentre, randomised, double-blind, active-comparator-controlled clinical trial to study the safety and efficacy of the addition of ertugliflozin compared with the addition of glimepiride in subjects with type 2 diabetes mellitus who have inadequate glycaemic control on metformin. Accessed 14 October ClinicalTrials.gov. A phase 3, randomised, double-blind, placebo-controlled, 26-week multicentre study with a 78-week extension to evaluate the efficacy and safety of ertugliflozin in subjects with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy. Accessed 14 October ClinicalTrials.gov. A phase 3, randomised, double-blind, multicentre study to evaluate the efficacy and safety of the combination of ertugliflozin with sitagliptin compared with ertugliflozin alone and sitagliptin alone, in the treatment of subjects with type 2 diabetes mellitus with inadequate glycaemic control on metformin monotherapy. Accessed 14 October ClinicalTrials.gov. A phase 3, multicentre, randomised, double-blind, placebo-controlled, parallelgroup clinical trial to evaluate the safety and efficacy of ertugliflozin in the treatment of subjects with type 2 diabetes mellitus who have inadequate glycaemic control on metformin and sitagliptin. Accessed 14 October Joint Formulary Committee. British National Formulary. BNF September BMJ Group and Pharmaceutical Press. 10