Legal Status Indication Treatment of Type 1 and Type 2 diabetes

Transcription

1 New Medicine Report (Adopted by the CCG until review and further notice) Document Status Recombinant human insulin analogues Following Suffolk D&TC Meeting Traffic Light Decision Green Date of Last Revision 11 th July 2005 Approved Name Various Trade Name Various Manufacturer Various Legal Status POM Indication Treatment of Type 1 and Type 2 diabetes Dosage As required Cost See document Possible Number of Suffolk See document Patients Number Needed to Treat Not calculated Treatment Alternatives See document Future Alternatives Insulin glulisine short acting insulin analogue Possible Future Indications None known Submitted for comment to: Dr G Rayman, The Ipswich Hospital Dr Parkinson, The Ipswich Hospital Dr Fowler, The Ipswich Hospital Dr T Lockington, The Ipswich Hospital Dr N Wijenaike, West Suffolk Hospital Dr J Clark, West Suffolk Hospital Dr J Majeed, West Suffolk Hospital Dr N Huston, James Paget Date Not to be used for promotional purposes Page 1 of 13 May be freely copied by NHS agencies

2 The following paper has been adapted to reflect the Suffolk population but was originally prepared for:- CAMBRIDGESHIRE JOINT PRESCRIBING GROUP Recombinant human insulin analogues aspart, detemir, glargine, lispro Treatment of type 1 & type 2 diabetes mellitus Date of last revision 1 April 2005, version 1 Prepared by Katie Smith, Medicines Review & Primary Care Support Pharmacist, East Anglia Medicines Information Service and Sue Ashwell, Cambridge Joint Prescribing Group pharmacist Purpose of document To review information currently available Points For Consideration There is a need to establish the analogues long term benefits & safety. There is no convincing evidence to justify switching patients from existing conventional therapy to analogues if they have appropriate glycaemic control and no troublesome hypoglycaemia. The insulin analogues provide useful options for patients with type 1 diabetes predominantly who have frequent severe hypoglycaemia or nocturnal hypoglycaemic episodes. Treatment Alternatives Type 1 diabetics metformin may have a role in patients who are overweight or require large doses of insulin Place in current therapy Type 2 diabetics diet control, weight loss, oral antidiabetic drugs Type 1 diabetics analogues used increasingly as first line therapy Type 2 diabetics -? Future Alternatives Insulin glulisine - short acting insulin analogue like aspart & lispro Review date NICE issued guidance on management of blood glucose in type 2 diabetics in September 2002, due to be reviewed September 2005 NICE issued guidance on use of insulin glargine in December 2002, due to be reviewed in November 2005 NICE issued guidance on use of insulin pump therapy in February 2003, due to be reviewed in February 2006 NICE issued guidance on management on type 1 diabetics in July 2004, due to be reviewed July 2008 Indication For the treatment of patients with diabetes mellitus Cautions [For more detail, refer to the NovoRapid, Levemir, Lantus, Humalog, NovoMix 30 & Humalog Mix25 Summaries of Product Characteristics on the Electronic Medicines Compendium (EMC) - Hypoglycaemia Hyperglycaemia Diabetic ketoacidosis Concomitant illness Children younger than 6 years old Pregnant women aspart & lispro ok, detemir?, glargine not ok Not to be used for promotional purposes Page 2 of 13 May be freely copied by NHS agencies

3 [For further detailed information refer to the NovoRapid, Levemir, Lantus, Humalog, NovoMix 30 & Humalog Mix25 Summaries of Product Characteristics on the EMC] Source of Review Humalog a new insulin analogue, DTB Aug 1997 Vol 35 (8) p57-8 Short acting insulin analogues vs regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews 2004, issue 4 Insulin detemir (Levemir) a new basal insulin analogue, London New Drugs Group APC/DTC Briefing August 2004 BNF 48 th Ed Sept 2004 p Update on insulin analogues, DTB Oct 2004 Vol 42 (10) p77-80 Insulin analogues, NEJM 13 Jan 2005 Vol 352 (2) p Current insulin therapies for people with type 1 diabetes, Prescriber 19 March 2005 Vol 16 (6) p48-65 Guidance on use The recombinant human analogues have been developed to closely match the amino acid structure of human insulin and also more closely duplicate insulin requirements. Before the introduction of insulin analogues, all diabetic patients requiring insulin were treated with a twice daily split mix regimen of NPH insulin (intermediate acting) and regular soluble human insulin (short acting). The split mix aims to cover the physiological insulin release although this is difficult to achieve in practice. Insulin replacement consists of prandial insulin and basal insulin. Prandial insulin is given in an attempt to mimic the response of endogenous insulin to food. The basal insulin component mimics the relatively small but constant release of insulin that regulates lipolysis and output of hepatic glucose. The split mix insulin regimen spans both the prandial and basal components whereas insulin analogues target prandial and basal components separately. When injected subcutaneously, soluble insulin has an onset of action within minutes, a peak action between 2 and 4 hours and a duration of action of up to 8 hours. Although termed short acting, problems have arisen because the increase in insulin level is slower and more prolonged compared to normal physiological insulin release. The speed of absorption is determined by how quickly the chain of amino acids breaks down to single molecule units, which can be rapidly absorbed. Endogenous insulin peaks about 1 hour after release and lasts for about 4 hours. NPH insulin accounts for over 80% of the insulin currently prescribed for basal therapy in the UK. NPH insulin however has a time course of action that may result in nocturnal hypoglycaemia. It peaks 3-5 hours after injection and its duration of action is 14 +/- 3 hours so it may need to be injected twice daily. The ideal basal insulin has a long duration of action, typically 24 hours with minimal variability in absorption & once daily administration. Not to be used for promotional purposes Page 3 of 13 May be freely copied by NHS agencies

4 Insulin aspart & insulin lispro are rapid acting analogues that are derivatives of human insulin. Their onset of action occurs in minutes, the peak action follows within hours and the duration of action is 3-5 hours. When the DTB reviewed insulin lispro in August 1997 they concluded that Following subcutaneous injection, it has a more rapid onset, time to peak and shorter duration of action than soluble human insulin. It can be given immediately before a meal. It does not appear to alter overall control (haemoglobin A1c levels) It is not clear whether it reduces the occurrence of hypoglycaemia compared with soluble human insulin. At present there is no indication for replacing soluble human insulin with insulin lispro in the majority of patients. It may help patients whose mealtimes are unpredictable, those who eat late in the evening and are prone to early nocturnal hypoglycaemia. A 2004 Cochrane review compared the data on short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. The systematic review of 42 randomised controlled trials concluded that - 7 trials compared insulin aspart, 34 trials compared insulin lispro and 1 trial compared both aspart & lispro with conventional human insulin. Trials lasted 1-12 months (mean 3.6 months). Patients included in the trials had type 1 (5,925), type 2 (1,901) or gestational (107) diabetes. The reviewers concluded that 83% of the studies were of poor methodological quality because of randomisation and allocation method issues. Compared with conventional human insulin, use of the analogues was associated with a small decrease in HbA1c levels in type 1 diabetics but not type 2 diabetics. Use of an analogue did not reduce the overall frequency of hypoglycaemia compared with human insulin in either type 1 or type 2 diabetics. Severe hypoglycaemia occurred less often with the analogues than with human insulin (see below) Insulin analogues Type 1: 20.3 episodes/100 person years years Type 2: 0.6 episodes/100 person years years Human insulin 37.2 episodes/100 person 2.8 episodes/100 person None of the studies were designed to assess the possible long term benefits or safety of the short acting insulin analogues. Both insulin aspart and insulin lispro are also available as pre-mixed Not to be used for promotional purposes Page 4 of 13 May be freely copied by NHS agencies

5 formulations NovoMix and Humalog Mix. A percentage of the analogue (30-75%) is co-crystallised with protamine so that the absorption of insulin is slowed to a rate similar to that of an intermediate acting conventional insulin. Data from 9 randomised controlled trials involving 1,347 patients with type 1 or type 2 diabetes suggest that biphasic insulin aspart and biphasic insulin lispro have similar effects on HbA1c and incidence of hypoglycaemia as biphasic conventional insulin but reduce postprandial glucose concentrations more. Summary Compared to soluble human insulin, aspart & lispro result in a small decrease in HbA1c levels in type 1 but not type 2 diabetics. Aspart & lispro reduce the incidence of severe hypoglycaemia but not the overall likelihood of hypoglycaemia. Insulin detemir & insulin glargine are long acting insulins. There have not been any head to head comparisons of the safety and efficacy of the 2 analogues. Current information on insulin detemir was reviewed in the DTB in October 2004 and the London New Drugs Group in August The conclusions are that - Insulin detemir has a novel pharmacological profile in that the insulin molecule reversibly binds to albumin thus delaying its action and resulting in a prolonged duration of action up to 24 hours. It can be administered once or twice daily depending on the patients needs in combination with meal related short or rapid acting insulin. There is limited published information on insulin detemir. In clinical trials it has been compared to NPH insulin. In clinical trials there was no difference in HbA1c levels with insulin detemir and NPH insulin. Insulin detemir appears to provide more stable glycaemic control with less risk of nocturnal hypoglycaemia. Although in one study the total number of hypoglycaemic episodes was similar to NPH insulin and some of the episodes were more serious. Patients using NPH insulin gained on average 0.6kg more weight than those on insulin detemir. 2 small studies have compared patients using soluble human insulin + NPH insulin with patients using insulin detemir + insulin aspart. An 18 week study of 595 type 1 diabetics showed that the patients using the detemir + aspart combination had lower mean HbA1c levels than those using the soluble + NPH combination (7.88% vs. 8.11%, p<0.001) and also had a lower risk of overall and nocturnal hypoglycaemia. Those on insulin detemir had a 1kg lower final body weight (p<0.001). A 22 week study of 395 type 2 diabetics showed that patients using the 2 regimens had similar HbA1c levels and similar numbers of nocturnal hypoglycaemic episodes. The patients on insulin detemir experienced less weight gain (0.51kg vs. 1.13kg, p=0.038). Insulin detemir may offer an advantage over insulin glargine in that it Not to be used for promotional purposes Page 5 of 13 May be freely copied by NHS agencies

6 can be administered using the already widely used Novopen 3 device whereas insulin glargine has to be administered via the less familiar Optipen or Autopen devices. For patients requiring high doses of basal insulin, up to 70 units can be delivered with the single injection with the Novopen however with the Optipen and Autopen devices, the single maximum doses are 60 units and 42 units respectively. It is worth noting that on January 6 th 2004 the MHRA issued a Medical Device Alert for the Aventis Optipen Pro Insulin pen injection system as there was a problem with the plunger as well as dose settings difficulties resulting in insulin administration problems (MDA/2004/002). In excess of 1000 product technical complaints had been received by Aventis by January 2004, after over 130,000 pens had been distributed in the UK. The advice given was to ensure that all patients were adequately trained and proficient in the safe use of the pen. Then On January 11 th 2005 the MHRA issued another medical device alert for the Aventis Optipen Pro insulin pen injection system (MDA/2005/003). There was the potential for the dosage button to fail to engage at the end of an injection, which may lead patients to believe that the injection has not been successful and consider giving another dose. It was advised that patients should be aware of the potential for the dosage button to fail to engage and that if this occurred, they should replace their Optipen with a new one. Use of insulin glargine is reviewed in the October 2004 DTB article, Jan 2005 NEJM paper and March 2005 Prescriber review. Points to highlight include Following subcutaneous injection, insulin glargine forms microprecipitates which gradually redissolve back into solution to enable slow absorption over hours. There is no pronounced peak of action. The injection must be given at the same time each day and can be used with oral antidiabetic drugs in type 2 diabetics. In some people, optimal basal coverage is not obtained with a single injection and a growing minority of users are now taking it twice daily. Variability of absorption remains a problem and erratic glucose control and nocturnal hypoglycaemia, while improved, still trouble some users. Seven randomised controlled trials, involving 2,536 patients with type 1 diabetes and lasting 4-28 weeks have compared once daily insulin glargine with once, twice or four times daily NPH insulin in addition to soluble human insulin or insulin lispro. Only 4 trials assessed HbA1c levels 2 showed a reduction with insulin glargine (0.14% & 0.4%) and 2 showed no change. In terms of hypoglycaemia with insulin glargine, 2 studies reported a significant reduction in symptomatic hypoglycaemia (~10% fewer Not to be used for promotional purposes Page 6 of 13 May be freely copied by NHS agencies

7 patients); 1 study reported a significant reduction in mild hypoglycaemia (~1/3 fewer episodes); 2 studies reported a significant reduction in nocturnal hypoglycaemia (~10-20% fewer patients) and 2 reported no difference in hypoglycaemia. One of the studies did also report more hypoglycaemic episodes with insulin glargine than NPH insulin (p=0.03). Only 3 trials measured weight changes 2 reported no weight gain in either group and one showed reduced weight gain with insulin glargine compared to NPH insulin (0.12kg vs. 0.54kg, p=0.034). In one 28 week trial with 518 type 2 diabetics, changes in HbA1c levels were similar with insulin glargine and NPH insulin as was the frequency of mild symptomatic hypoglycaemic episodes. Nocturnal hypoglycaemia was less likely with insulin glargine (26.5% vs 35.5%, p=0.0136) and there was less weight gain (0.4kg vs. 1.4kg, p<0.0007). A 52 week trial in 426 type 2 diabetics who had not used insulin before found HbA1c levels improved similarly in those on insulin glargine and NPH insulin and weight gain was comparable. Summary Both detemir & galrgine are longer acting analogues given once daily, although detemir is often given twice daily. Both detemir & glargine seem to result in glycaemic control that is at least comparable with NPH insulin. Detemir appears to reduce nocturnal hypoglycaemia & result in less weight gain than NPH insulin in type 1 diabetics. Glargine seems to reduce nocturnal hypoglycaemia in patients with type 1 or 2 diabetes. Impact for Suffolk network NICE recommendations were that glargine is not recommended for routine use in type 2 diabetics who require insulin, but it may be considered in those who Require assistance with injecting insulin Lifestyle is significantly restricted by recurrent symptomatic hypoglycaemia Would otherwise need twice daily basal insulin injections in combination with oral antidiabetic drugs Currently over 250,000 people have been diagnosed with type 1 diabetes in the UK and require life-long insulin. Approximately 1.5 million people have type 2 diabetes, of which it is estimated that about 30% may receive insulin in order to achieve tight glycaemic control. The UK population in 2003 was about 59,600,000. Not to be used for promotional purposes Page 7 of 13 May be freely copied by NHS agencies

8 For full Suffolk details please see Table at end of this section Currently insulin therapy is seen as a last line treatment for type 2 diabetics, however there is a trend to use insulin earlier in type 2 diabetics as a result of information from the UKPDS studies. The UK Prospective Diabetes Study (UKPDS) showed that intensive control of blood glucose, using sulphonylurea or insulin - and, for overweight people, metformin - could reduce the risk of diabetic complications substantially. In addition, the study showed that Type 2 diabetes is characterised by a steady decline in beta cell function that leads to progressive hyperglycaemia despite continued therapy with sulphonylurea or metformin. To offset this, most people with Type 2 diabetes will, in time, need insulin therapy. The RCN produced a publication in 2004 on how to start insulin therapy in adults with type 2 diabetes. s%20with%20type%202%20diabetes.pdf Strong indications for insulin therapy include: symptoms of hyperglycaemia such as polyuria, thirst, recurrent fungal infections (especially genital thrush) or bacterial infections (especially urine infections) pregnancy or planning pregnancy oral hypoglycaemic treatments not tolerated/contra-indicated weight loss without dieting in someone of low or normal weight. Possible indications for insulin therapy include: unsatisfactory glycaemic control, even with the maximum tolerated dose of oral hypoglycaemic agents (HbA1c > 7%, self blood glucose monitoring results > 7 mmols/l before meals or 9 mmols/l 2 hrs after meals) personal preference myocardial infarction - the DIGAMI study (Malmberg et al 1995) suggests that intensive insulin treatment following myocardial infarction improves long-term survival) painful neuropathy foot ulceration and infection. Who may not benefit from insulin treatment? Some obese people - insulin treatment can lead to further weight gain, with little or no improvement in HbA1c. People whose oral hypoglycaemic treatment regimen could be improved - would they prefer to change to a more effective oral Not to be used for promotional purposes Page 8 of 13 May be freely copied by NHS agencies

9 treatment regimen? Elderly people with a short duration of diabetes and no symptoms of hyperglycaemia - are disabling long-term diabetic complications likely to develop in their lifetime? People with other physical or mental health problems - do the potential benefits of insulin treatment outweigh the potential risks, especially the risk of hypoglycaemia? When should insulin treatment be started? Insulin therapy should be discussed as a treatment option at the time of diagnosis. It should not be used as a threatened punishment for poor compliance. Treatment should start: as soon as there is evidence of deteriorating glycaemic control after exploring whether the person could change their lifestyle or current medication after a full discussion of all the pros and cons of insulin therapy. When people don t want insulin therapy Bear in mind that there will be some situations or factors that may put people off starting insulin therapy: occupation - people using insulin cannot hold an LGV or PCV licence, and must undergo a medical assessment before applying for a C1 licence in order to drive vehicles between 3.5 and 7.5 tonnes fear of needles - accurate information can help with this. misconceptions - some people overestimate the risk of hypoglycaemia, while others may be basing their ideas on stories about outdated treatments and equipment live for today - some people may prefer to live with the increased risk of complications, particularly if they do not currently have any symptoms. Costs Insulin analogues Approx. annual cost Short acting Aspart (Novorapid) 360 Lispro (Humalog) 360 Longer acting Detemir (Levemir) 190 Glargine (Lantus) Biphasic Aspart (Novomix 30) Lispro (Humalog Mix25) Conventional human insulin Short acting Actrapid Humulin S Longer acting Humulin I Insultard Biphasic Humulin M3 Mixtard Not to be used for promotional purposes Page 9 of 13 May be freely copied by NHS agencies

10 Prices are taken from MIMS March Costs calculated on cartridge costs, assuming the patient is using 50 units daily of a short acting insulin, 20 units daily of a longer acting insulin or 50 units daily of a biphasic insulin. Economic Information Number of patients in Suffolk with Type 1 and Type 2 Diabetes PCT Type 1 diabetes Type 2 diabetes Central Suffolk 413 1,652 Ipswich 595 2,381 Suffolk Coastal 414 1,657 Waveney 510 2,042 Suffolk West 900 3,600 East system 1,422 5,690 Suffolk total 2,832 11,332 Not to be used for promotional purposes Page 10 of 13 May be freely copied by NHS agencies

11 Charts to be used in the decision making process in Suffolk Quality of Evidence categories Cost utility categories Per life year gained I Strong evidence from at least 1 RCT A Less than 3,000 II-1 Evidence from a well designed CT without randomisation B 3,000 to 20,000 II-2 Evidence from well designed cohort or case controlled study C > 20,000 II-3 Evidence from multiple time series or dramatic results D Negative life years III Opinions of respected clinicians or expert committees IV Evidence inadequate Recommendations informed by cost utility and quality of evidence Key to Table at Right Quality of evidence A B C D ++ Strongly recommended I ++ (high) ++ - X + Recommended II X - Beneficial but high cost III X X Not recommended IV (low) 0 Not proven Adapted from Quick and Clean : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No Not to be used for promotional purposes Page 11 of 13 May be freely copied by NHS agencies

12 To Decide If A Medication Is To Be Used In Suffolk Criterion Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed IV III II-2 II-1 I Magnitude of effect inferred from the trials reviewed Low Medium High Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For Poor Medium Good The Same Condition Severity of Condition to be Treated Trivial Medium Severe Cost Utility Score D C B?A A Recommendations informed by cost utility and quality of evidence 0 X Not to be used for promotional purposes Page 12 of 13 May be freely copied by NHS agencies

13 To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green D Green Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy Green Not to be used for promotional purposes Page 13 of 13 May be freely copied by NHS agencies