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NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Centre for Clinical Practice

Review of Clinical Guideline (CG66 and CG87 partial update) ­ Type 2 Diabetes: the management of type 2 diabetes

Background information

CG 66 Guideline issue date: May 2008 CG87 (partial update of CG66) Guideline issue date: May 2009 Review date for CG66 & CG87: 2011 National Collaborating Centre: NCGC

Review recommendation

The guideline should be updated at this time.

Factors influencing the decision

Literature search 1. From initial intelligence gathering and a high-level randomised control trial (RCT) search clinical areas were identified to inform the development of clinical questions for focused searches. Through this stage of the process 590 studies were identified relevant to the guideline scope. The identified studies were related to the following clinical areas within the guideline: Patient Education Lifestyle/non-pharmacological management Glucose control levels Self-monitoring of plasma glucose

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Oral glucose control therapies (1): metformin, insulin secretagogues and acarbose Oral glucose control therapies (2): other oral agents and exenatide (DPP-4 inhibitors (sitagliptin, vildagliptin), Thiazolidinediones (pioglitazone, rosiglitazone), GLP-1 mimetic (exenatide)) Glucose control: insulin therapy (Oral agent combination therapy with insulin and insulin therapy) Cardiovascular risk estimation Management of blood lipid levels (statins and ezetimibe, fibrates, and nicotinic acid) Anti-thrombotic therapy

2. The need for more focussed searches was considered based on the qualitative feedback from other NICE departments and the views expressed by the Guideline Development Group. A search was performed on one topic only; the effectiveness of Tredaptive, a nicotinic acid/laropiprant combination, in people with type 2 diabetes. Fifty papers were identified but none of the studies were found to be based on diabetic populations.

3. There is new evidence in seven of the areas examined which may potentially change the current recommendation(s), they are: Target HbA1c levels and units Self-monitoring of blood glucose Pharmacological intervention evidence updates including the effect of drugs coming off patent and newly licensed medications and their health economic impact: The use of aspirin for the primary prevention of cardiovascular events New members of the DPP-4 (gliptin) class (linagliptin, saxagliptin, alogliptin), and new indications within licensed class members Simvastatin maximum dose and concurrent use of other lipid lowering medications

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Pioglitazone and atorvastatin are both due to come off patent later this year

4. New evidence was identified which directly answered the six research recommendations presented in the original guideline. The effect of metformin on cardiovascular outcomes. Self-monitoring plasma glucose as part of patient education. ACE inhibitors and angiotensin II-receptor antagonists GLP-1 mimetics. DPP-4 inhibitors. Long-acting insulin and quality of life. No papers were found to address research recommendations 4.2, 4.5 and 4.8.

5. Several ongoing clinical trials and research (some publication dates unknown and references not provided) were identified by the GDG:

NHS Diabetes commissioned an evaluation for the self-monitoring of blood glucose Meta-analysis of the six major self monitoring of blood glucose trials (Summer 2011) Testing intervals for HbA1c Effects of metformin therapy on HbA1c levels (submitted for publication). New Type 2 diabetes pharmacological agents including GLP-1 mimetics, SGLT2 inhibitors, dapagliflozin, insulin degludec, new DPP4s. The 2012 ORIGIN (insulin glargine) reports. ASCEND (A Study of Cardiovascular Events iN Diabetes) trial on aspirin ± omega-3 fatty acids and risk of cardiovascular events in people with type 1 or type 2 diabetes (completed in March 2011).

6. In conclusion, new emerging and future evidence was identified that may impact the current guideline recommendations.

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Guideline Development Group and National Collaborating Centre perspective 7. A questionnaire was distributed to members of the GDG regarding the need for an update of the guideline. Eight responses were received with respondents highlighting a number of ongoing research studies and that since publication of the guideline more literature has become available on: Patient education Glucose control levels Oral glucose control therapies: metformin, insulin secretagogues and acarbose Oral glucose control therapies: other oral agents and exenatide Glucose control: Insulin therapy Blood pressure therapy Cardiovascular risk estimation Management of blood lipid levels Kidney and eye damage Nerve damage 8. Of note inpatient care was excluded from the previous CG66, but inpatient insulin prescribing has been highlighted as a safety issue and potential risk area by a GDG member. Implementation and post publication feedback 9. Key themes emerging from post-publication feedback were: Concerns over BMI and the use of exenatide Units of HbA1c (not an evidence issue) Definition of 'markedly hyperglycaemic' Optometry referrals Cost implications of implementing CG66

10. An analysis by the NICE implementation team indicated:

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Relationship with the obesity guidance and what push was there to ensure action on prevention. It would be useful if guidance clearly identified whether it is relevant to childrens services Difficulties in implementing the guideline because of high cost impact and for mental health trusts because not written for this specific audience There was some concern that an increase in admissions for hypos may be linked with the HbA1c levels and anomalies between the NICE guideline and QOF indicators. There was a suggestion that NICE consider including the use of ketone testing devices in the management of diabetes Pathway including podiatry, as part of the diabetes pathway, would be useful There was a request that quality standards incorporate more standards relevant to children and ensure that quality standards cover the whole life span, including transition from child to adult services.

Relationship to other NICE guidance 11. NICE guidance related to CG87 and CG66 can be viewed in Appendix 1. These include technology appraisals (TA) on drugs that the stakeholders requested including in this guideline: long acting insulin analogues (TA53); insulin pump therapy (TA151); liraglutide (TA203); thiazolidinediones (replaced by CG66, TA63); and TAs in progress on exenatide, dapagliflozin and buccal insulin as well as those currently progressing through topic selection. The appropriateness of the inclusion of these in the guideline will need further discussion with CHTE during scoping of the update.

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Summary of Stakeholder Feedback

Review proposal put to consultees: The guideline should be updated at this time.

12. In total 22 stakeholders commented on the review proposal recommendation during the 2 week consultation period. The majority of stakeholders (18) agreed overall with the decision to update, although three felt that the update should be delayed to await evidence on new drugs (including GLP-1 mimetics, DPP-4 inhibitors, thiazolidinediones, oral glucose therapies, statins and ezetimibe, long acting insulins). 13. Literature was submitted through stakeholder consultation relating to: DPP-4 inhibitors (linagliptin, sitagliptin) GLP-1 mimetics (exenatide when used with insulin) Thiazolidinediones (pioglitazone) Metformin Oral agent combination therapy with insulin (with Lantus insulin) Statins Anti-thrombotic therapy (aspirin) Nicotinic acid Other literature submitted related to areas excluded from the original scope: Bariatric surgery, testosterone therapy.

14. During consultation, additional areas from the original scope to consider for review in an update of the guideline were highlighted including:

Self-monitoring of plasma glucose (1.4.1-1.4.3) Glucose control levels - HbA1c targets (1.3.1-6) CV Risk assessment (1.9.1) Hypertension (1.8.1-13) Metformin (1.5.1) Statins and ezetimibe (1.10.1) Fibrates (1.10.2)

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Oral agent combination therapy with insulin (1.7.1) Nicotinic Acid (1.10.3) Anti-thrombotic therapy (1.11.1). Dietary advice (1.2.1.1-9) Insulin therapy including long-acting insulins (e.g. degludec) (1.7.2).

15. In summary while a number of stakeholders felt we should delay the update of the guideline because of pending licenses and the publication of new data, many other SHs believe the guideline has needed substantial updating for some time and feel that this should occur as rapidly as possible. For this reason, and because new data will always be rapidly becoming available in this field, it is recommended that an update of this guideline should go ahead now.

16. During consultation, new areas outside of the original scope to consider in an update of the guideline were highlighted including: testosterone therapy.. the role of bariatric surgery in the management of T2DM. management and treatment of T2DM patients with renal disease. the inequality in the access and quality of healthcare for people with a poorer background and to include the White Papers standards on providing a choice of treatments for patients.

Anti-discrimination and equalities considerations

17. No evidence was identified to indicate that the guideline scope does not comply with anti-discrimination and equalities legislation. The original scope is inclusive of all adults diagnosed with type 2 diabetes, including specific patient subgroups for whom the impact of agents might differ. The original scope did not include people with type 2 diabetes who are younger than 18 years and pregnant women with type 2 diabetes or gestational diabetes.

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Conclusion 18. From the evidence and intelligence identified through the process, it is suggested that a number of areas of the guideline currently need updating, particularly in relation to:

Self-monitoring of blood glucose levels and drug therapies such as DPP-4 inhibitors, thiazolidinediones, GLP-1 mimetics, metformin, and oral agent combination therapies with insulin.

19. There are a number of related technology appraisals either in development or proposed and recent discussions through the topic selection process have indicated that it may be appropriate for these to be developed within the context of the update of the guideline. During the scoping of the update, further discussions will need to take place with CHTE regarding the incorporation of existing technology appraisals and those that are currently in development or in the topic selection process.

Relationship to quality standards 20. There is currently a quality standard on diabetes in adults which covers both type 1 and type 2 diabetes. This will need to be updated alongside an update of this guideline.

21. There has been a referral for a quality standard on diabetes in children to cover both type 1 and type 2 diabetes . It is therefore proposed that the update of this guideline be extended to cover children as well as aspects of footcare not covered by either of the 2 diabetic footcare guidelines (CG10 and 119).

22. The guideline should be considered for an update at this time.

Fergus Macbeth, Centre Director, CCP Sarah Willett, Associate Director, CCP Review produced by the National Clinical Guideline Centre August 2011

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Appendix 1

The following NICE guidance is related to CG87: Guidance TA63: Glitazones (thiazolidinediones) for the treatment of type 2 diabetes (replaced by CG66), 2003 TA53: Diabetes (types 1 and 2) ­ long acting insulin analogues, 2002 TA60: Diabetes (types 1 and 2) ­ patient education models, 2003 (reviewed 2006, partially updated by CG66 and CG87) CG43: Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children, 2006 CG10: Type 2 diabetes: the prevention and management of foot problems, 2004 CG15: Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults, 2010 CG34: Hypertension: Update due to be published Review: July 2011 Review: July 2011 Review: December 2011 Review: TBC Review: TBC Review date N/A

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management of hypertension in adults in primary care, 2006 CG63: Diabetes in pregnancy ­ management of diabetes and its complications from preconception to the post natal period, 2008 CG66: Type 2 diabetes (partially updated by CG87): the management of type 2 diabetes (update), 2008 CGE: Management of type 2 diabetes: retinopathy (replaced by CG66), 2002 CGF: Management of type 2 diabetes: renal disease, prevention and early management (replaced by CG66), 2002 CGG: Management of type 2 diabetes: management of blood glucose (replaced by CG66), 2002 CGH: Management of type 2 diabetes: management of blood pressure and blood lipids (replaced by CG66), 2002

August 2011

Review: May 2011

Review: July 2011

N/A

N/A

N/A

N/A

Related NICE guidance not included in CG87 CG96: Neuropathic pain: Review: March 2013

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the pharmacological management of neuropathic pain in adults in nonspecialist settings, 2010 Quality Standard: Diabetes in adults, 2011 TA151: Diabetes ­ insulin pump therapy, 2008 TA203: Diabetes (type 2) ­ Liraglutide, 2010 TA210: Vascular disease ­ clopidogrel and dipyridamole: Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90), 2010 QOF indicator NM13: The percentage of patients with diabetes with a record of a foot examination and risk classification: 1) low risk (normal sensation, palpable pulses), 2) increased risk (neuropathy or absent pulses), 3) high risk (neuropathy or absent pulses plus deformity or skin changes or previous ulcer) or 4) ulcerated foot within the preceding 15

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Review: TBC

Review: February 2011

Review: May 2012

Review: TBC

Review: TBC

months, August 2010 QOF indicator NM12: The percentage of patients with diabetes with a record of testing of foot sensation using a 10g monofilament or vibration (using biothesiometer or calibrated tuning fork), within the preceding 15 months, August 2010 Commissioning Guide: Foot care service for people with diabetes, December 2006 Related NICE guidance in progress CG119: Diabetic foot ­ inpatient management of people with diabetic foot ulcers and infection, 2011 TA in progress: Diabetes (type II) exenatide (prolonged release) TA in progress: Diabetes ­ buccal insulin TA in progress: Diabetic macular oedema ­ fluocinolone acetonide intravitreal implant TA in progress: Macular oedema (diabetic) ­ pegaptanib sodium TA in progress: Macular oedema (diabetic) ­

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Review: TBC

Review: TBC

TBC

Publication: February 2012

Publication: TBC

Publication: TBC

Publication: TBC

Publication: TBC

ranibizumab TA in progress: Dapagliflozin for the treatment of type 2 diabetes Public health guidance: Preventing type 2 diabetes: population and community interventions, 2011 Public health guidance: preventing the progression from pre-diabetes, in progress Public health guidance (PH1): Brief interventions and referral for smoking cessation, 2006 Review: March 2012 Publication: May 2012 Review: 2014 Publication: TBC

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APPENDIX 2 National Institute for Health and Clinical Excellence Type 2 Diabetes Guideline Review Consultation Comments Table 1June 2011 - 14 June 2011

Agree with proposal to update? Agree Comments on equality issues

Stakeholder ABCD

Comments Self monitoring of blood glucose in non-insulin treated patients continues to be an area of contention in clinical practice, particularly in Primary Care, re-assessment of recent trials and more clarification would be helpful. We would recommend a change in emphasis to when SMBG should be used. In particular, some reference should be made to hypoglycaemia avoidance in individuals with T2DM on insulin and sulphonylureas. The publication of large trials looking at intensive lowering of glycaemia and the adverse (ACCORD) and neutral outcomes (ADVANCE) indicate that NICE should look at the appropriateness of the present recommendation for HbA1c targets Whilst ABCD recognises that NICE is able to offer advice on licensed agents only, ABCD is hopeful that the licensed indications of the GLP-1 mimetcs, liraglutide and exenatide (and perhaps other GLP-1 mimetics) will have changed by the time new guidance is considered to allow co-prescription of these agents with insulin. ABCD would draw NICEs attention to the nation-wide audit of the use of these agents including a recently accepted paper in Diabetes, Obesity and Metabolism:. Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists (ABCD) 1 1 nationwide exenatide audit. K. Y. Thong , B. Jose , N. 1 Sukumar , et al. (in press)

Comments on areas excluded from original scope

ABCD

Agree

ABCD

Agree

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments The launch of once weekly exenatide in the UK will also need to be addressed by the GDG. Saxaglipitin now has a licence for use in patients with moderate kidney disease and ABCD feels this should be considered by NICE in the DPP-4 section. Sitagliptin now has a licence to used with insulin and this will need to be considered also. Rosiglitazone has been withdrawn from the market and the thiazolidinedione section needs to be updated to reflect this; further analysis of the role and safety of pioglitazone is required. Also, pioglitazone is now off patent and may become significantly less expensive which will alter the health economic calculations. Furthermore, at the time of writing the French authorities have suspended pioglitazones licence and the EMEA are studying its safety profile. There have been long running concerns regarding the safety of Lantus insulin, but further data have recently been published. A forthcoming paper in Diabetalogia (Suissa et al, Diabetologia 011-2190-9) will provide reassurance. The producers have data suggesting that the active agent is a metabolite of lantus insulin which has low affinity to the IGF-1 receptor. NICE will need to comment. The use of NPH as first-line insulin in most patients with type 2 diabetes requiring insulin has not gained acceptance in most health economies; another analysis of insulin use in type 2 diabetes, with perhaps an alternative calculation on the cost of hypoglycaemic episodes, is, in ABCDs opinion, appropriate. Newer longer acting insulins such as degludec may be licensed in time for an update guideline, it would be helpful if this were the case. The update of the UKPDS risk engine for calculating cardiovascular risk needs to be assessed in the light of the lipidlowering, as well as the anti-hypertensive, recommendations. Newer statins (such as rosuvastatin) may have a better safety profile than more established statins such as simvastatin and

Comments on areas excluded from original scope

Comments on equality issues

ABCD

Agree

ABCD

Agree

ABCD

Agree

ABCD

Agree

ABCD

Agree

ABCD

Agree

ABCD

Agree

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update? Agree

Comments this should be recognised. The role of the fibrates in the management of patients with raised triglyceride levels is changing. The ACCORD lipid trial confirming beneficial microvascular outcomes in individuals treated with fibrates has opened the debate. Updated guidance from NICE would be helpful, although synchronisation with the forthcoming JBS3 guidelines would be important. The present recommendation to use aspirin as primary prevention for CV disease in type 2 diabetes is recognised to be incorrect; re-assessment of this recommendation and further analyses of the role of clopidogrel would be helpful.

Comments on areas excluded from original scope

Comments on equality issues

ABCD

ABCD

Agree

Allergan

Agree with the proposal to update

The role of bariatric surgery for the management of type 2 diabetes: CG43 specifically focus on the use of bariatric surgery in the management of obesity and patient with obesity who may or may not have type 2 diabetes This is a rapidly advancing field and area of medicine with new clinical data supporting the role of surgery in the management of type 2 diabetes IDF has recently (April 2011) released a positioning statement on the role of bariatric surgery for the management of type 2 diabetes

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments

Comments on areas excluded from original scope American Diabetes Association has a positioning statement on the role and utilisation of bariatric surgery in the management of type 2 diabetes NHS Diabetes is formalising its position and guidance on access to and the role of bariatric surgery The role of bariatric surgery as a treatment for and in the management of type 2 diabetes is supported by a number of clinical studies, surgical registries and randomised controlled clinical trials (Dixon et al., JAMA 2008) Data suggest that both the health economic and budget impact arguments support the utilisation of bariatric surgery in the type 2 diabetic population

Comments on equality issues

AstraZeneca

AstraZeneca

We agree with the proposal to update the guidelines. We agree with the proposal to

1.3.1, 1.3.3-1.3.6 We agree that the target of HbA1c needs to be reviewed but this shouldnt be in the form of a blanket statement to all type 2 diabetes patients as certain groups of patients may benefit from intensification or a lower target. 1.4.1 ­ 1.4.3 As above, this shouldnt be a blanket statement referring to all patients as motivated patients may benefit from SMBG.

.

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

AstraZeneca

AstraZeneca

AstraZeneca

Agree with proposal to update? update the guidelines. We agree with the proposal to update the guidelines. We agree with the proposal to update the guidelines. We agree with the proposal to update the guidelines. We agree with the proposal to update the guidelines. We agree that the guidelines around use of statins should be updated

Comments

Comments on areas excluded from original scope

Comments on equality issues

1.6.1.1 ­ 1.6.1.5 Whilst the introduction of new DPP4s does not change the direction of the guidelines, an update is warranted to keep them current as saxagliptin, a further DPP4, is now on the market. 1.6.2.1 ­ 1.6.2.8 When re-evaluating pioglitazone, fracture rates and heart failure should be taken into account. It should also be noted that pioglitazone has been withdrawn in France and that the EMA are reviewing its risk/benefit analysis Clinical area 6: Oral glucose control therapies (2): other oral agents and exenatide Under this section we would like to highlight that dapagliflozin, first in class for the new SGLT2 class is likely to receive marketing authorisation before the publication of these guidelines and so should be considered for inclusion. 1.6.1.1 ­ 1.6.1.5 Clearer guidance on the use of glycaemic agents in moderate and severe renal disease is required. Currently there is only information available on changing metformin dose; guidance on all other classes that can be used in this population will aid clinical practice and maintain patient safety. 1.10.1.2-7 We are unsure as to why the ezetimibe study has been highlighted. The guidance (TA132) states that ezetimibe in combination with a statin should be used only after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance and consideration is being given to changing from initial statin therapy to an alternative statin. We believe that when identifying a suitable alternative to simvastatin 80 mg the full body of evidence on statins should be considered 1 and this includes the 2010 CTT meta analysis . .

AstraZeneca

AstraZeneca

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments The studies CORALL and URANUS compare the use of rosuvastatin with atorvastatin in patients with type 2 diabetes and should also be included in the review. We also question the rationale for having ezetimibe considered in the statin section when fibrates have their own section. Large 1 pieces of work such as the 2010 CTT meta analysis provide a basis for considering statins in isolation and other lipid modulators separately. We note that reference 296 is for a cost-effectiveness analysis and therefore appears to have been identified as a relevant RCT in error. In reference to the statement that atorvastatin "may displace simvastatin in terms of .... lower toxicity", we are not aware of the direct evidence for comparative toxicity between all the statins across the dose range. When considering toxicity, apart from dose of statin other factors to consider include the route of metabolism, relative lipophilicity:hydrophilicity and potential 4 concomitant drug interactions as these differ between statins . We are therefore interested in the evidence base for this statement. In light of the nature of the new evidence identified it would seem appropriate for the update of the lipid modification guidelines to be undertaken in parallel.

2 3

Comments on areas excluded from original scope

Comments on equality issues

AstraZeneca

AstraZeneca

AstraZeneca

We agree with the proposal to update the guidelines. We agree with the proposal to update the guidelines. We agree with the proposal to update the guidelines.

AstraZeneca

Bayer plc.

We agree with the proposal to update the guidelines. Agree with the proposal to update.

Hypogonadism is a prevalent condition in men with Type 2 diabetes. In a UK cross-sectional study of 355 Type 2 diabetic men by Kapoor et al. (2007), overt hypogonadism was seen in 17% of men with total testosterone <8 nmol/l, and a further 25% had symptoms of hypogonadism associated with total i testosterone between 8 and 12 nmol/l. An increasing body of evidence has been published suggesting that testosterone therapy has beneficial effects on components

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments of the metabolic syndrome and the clinical characteristics of Type 2 diabetes in men with low testosterone (reviewed by ii Jones 2011 ). A number of recent studies involving hypogonadal men with Type 2 diabetes, have demonstrated improvements to insulin resistance, HbA1c, waist circumference, and glycemic iii,iv,v control following testosterone therapy. Beneficial effects on lipids and blood pressure have been reported in some, but not all studies. In addition, data was recently presented at the Society for Endocrinology BES in Birmingham (April 2011), which shows that low testosterone predicts increased mortality, and testosterone therapy improves survival in men with Type 2 vi diabetes. The same group have also recently demonstrated that low testosterone equates to a reduction in quality of life for vii men with diabetes. An evaluation of cost-effectiveness of screening for and treating testosterone deficiency in men with Type 2 diabetes was th viii presented in 2010 at the 7 Mens World Health Congress. The evaluation, based on the IMS Core Diabetes Model and 3 data from the trial by Kapoor et al. (2006), projected health outcomes and economic consequences over 50 years. A UK NHS perspective was adopted with costs and outcomes discounted at 3.5% per year, as per the NICE reference case. The conclusions of this work were that testosterone therapy could improve outcomes in Type 2 diabetes patients with hypogonadism in a cost-effective manner. However, the authors highlighted that conclusions are limited due to the small size of the original clinical study, and that additional research confirming the impact of testosterone therapy on cardiovascular risk factors in hypogonadal men with Type 2 diabetes is warranted. The above suggests that testosterone testing should take place in all men with Type 2 diabetes and symptoms of testosterone deficiency. This is in line with recommendations from the British ix Society for Sexual Medicine (BSSM) (section 3.9.1), the x Endocrine Society (table 3) and the International Society of

Comments on areas excluded from original scope

Comments on equality issues

Bayer plc.

Agree with the proposal to update.

Bayer plc.

Agree with the proposal to update.

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments Andrology (ISA), the International Society for the Study of Aging Male (ISSAM) the European Association of Urology (EAU) European Academy of Andrology (EAA) and the American xi Society of Andrology (ASA) (recommendation 8.1). The suggested topics for the new QOF Recommendations for Indicator Development, published in January 2011, also contains a recommended indicator for the measurement of testosterone xii level in the annual assessment men with Type 2 diabetes. Comment on section 13 Cardiovascular risk estimation, p181 of CG66. There is evidence to suggest that erectile dysfunction is also a xiii marker of underlying cardiovascular disease, and therefore should also be covered in section 13 - Cardiovascular risk estimation. Comment on section 18.4 Erectile dysfunction, p250 of CG66. According to guidelines on the management of erectile dysfunction published by the British Society for Sexual Medicine (BSSM), hypogonadism is a treatable cause of erectile dysfunction that may also make men less responsive, or even nonresponsive, to phosphodiesterase type 5 (PDE5) inhibitors; therefore, all men with erectile dysfunction should have their xiv serum testosterone measured. NHS Diabetes have produced a factsheet on diabetes and xv erectile dysfunction which discusses hypogonadism. Recommendations 1.4.1- 1.4.3 The literature search has not shown Self Monitoring Blood Glucose (SMBG) to be cost effective and this may be due to the high acquisition costs associated with testing strips, sometimes almost a similar price to newer anti diabetes drugs. However, The use of this monitoring is closely associated with either secretagogues (SUs or glinides or Insulin) and is arguably not required if using agents such as metformin, TZDs or DPP4 inhibitors. However, it should be considered that recent DVLA

Comments on areas excluded from original scope

Comments on equality issues

Bayer plc.

Agree with the proposal to update.

Bayer plc.

Agree with the proposal to update.

Bristol-Myers Squibb Pharmaceuticals

We agree with the proposal to update

There are new indications for DPP4s that should be considered on the remit of this Clinical Guideline. Saxagliptin has been recently granted a licence to treat patient with moderate and severe renal impairment.

None

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments guidance for diabetic patients on SUs or glinides requires close monitoring. Indeed, there are medico legal precedents where patients found not have tested themselves prior to driving were found guilty of a hypoglycaemia induced accident. The use of agents such as saxagliptin in combination with metformin or TZD would considerably reduce the need for monitoring. Recommendations 1.3.1 ­ 1.3.3. Meta analyses based on these large studies need to be interpreted with caution. The patient population being studied was different and the intervention and more importantly, the manner in which in this was implemented was significantly different. This shows up in the high heterogeneity (i2 values) found in the analyses. All these studies illustrate the need to personalise hba1c targets to the right patient at the right time. In clinical practice, physicians could use these agents to achieve a low target of 6.5% with out increasing the risk of hypoglycaemia, while maintaining non inferiority to an agent such as sulphonylurea. In a more vulnerable patient where CV risk factors may be present, use of an agent with a low risk of hypoglycaemia with a good CV safety profile may be advantageous. Section 1.6.1 Comment: Trials including Saxagliptin will be completed and new licenses are expected before the publication of this guidance. A cross trial comparison would be required as there are no published studies for the purpose of the comparisons and statements written on this section. No agents have a license in quadruple therapy. Use of such a combination would then be at the physician discretion as well as patient choice, where insulinisation may be unacceptable due to

Comments on areas excluded from original scope

Comments on equality issues

Bristol-Myers Squibb Pharmaceuticals

We agree with the proposal to update

Bristol-Myers Squibb Pharmaceuticals

We agree with the proposal to update

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments needle phobia, weight gain, hypoglycaemia, work/driving requirements. Section 1.6.1.1 Comment: The FDA rejected alogliptin on cardiovascular safety grounds Section 1.6.2.1 Comment: When considering the cost of pioglitazone, the effective dose should also be considered. The most commonly used doses are 30 -45 mg which are considerably more expensive than the starting 15 mg dose. The additional cost of possible adverse events, especially in patients with a history of CVD, should also be considered. The additional cost of increase in fractures in both men and women associated with pioglitazone should also be considered. Section 1.7.1.1 Comment: The SMpc of pioglitazone warns against the concomitant use of pioglitazone and insulin. There are concerns about increased risk of heart failure so careful patient selection needs to take place. The additional effects of both agents on weight should also be considered. Currently, no GLP-1 mimetics are licensed for use with insulin. Section: 1.11.1 Comment: The popadad study highlighted that aspirin use in patients with diabetes or PAD was not beneficial. Several other studies and meta analyses have confirmed that aspirin may not be effective in primary prevention. Intensification of antiplatelet therapy using an alternate agent like clopidogrel may provide some benefit. Subgroup analyses of diabetic patients in the CAPRIE trial showed a benefit of using clopidogrel vs aspirin. Use of dual antiplatelet therapy as in the primary prevention arm of the CHARISMA trial however is not recommended due to the increase in bleeds.

Comments on areas excluded from original scope

Comments on equality issues

Bristol-Myers Squibb Pharmaceuticals Bristol-Myers Squibb Pharmaceuticals

We agree with the proposal to update We agree with the proposal to update

Bristol-Myers Squibb Pharmaceuticals

We agree with the proposal to update

Bristol-Myers Squibb Pharmaceuticals

We agree with the proposal to update

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

23 of 48

Stakeholder British Psychological Society BSIR Department of Health

Agree with proposal to update?

Comments We note that the recommendation is to review the guidance at this time, and the Society would not disagree with this recommendation. The British Society of Interventional Radiology welcome and support the guidance and have no further comments to add CG 66/87 has needed substantial updating for some time and I absolutely agree that this should occur as rapidly as is consistent with careful consideration of the new evidence. Indeed, I would suggest an annual review for the need of updating as this is a rapidly moving field affecting hundreds of thousands of patients. 1.3.1, 1.3.3-1.3.6 I note the comments on hyperglycaemia in ACS. I am concerned that the draft guidance on the management of hyperglycaemia in ACS has not fully considered all relevant aspects and wonder if it should be delayed until after the review of CG66/87. Page 34 The work commissioned by NHS Diabetes reported is here: Self Monitoring of Blood Glucose Review It is based on the HTA quoted on page 10: "In a 2010 Health Technology Assessment98, SMBG was also shown to have limited clinical effectiveness in non-insulin managed patients with type 2 diabetes and is therefore thought not to be cost-effective. SMBG may be more effective with appropriate education and if patients can self adjust their medication in response to the glucose readings. NHS Diabetes 2010, provide full summaries of the evidence, that for many people with non-insulin treated diabetes, whether or not integrated with self-management education, the impact of SMBG may not be clinically important" The comment above is selectively negative. Specific positive recommendations were made in the NHS Diabetes report for

Comments on areas excluded from original scope

Comments on equality issues

Agree

More could be included on therapeutic and lifestyle issues affecting South Asian and African Caribbean communities, and those affected by social deprivation.

Department of Health

Agree

Department of Health

Agree

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

24 of 48

Stakeholder

Agree with proposal to update?

Comments situations where SMBG is useful. It is regarded as essential for patients on sulphonylureas as they are prone to hypoglycaemia. We will be publishing evidence- based nutrition guidelines for the prevention and management of diabetes in Diabetic Medicine this year which will influence the current guideline recommendation regarding dietetic advice (recommendation 1.2.1.1-1.2.1.9).

Comments on areas excluded from original scope

Comments on equality issues

Diabetes UK

Agree an update is necessary.

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

1.6.3 GLP-1 mimetic (exenatide) (page 17) The Byetta Summary of Product Characteristics (SPC) describes exenatide as a glucagon-like peptide-1 (GLP-1) receptor agonist. This is the preferred drug class term over GLP-1 mimetic as stated throughout the consultation document.

Inpatient care- this now needs to be included in this Type 2 diabetes clinical guideline with signposting to Joint British Diabetes Societies inpatient care group and NHS diabetes guidance covering inpatient care. In addition our position statement addressing in patient diabetes care. Exenatide once weekly for the use in patients with type 2 diabetes was not included in the original scope. Eli Lilly suggest this be included in the new guideline scope.

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

1.6.3 GLP-1 mimetic (exenatide) (page 17) The current clinical questions upon which the literature searches have been based on focus on placebo as a comparator. Eli Lilly would like to make the GDG aware that data for the efficacy and safety of exenatide twice daily and once weekly versus active comparators is available. Recommendations 1.6.3.1-1.6.3.3 (page 18) Eli Lilly are aware of the recently published studies involving exenatide were not identified in the literature search as the cut off was 28 January 2011:

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

25 of 48

Stakeholder

Agree with proposal to update?

Comments Blevins T, Pullman J, Malloy J, et al. DURATION-5: Exenatide Once Weekly Resulted in Greater Improvements in Glycemic Control Compared with Exenatide Twice Daily in Patients with Type 2 Diabetes. J Clin Endocrinol Metab 2011;96(5):0000­ 0000. First published ahead of print February 9, 2011 as doi:10.1210/jc.2010-2081 Taylor K, Gurney K, Han J, et al. Exenatide Once Weekly Treatment Maintained Improvements in Glycemic Control and Weight Loss Over 2 Years. BMC Endocrine Disorders 2011;11:9 C. Wysham, R. Bergenstal, J. Malloy, et al. DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med 2011;28:705­714 Additionally, the following papers were published within the literature search dates however were not identified: Kim D, MacConnell L, Zhuang D, et al. Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes. Diabetes Care 2007;30:1487­1493 Lorenzi G, Schreiner B, Osther J, Boardman M. Application of Adult-Learning Principles to Patient Instructions: A Usability Study for an Exenatide Once-Weekly Injection Device. Clinical Diabetes 2010;28(4):157-162

Comments on areas excluded from original scope

Comments on equality issues

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

Recommendations 1.6.3.1-1.6.3.3 (page 18) The consultation document highlights one systematic review (ref 22) suggesting a possible link of exenatide and acute pancreatitis.

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

26 of 48

Stakeholder

Agree with proposal to update?

Comments The literature search did not identify the following data which provides evidence to show no causal association between exenatide and acute pancreatitis: Bloomgren G, Dore DD, Wenten M, et al. Incidence and Relative Incidence of Medical Record Confirmed Acute Pancreatitis: Exenatide Initiators Compared to Other Antidiabetic Drug Initiators. American Diabetes Association 70th Scientific Sessions, Orlando, June 25-29, 2010 Dore DD, Bloomgren GL, Wenten M, et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes, Obesity and Metabolism Accepted Article 2011 doi:10.1111/j.16000854.2011.01376.x Tatarkiewicz K, Smith PA, Sablan EJ, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab 2010;299:1076-1086. First published Oct 5, 2010; doi:10.1152/ajpendo.00479.2010 Wenten M, Gaebler J, Hussein M, et al. A retrospective cohort study to assess the relative risk of acute pancreatitis among initiators of exenatide compared to initiators of other anti-diabetic medications: a follow-up study. American Diabetes Association 70th Scientific Sessions, Orlando, June 25-29, 2010

Comments on areas excluded from original scope

Comments on equality issues

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

Recommendations 1.6.3.1-1.6.3.3 (page 18) The review consultation mentions ref 145 [Diamant 2010] a study comparing exenatide once weekly and insulin glargine. This study also showed 79% of exenatide once weekly patients had both a reduction in HbA1c and bodyweight, whereas 63% of

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

27 of 48

Stakeholder

Agree with proposal to update?

Comments patients taking insulin glargine had a reduction in HbA1c paired with weight gain [Diamant 2010].

Comments on areas excluded from original scope

Comments on equality issues

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

Recommendations 1.6.3.1-1.6.3.3 (page 18) The consultation document states: A study (ref 83) comparing liraglutide once a day and exenatide twice a day found liraglutide to have greater improvement in glycaemic control and was generally better tolerated. Reference 83 [Buse 2009] evaluated liraglutide 1.8mg daily versus exenatide 10µg twice daily. NICE does not recommend liraglutide 1.8 mg daily for the treatment of people with type 2 diabetes [TA203] and there is no comparative study evaluating exenatide 10µg twice daily against the NICE recommended dose of liraglutide 1.2mg daily [TA203].

Eli Lilly and Company Ltd

Agree with the decision to update CG66 and CG87

Recommendations 1.7.2.4 & 1.7.2.5 Eli Lilly support a review of the recommendations around the use of insulin therapy. However the review consultation, page 24, discusses insulin degludec which is currently not licensed and approximately 2 years from launch. Eli Lilly do not think it is appropriate to include insulin degludec in the review consultation due to the length of time to launch and ask for this to be removed. We would like to comment that if this is to be included in the review consultation, then there are other agents in the pipeline for treatment of type 2 diabetes with similar timelines to launch that should also be discussed. (COMMERCIAL IN CONFIDENCE DATA REMOVED)

Eli Lilly and Company Ltd

Agree with the

References

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

28 of 48

Stakeholder

Agree with proposal to update? decision to update CG66 and CG87

Comments Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374(9683):39-47 Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010;375:2234­43 Eli Lilly and Company. Byetta (exenatide) Summary of Product Characteristics National Institute for Health and Clinical Excellence, 2010. Liraglutide for the treatment of type 2 diabetes mellitus. TA203. London: NICE National Institute for Health and Clinical Excellence. Type 2 diabetes. CG87. London: NICE; May 2009 National Institute for Health and Clinical Excellence. Type 2 diabetes. CG87 Appendix 6.1 Scope. London: NICE; May 2009

Comments on areas excluded from original scope

Comments on equality issues

Janssen-Cilag Ltd

Agrees with proposal to update the guidelines

Lilly UK/Boehringer Ingelheim (BI/Lilly UK)

BI/Lilly UK agree with the proposal to

It is stated that the timeframe for the literature search was ,,2007 th - 28 January 2011. We believe this time timeframe should be updated as follows: ,,2007 until present time so that all the relevant publications on newer agents such as the SGLT2 inhibitors will be included in the updated guidelines. ,,Present time is defined as the date of commencement of the guidelines update process and literature search. Recommendations 1.6.1.1-1.6.1.5 (page 14) The review consultation states that the recommendations would not be likely to change but may include adding further members

The original scope for CG66 addresses renal disease in type 2 diabetic patients but is mostly concerned with detection

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

29 of 48

Stakeholder

Agree with proposal to update? update CG66 and CG87.

Comments of the class and that the identified evidence does not change the direction of the guideline. The following studies have not been identified by the literature search and BI/Lilly believe they may change the direction of the current guideline: Linagliptin in the following randomised, double-blind, placebo controlled studies showed significantly improved reductions in HbA1c levels. Metformin plus sulphonylurea plus linagliptin Owens D, Swallow R, Woerle HJ, et al. Linagliptin improves glycaemic control in type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain and low risk of hypoglycaemia. Poster No. 548, Presented at American Diabetes Association 70th Scientific Sessions, Florida, June 2010]. Linagliptin monotherapy Del Prato S, Barnett A, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomised controlled trial. Diabetes Obes Metab 2011;13:258-267. Linagliptin plus pioglitazone Gomis R, Espadero RM, Jones R, et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes. Poster No. 551, Presented at American Diabetes Association 70th Scientific Sessions, Florida, June 2010. Linagliptin plus Sulphonylurea Lewin AJ, Arvay L, Dacheng L et al. Safety and Efficacy of

Comments on areas excluded from original scope and secondary prevention of kidney damage. BI/Lilly UK suggest extending the scope to include: The appropriate management of patients with type 2 diabetes and renal impairment including recommendations on which antidiabetic treatments are appropriate to use in those with renal impairment? The consequences of suboptimal care in those type 2 diabetic patients with renal impairment?

Comments on equality issues

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

30 of 48

Stakeholder

Agree with proposal to update?

Comments Linagliptin as Add-on Therapy to a Sulphonylurea in Inadequately Controlled Type 2 Diabetes. Poster No. 821. European Association for the Study of Diabetes 46th Annual Meeting, Stockholm, Sweden. 20­24 September 2010.

Comments on areas excluded from original scope

Comments on equality issues

Lilly UK/Boehringer Ingelheim (BI/Lilly UK)

BI/Lilly UK agree with the proposal to update CG66 and CG87.

GDG identification of research currently in progress (page 34) There is a bullet point that states: A new member of class (Linagliptin) may be licensed later this year. Minor changes to the recommendations may be needed as it can probably be used if renal impairment is present BI/Lilly UK would like to state that linagliptin is primarily excreted through bile and gut, whilst other available DPP-4 inhibitors are primarily excreted renally [Januvia SPC, Onglyza SPC, Galvus SPC]. (COMMERCIAL IN CONFIDENCE DATA REMOVED)

Lilly UK/Boehringer Ingelheim (BI/Lilly UK)

BI/Lilly UK agree with the proposal to update CG66 and CG87.

Recommendations 1.7.2.4 & 1.7.2.5 The review consultation, page 24, discusses insulin degludec which is currently not licensed and approximately 2 years from launch. BI/Lilly UK do not think it is appropriate to include insulin degludec in the review consultation due to the length of time to launch and ask for this to be removed. We would like to comment that if this is to be included in the review consultation, then there are other agents in the pipeline for treatment of type 2 diabetes with similar timelines to launch that should also be discussed (COMMERCIAL IN CONFIDENCE DATA REMOVED)

Lilly UK/Boehringer Ingelheim

BI/Lilly UK agree with the

References: Bristol-Myers Squibb/AstraZeneca EEIG. Onglyza (Saxagliptin) Summary of Product Characteristics.

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

31 of 48

Stakeholder (BI/Lilly UK)

Agree with proposal to update? proposal to update CG66 and CG87.

Comments

Comments on areas excluded from original scope

Comments on equality issues

Merck Sharp & Dohme Limited. Januvia (sitagliptin) Summary of Product Characteristics. National Institute for Health and Clinical Excellence. Type 2 diabetes. CG66 Appendix B Scope. London: NICE; May 2008 Novartis Pharmaceuticals UK Ltd. Galvus (vildagliptin) Summary of Product Characteristics.

Merck Serono

Agree and Disagree with proposal to update

In the clinical area 4 (self-monitoring of plasma control), we agree that self-monitoring blood glucose (SMBG) may be more effective with appropriate education however we believe that an appropriate life style with appropriate diet and exercise is also contributing to the efficacy of SMBG. Adherence to treatment should be encouraged, checked and monitored with the new available technologies before progression to an alternative formulation or escalation to another treatment.

Merck Serono

Disagree with proposal

In the clinical area 5 (Metformin) relative to the high level of RCT, the Garber et al. 1997 study (a double blinded RCT) is not cited. From this study, the optimal dose for treatment is established for posology at 2g/day. We strongly believe, based on the Garber et al1997 study, that patients with type II diabetes should maximise their metformin treatment by taking the optimal dose of metformin (2g/day) and alternative metformin formulations (metformin SR or powder) should be considered before starting additional classes of medications.

Consequently, we feel that the key messages of the guideline CG66 (section 3) should refer to the maintenance of glycaemic control using the optimal dose of monotherapy with metformin. The algorithm (CG66 section 3.2) should reflect that the optimal (or maximal) dose of metformin should be achieved (in order to control HbA1c), and alternative metformin formulations (metformin SR or powder) should be considered before additional

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

32 of 48

Stakeholder

Agree with proposal to update?

Comments

Comments on areas excluded from original scope classes of medication are initiated. In addition, adherence to metformin should be checked and monitored before progression to another treatment. A clear statement should propose that alternative formulation of metformin should be considered in the following situations (From SMC guidance - Glucophage SR 2009, and Claxton et al. 2001): In order to achieve the optimal dose of metformin some patients may necessitate the use of a slow released or powder formulation Furthermore minimisation of tolerability issues should lead to the use of alternative metformin formulation. When substituting formulations it is important to ensure they are therapeutically equivalent Reduction of pill burden to improve adherence We believe that the algorithm should include reference to the use of alternative metformin

Comments on equality issues

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

33 of 48

Stakeholder

Agree with proposal to update?

Comments

Comments on areas excluded from original scope formulations where necessary. NB:Claxton et al. 2001. A systematic review of the associations between dose regimens and medication compliance. Clin Ther / vol 23, no 8

Comments on equality issues

Merck Serono

Disagree with proposal

In the clinical area 5, Merck Serono firmly believes that alternative formulations of metformin (e.g. sustained released and powder) should be used for their potential to improve adherence to metformin treatment (Claxton et al 2001, Donnelly et al. 2009), and potentially reduce tolerability (Blonde et al. 2004, further references highlight this finding) issues or swallowing difficulties. NB: Donnelly et al. 2009. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population based study. Diabetes, Obesity and Metabolism, 11, 2009, 338-342. Blonde et al. 2004. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

34 of 48

Stakeholder

Agree with proposal to update?

Comments

Comments on areas excluded from original scope release metformin tablets: results of a retrospective cohort study. Current Medical Research and Opinion, vol 20, no 4, 565-572 The White paper (Equity and Excellence: Liberating the NHS, DoH 2010) illustrates that patients will have and should have choice of practice and treatment:"No decision about me without me". We believe that there are significant benefits to be gained by enhancing the NHS services around patients choice and involvement. Patients choice to have a healthier living should have the choice of treatment including selfmanagement support and selfmonitoring blood glucose. NB: By the end of 2011, Merck Serono will offer to NHS patients a friendly-user package allowing type II diabetes patients to measure diet, lifestyle, exercise and blood glucose remotely. Consequently, we would like to collaborate with the GDG and NCC to consider these data on file. We believe that once these data characterised and measured, physicians would be able to better

Comments on equality issues

Merck Serono

Agree/Disa gree

We support the GDG and NCC perspective (p35 of the consultation) describing education in diabetic population as an important factor for the treatment of long term condition such as diabetes. We would also add that life style, diet and adherence to treatment are of same relevance. Furthermore, we would like to associate the use of Smart devices and remote applications with the success factor of patient education.

The Department of Health highlights (in "Who get diabetes: health inequalities") that there is significant inequalities in the risk of developing diabetes, in access of healthcare, the quality of health services and in the health outcomes particularly with type II diabetes patients. People with poorer background tend to have poorer blood glucose control, lower education and lower access to services.

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

35 of 48

Stakeholder

Agree with proposal to update?

Comments

Comments on areas excluded from original scope manage patient therapy whilst patients would get a better understanding of their condition.

Comments on equality issues

Merck Serono

Agree

We agree with GDG and NCC that more guidance about treatment side effect should be provided to patients. We would ask that NICE specifically supports the use (and includes) any alternative formulations that are available to minimise side effects to treatment and / or support improved adherence. If the NCC perform a review of the self-monitoring options (p36 of the consultation document), we would like to share sensitive commercial information constituting an innovation in patients self-management and self-monitoring. The White paper (Equity and Excellence: Liberating the NHS, DoH 2010) illustrates that patients will have and should have choice of practice and treatment: "No decision about me without me". We believe that there are significant benefits to be gained by enhancing the NHS services around patients choice and involvement. Patients choice to have a healthier living should have the choice of treatment including selfmanagement support and selfmonitoring blood glucose. The White paper (Equity and Excellence: Liberating the NHS, DoH 2010) illustrates that patients will have and should have choice of practice and treatment:"No decision about me without me". We believe that there are significant benefits to be gained

Merck Serono

Agree/Disa gree with the proposal to update

Merck Serono

Agree

We agree with the suggestion (p36 of the consultation) requesting metformin sections to be reorganised. This should incorporate all alternative formulations of metformin and refer to the optimal dose of metformin (2g/day). With regard to this consideration, we would suggest that the treatment algorithm integrate the findings related to metformin, notably the use of alternative formulations (e.g. metformin SR once a day administration and/or metformin powder avoiding

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

36 of 48

Stakeholder

Agree with proposal to update?

Comments swallowing issues) to overcome tolerability issues and increase adherence to treatment before escalation to other classes of therapy.

Comments on areas excluded from original scope by enhancing the NHS services around patients choice and involvement. Patients choice to have a healthier living should have the choice of treatment including selfmanagement support and selfmonitoring blood glucose.

Comments on equality issues

Merck Serono

Disagree

Merck Serono informs GDG and NCC that the Scottish Medicines Consortium (SMC) recommends the use of Glucophage sustained release tablets. The economic case demonstrate a cost-effective use of once daily Glucophage sustained release tablets, delaying high cost associated with additional classes of treatment. Consequently, we are expecting an update of the health economic section (CG66 section 7.1.5) related to the use of Glucophage prolonged release tablets. It is noteworthy to add that all branded metformin sustained release preparation (e.g.Glucophage SR) or generic sustained released preparation are at the same price. 3. Review Recommendation

MSD Ltd

We agree

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

37 of 48

Stakeholder

Agree with proposal to update? with the need to update this guideline, but believe this should be undertaken later than the current schedule, when more information will be available (see detailed comments).

Comments New safety data on existing agents are expected to be published over the course of the next 12 months. These data include findings of an ongoing safety analysis of TZDs. There are still outstanding safety concerns with pioglitazone, which have not yet been fully resolved. These issues, which include the possibility of an increased incidence of certain cancers with this class, should be carefully considered in any review of recommendations for the use of TZDs. Furthermore, it is anticipated that there will be several new treatments made available for the treatment of type 2 diabetes in the near future. In addition, several clinical trials and analyses are expected to report their findings. In order to avoid the potential for confusion amongst clinicians, decision makers and patients, it is appropriate to delay the review of these guidelines. The first in a new class of agents for type 2 diabetes, (dapagliflozin, a SGLT2 inhibitor), is expected to reach the market at the end of this year, and is the subject of a scoping workshop on June 21. We suggest it is appropriate to delay the review of this guideline to allow inclusion of this agent in the update (whether reviewed by a TA or not). New DPP4 inhibitors (linagliptin and aloglitpin), fixed dose combinations of existing treatments, and a once weekly formulation of exenatide are expected to come to market over the course of the next 12 months, and should be included in the updated guideline. New cljnical data will shortly be published on the use of sitagliptijn in patients with renal insufficiency. Uncertainty also exists around the generic status of TZDs which should be taken into account in the review of the guideline.

Comments on areas excluded from original scope

Comments on equality issues

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

38 of 48

Stakeholder

Agree with proposal to update? Agree

Comments Clinical Area 6 ­ 1.6.1 DPP4-inhibitors (p.13-15) We agree with that there are no new data regarding DPP4 inhibitors which would change the direction of the current guideline. Clinical Area 6 ­ 1.6.2 Thiazolidinediones (p.15-17) There are still outstanding safety concerns with pioglitazone, which have not yet been fully resolved. These issues, which include the possibility of an increased incidence of certain cancers with this class, should be carefully considered in any review of recommendations for the use of TZDs. It should be noted that the patent for pioglitazone has now expired and as yet there is no evidence of generic versions of the agent, or of any price reduction.

Comments on areas excluded from original scope

Comments on equality issues

MSD Ltd

MSD Ltd

Agree

MSD Ltd

Agree

Clinical Area 9 ­ 1.10.1 Statins and ezetimibe (p.26-28) The Study of Heart and Renal Protection (SHARP) has recently been published, which investigated the effect of simvastatin plus ezetimibe, vs. placebo, on the incidence of major atherosclerotic events in patients with chronic kidney disease. Major atherosclerotic events included non-fatal MI or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure. Amongst the 9,270 patients with CKD (median follow-up 4.9 years), simvastatin plus ezetimibe reduced the incidence of major atherosclerotic events in by 17%, vs. placebo (risk ratio [RR] 0.83, 95% CI 0.74-0.94, p=0.0021). Twenty-three percent of the study population had diabetes (over 2,000 patients). Within this pre-specified subgroup, the RR of was 0.78 (0.64-0.94).

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

39 of 48

Stakeholder

Agree with proposal to update?

Comments An application for marketing authorisation for the use of simvastatin/ezetimibe in CKD patients has been submitted, and is currently under review. We would, therefore, recommend that this update is delayed until the decision on this application is available. Reference: Baigent C., Landray M.J., Reith C. et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet, June 9 2011. DOI:10.1016/S0140-6736(11)60739-3.

Comments on areas excluded from original scope

Comments on equality issues

MSD Ltd

Agree

Clinical Area 9 ­ 1.10.3 Nicotinic Acid (p.30-31) Contrary to statements made within the RCD, clinical data for extended-release niacin/laropiprant in patients with diabetes are available. A recent publication (published after the 28th January cut-off date for the literature search) describes a clinical trial which investigated the use of extended release nicotinic acid/laropiprant, vs. placebo, in patients with type 2 diabetes. At 12 weeks, there were significant changes from baseline in LDL (17.9%), HDL (23.2%) and triglycerides (-23.1%), relative to placebo. Reference: MacLean A., McKenney J.M., Scott. et al. Efficacy and safety of extended release niacin/laropiprant in patients with type 2 diabetes mellitus. Br J Cardiol 2011;18(1):37-45. Another clinical trial, conducted in patients not at their LDL target, assessed the effect of adding extended release niacin/laropiprant vs. doubling the initial statin dose. The trial included a pre-defined sub-group of patients with diabetes (n=319, 26.2% of the study population). The study identified significant improvement in all lipid parameters, with consistent

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments results in those patients with diabetes. Reference: Shah S., Ceska, R., Gil-Extremera B. et al. Efficacy and safety of extended release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract 2010;64(6):727-738.

Comments on areas excluded from original scope

Comments on equality issues

MSD Ltd

Agree

GDG Identification of Research Currently in Progress (p.34) The GDG have noted that a new DPP4 inhibitor (linagliptin) may be licensed later this year, and is likely to be appropriate for use in patients with renal impairment. We would like to make the GDG aware that data on the use of sitagliptin in patients with renal impairment are expected to be published in the near future, with a potential revision to the marketing authorisation in early 2012 to allow use in such patients.

MSD Ltd

Agree

GDG and NCC Perspective ­ Other (p.38) We support the intention to consider the new guidelines to be published by the Joint British Societies when this guideline is reviewed.

NHS Direct Novartis Pharmaceutical UK Ltd

Agree to update Agree

We welcome the update of the guidelines because, for example, since the last NICE guidance was issued, there has been an update to the Vildagliptin licence. The precautionary statement pertaining to elderly patients 75 years and older has been removed from the Vildagliptin Summary of Product Characteristics (SmPC). Thus, Vildagliptin is the only DPP-4 inhibitor available without a specific SmPC caution in the very elderly.

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder Novo Nordisk

Novo Nordisk

Agree with proposal to update? Agree with proposal to update the Clinical Guideline (CG 66 & CG87): Type 2 Diabetes: the manageme nt of type 2 diabetes Agree with proposal to update the Clinical Guideline (CG 66 & CG87): Type 2 Diabetes: the manageme nt of type 2 diabetes

Comments Novo Nordisk agrees with the proposal to review the guidelines in light of new evidence and new pharmacological therapies that have become available since the guideline was published. In addition further treatments for type 2 diabetes are due to enter the market in the next few years.

Comments on areas excluded from original scope

Comments on equality issues

Novo Nordisk is currently developing insulin degludec and the combination of insulin degludec/insulin aspart for the treatment of type 1 and 2 diabetes. These products were assessed by the th ,,Vascular and Metabolic Conditions panel on 25 March 2011. The panel gave both insulin degludec and the combination of insulin degludec/insulin aspart a score of 16 out of 20 for type 2 diabetes. After discussion the panel decided not to progress the technologies for appraisal (despite the high score) preferring to refer the technologies to the clinical guideline team. It is critical that insulin degludec and the combination of insulin degludec/insulin aspart are included in the guidelines as they will not be reviewed through the STA process. Therefore we feel timely initiation of this guideline is necessary to incorporate these new technologies. Regulatory submission of insulin degludec and the combination of insulin degludec/insulin aspart for marketing authorisation is expected in the EU in the second half of 2011. This is earlier 1 than the expected marketing authorisation for alogliptin (ref).

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments 1.) Takeda press release (4 June 2009) accessed from website th on 7 June 2011. http://www.takeda.com/press/article_34454.html The RCP is grateful for the opportunity to comment. We would like to endorse the comments submitted by the ABCD. We support the recommendation to update these guidelines at the earliest opportunity. Our experts believe that this guideline will need updating regularly as new agents come on to the market in coming years. As described in the review, new drugs are now available (within the classes previously looked at eg liraglutide,saxagliptin). Even though eg liraglutide has had a STA, its place in the treatment protocol needs to be reviewed. Likewise new drugs will probably be available before this guideline is updated eg the combination of insulin and GLP-1s which may be best reviewed within this process rather than as a separate STA. The blood glucose guidance statements in the review are a little controversial but there would be an opportunity for debate when reviewed. We have had a look at various areas and made comments on the draft where we think they may affect patient care in our wider practice. We have a concern that if GPs are encouraged not to issue blood glucose testing strips to patients not treated with insulin, as there is data that this is in general may not be cost effective, we will have difficulty in getting GPs to prescribe testing strips in particular situations where achieving rapid tighter control is particularly critical. With relevance to our practice at RBH/Harefield this would particularly be pre and post cardiac surgery. The concern is that if limits are to be placed on glucose monitoring for patients not on insulin therapy, exceptions should be made for situations such as these in which rapid aggressive glucose lowering is indicated, but insulin may not necessarily be required.

th

Comments on areas excluded from original scope

Comments on equality issues

RCP

Agree

Royal Brompton & Harefield NHS Foundation Trust

disagree

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder Royal College of Nursing Sanofi Aventis

Agree with proposal to update? Agree Potential Error

Comments

Comments on areas excluded from original scope

Comments on equality issues

In the section regarding treatment of hypertension (1.8.1 1.8.13), reference is made to losartan and valsartan as being the two Angiotensin Receptor Blockers (ARBs) used for the treatment of hypertension and associated diabetic renal disease, and due to come off patent in 2010/11. Sanofi-aventis question whether this statement is made in error and would like to ensure that the following is considered to ensure accuracy. Valsartan is licensed for the treatment of hypertension and heart failure, not diabetic renal disease; losartan and irbesartan are the two ARBs licensed for hypertension and associated diabetic renal disease, both with patents expiring in the stated timeframe. Sanofi-aventis ask that you reconfirm this statement, and amend appropriately. As mentioned on page 34, the Outcome Reduction with Initial Glargine Intervention (ORIGIN) study, is currently ongoing. This is a large scale international trial covering 578 clinical sites in 40 countries, with more than 12,500 patients and 6.3 year follow-up. The study considers high CV risk patients, patients with impaired glucose tolerance, or newly detected or established type 2 diabetics. Insulin glargine is compared with standard glycaemic control. Therefore, this trial will be the first to estimate the effect of early replacement insulin therapy on CV outcomes. Furthermore, this trial may make insulin glargine the first antidiabetic agent to get an indication for CV event reduction. The results of this trial are due to be presented at ADA in June 2012, and therefore are likely to be overlooked if the guideline update commences in 2011. Given the strong demand within the clinical community for long term evidence on the link between insulin use and CV outcomes we feel the guideline update should be delayed to incorporate the results of this important research. There is a strong possibility that the results of ORIGIN could influence the position of insulin glargine, and consequently the other insulins, within the guidelines.

Sanofi-Aventis

Disagree ­ Propose a delay to the update

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder Sanofi-Aventis

Agree with proposal to update? Disagree ­ Propose a delay to the update

Comments Sanofi-aventis agree that the guidelines need updating, but feel a delay is warranted to allow the inclusion of a large body of forthcoming evidence, as outlined below. More broadly, if and when an update takes place, sanofi-aventis recommends that the review of the guideline take action on the wider challenge of implementation (referred to in part o page 36, in which many recommendations are recognised as poorly implemented). The QoF return for 2009-10 shows that only 53.8% of patients in England had managed to reach a target HbA1c of 7% at any one time within the previous 15 months, to add to which was an exception reporting figure of nearly 13%. 22.6% of patients had failed to reach the 8% target and 12% the 9% target. Whilst individual target levels might partly explain the low proportion reaching a 7% target, these are no doubt reflected in the high exception reporting figure, and taking all three measures into account, it is clear that the average level of control in patients with diabetes falls below that which would translate into improved health outcomes. In reviewing the guideline it would therefore be appropriate to consider what strategies NICE could recommend to improve the overall level of control of diabetes at a national level. Patients early in their disease have the greatest capacity to benefit from tighter control ­ early intervention maximises the improvement in long term health outcomes. Overall, the nation needs to move from a position of only adding in additional therapies once control deteriorates to one of rapid, early, multiple intervention until target is reached, as advocated by the EASD/ADA consensus guideline on treatment of hyperglycaemia. Setting a national average HbA1c target as a single, visionary goal would be both a unifying objective for all healthcare professionals treating diabetes as well as a simple measure against which to track progress. (The benefits of such a strategy having been clearly demonstrated by the CMOs goal of reducing death from

Comments on areas excluded from original scope

Comments on equality issues

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments coronary heart disease "by 40% within 10 years" ­ set in 1999, with a 47% reduction achieved by 2006-8). Without such an approach, sanofi-aventis doubt that significant progress will be achieved in improving the health and the health outcomes of those with diabetes. A comment is made on page 23 regarding the possible association between insulin glargine and cancer. Although the comment restates the position of the European Medicines Agency that "the available data does not provide cause for concern ...", a publication by Mannucci et al is cited (your ref 350) suggesting there is an association between insulin glargine and cancer at higher glargine doses. Without dismissing the validity of the findings of this study, it is important to recognise that the primary outcome of this trial was that "No significant difference was observed between cases and controls in the proportion of patients exposed to each insulin" (i.e. no association was found between insulin glargine and the incidence of cancer). The "possible association at higher doses of glargine" is inferred from a sub-group analysis, based on an arbitrarily selected dose level resulting in a small number of patients and only thirteen cases. It is clear that considerable caution therefore needs to be taken into account in the interpretation of this finding. More relevant to the debate regarding glargine and cancer is the ongoing major epidemiology programme that seeks to provide a definitive answer as to whether or not insulin glargine is associated with cancer. This programme comprises three independent pharmaco-epidemiological studies, the design of which has been agreed with the European Medicines Agency. The first two of these studies will conclude in 2011 (Northern European Cohort Study in Q2, the North American Cohort Study in Q3-4), and report in late 2011/early 2012 once analysis is complete. The third study, the ISICA case control study

Comments on areas excluded from original scope

Comments on equality issues

Sanofi-Aventis

Disagree ­ Propose a delay to the update

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder

Agree with proposal to update?

Comments (Grimaldi-Bensouda et al. Lancet. 2010, 376(9749):1302) will conclude in Q2-3 2012. If the guideline is updated before these definitive studies are reported, information regarding the safety of insulin glargine and the association with cancer is likely to be omitted and we feel the guideline update should therefore be delayed to incorporate the results of this important research. [COMMERCIAL IN CONFIDENCE DATA REMOVED]

Comments on areas excluded from original scope

Comments on equality issues

Sanofi-Aventis

Sanofi-Aventis

Disagree ­ Propose a delay to the update Disagree with proposal to recommend against BG self-testing for noninsulin users

The BDA

Agree to update

United Kingdom Clinical Pharmacy Association

Clinical Area 4, self-management of blood glucose, suggests the guidelines are likely to recommend against self-testing for noninsulin users. We would warn against such a move as there is a significant risk of hypoglycaemia associated with sulphonylurea use. BG self-testing is advisable for these patients, particularly vehicle drivers. Indeed, current DVLA guidelines (http://www.dft.gov.uk/dvla/medical/ataglance.aspx) suggest it may be appropriate for car drivers using SUs "to monitor blood glucose regularly and at times relevant to driving to enable the detection of hypoglycaemia". In the case of lorry and bus drivers using SUs regular BG testing is mandatory. We are especially keen to see changes to the HbA1c targets for type 2 and to have guidance on the use of newer agents in combination with other diabetic meds especially insulin. 1. Will an update be able to include the commonly used off license combination of GLP-1 analogues and insulin?

United Kingdom Clinical Pharmacy Association United Kingdom

2. Needs liraglutide added because of the dual therapy indication (exenatide is only on there as a third line therapy)

3. DPP4's - needs to have saxagliptin mentioned as it has a

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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Stakeholder Clinical Pharmacy Association United Kingdom Clinical Pharmacy Association

Agree with proposal to update?

Comments licence now for end stage renal disease whereas none of the other DPP4 inhibitors have a license in patients with severe renal impairment 4. Sitagliptin only one licensed for use with insulin. There is an increased use of this combination- should this be considered for inclusion in the guideline with recommendations on its place as a combination and when to stop?

Comments on areas excluded from original scope

Comments on equality issues

These organisations were approached but did not respond:

PLEASE NOTE: Comments received in the course of consultations carried out by the Institute are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that the Institute has received, and are not endorsed by the Institute, its officers or advisory committees.

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