1. No difference between different types of 3 rd line agent Meta analysis. 19 Articles, c 5k patients Cross et al Ann Int Med 2011

2. Key messages from Cross et al 2010. 1.No clear differences between drug classes when adding a third agent 2.Option should be based on patient preference and characteristics. (NB - WHAT ABOUT COST) 3.Non insulin third agent (compared to insulin) – on incremental 0.2% to 0.3% reduction in HBAIC – bottom of Table 2 4.Insulin leads to more weight gain 5.GLP1 agents gives less weight gain and less hypos 6.Insulin do not seem to markedly differ from other classes re HBAIC 7.Insulin ranked first in the probability of being most effective when the meta analysis was done 8.Low dose of insulin may have contributed to under reporting of HBAIC on the (limited number) of trials comparing insulin and non- insulin third line agents 9.But insulin doubles frequency of severe hypo (enough to warrant HC intervention). Absolute risk is small however 10.But this freq of hypo does need to be taken into account in risk benefit judgment

3. Modest reduction in HBA1C compared to insulin GLP1 agents – more weight loss than other agents. Less hypo events

4. REAPPRAISAL OF INTENSIVE GLUCOSE LOWERING IN TYPE 2 DIABETES Yudkin et al Diabetologica 2010

5. Intro Perceived wisdom that intensive control of HBAIC leads to better CV and micro vascular complication This is based on epidemiological data and other observational studies, still some problems re interpretation of this and many nuances, UKPDS Does the trial data back up the epidemiology? Optimum mortality at 7.5? Based on epi studies But QOF and others push for tighter and tighter control of HBAIC – costs more is the extra benefit worth chasing this surrogate endpoint Glycaemia is a weaker (substantially) RF for CHD than cholesterol or BP

6. Relatively high NNT for 5 year event rate Implication BP and Cholesterol influence CV risk far more than HBAIC. The marginal impact of tight glycaemia seems marginal at best

7. CV benefits related to age! Emphasised in some, but not all, guidelines. But nuances lost in day to day practice A classic example of the weakness of an epidemiological/whole population approach not being tailored to individual risk UKPDS – intensified gylcaemic control would increase QALYs ……… by 0.27 or 99 days. Is it worth it? Huang et al – intensive control adds 106 days of life expectancy to a newly diagnosed DM patient aged 60- 64. This decreases markedly if there are co morbidities Models consistently highlight smoking cessation as the factor having – by far – the greatest impact on life expectancy CV benefits greater in younger patient Current estimates – the benefits of intensified monitoring on HBAIC on life expectancy are measured in days

8. Micro vascular complications – key points A newly diagnosed patient aged 65 is more likely to have CV event than micro vascular complication A 1% ↓ in HBAIC reduced risk of micro vascular complication by 25% (UKPDS). Most relevant for younger patient with T2 DM Absolute risk is important. ……. UKPDS found that the combined 10 year incidence of MI (17%) and stroke (5%) was more than 5 times greater than combined risk of renal failure (0.8%) and sight loss (3.5%) Subsequent calculation leads to NNT of 272. ie 272 patient treatment with intensified glycaemic control for 5 years to prevent one person developing blindness Corresponding NNT of 627 - patients treatments with intensified glycaemia control for 5 years to prevent one case of renal failure. 119 for CV events. Is it still worth the difference between new agents of insulin? The additional benefit diminishes with age. More benefit in younger patients

9. Risks of intensive control rarely takes into account when intensified control is advocated Unwanted consequences – weight gain, HF Unwanted osteopenic fractures Model shows that 1000 patient treatments for 5 years with intensified glycaemia control would experience 47 additional hypo events to prevent 8 major CV events Risks and benefits combined:- need to treat 119,272,627 DM patient for 5 years for each person who benefits from CV, eye, renal complications – with a treatment that diminishes QOL by up to a third The added benefits of target of 7% compared to 8% diminish with age and life expectancy Resources/time far better spent on those with higher levels of HBAIC?

10. population cost of preventing complications with intensive (compared to less intensive) glycaemic control can be estimated by combining drug costs & NNT So assuming an NNT of 272 for blindness You need to treat 272 pt to tight target (compared to less tight control) for 5yrs to prevent 1 person going blind And 5yr cost of £1000 on insulin (£2k for glitazone) It costs £272k to prevent that CV event, compared to £544k with glitazone. Costs can be altered in this model

11. My thoughts We spend a lot on 3d line agents Not much to choose between the various 3rd lines Evidence doesn't support tight control – it seems an expensive investment to avoid CV, renal and eye complications In NHSBA, in 2009/10 11,120 diabetic patients were recorded as having met the 7 target (DM23) out of 26,500 overall. The cost per patient at 7 target was an average of £286 per patient (range = £200 - £1800) It is widely acknowleded that getting a patient to the 7 target is poorly related to clinically relevant endpoints and could easily be argued that this is a poor use of resources Spending to get all patients to the 7 target might be a poor use of the primary care prescribing budget. And it might be arguied from a practice perspective that the additional QOF payment getting pt to the 7 target is not worth the additional prescribing expenditure. It is almost certainly better value spend to reinvest effort and spend elsewhere in the system, this may yield better outcomes The QIPP challenge in disease this area is approx £720k per year – established through the PBMA work. Would it be better buy to focus on the approx 8000 that did not meet the 8 HBA1C target (exception coded and not met)?

12. messages are the gliplins and glitazone still worth it? tailoring the gliplins and glitazones accordingly – younger? Might represent a greater use of scarce resources More insulin use? focus resources on CV through BP>Cholesterol less tight HBA1C control Focus on your exceptions and not met

13. Background info

14. Received wisdom re impact (NICE)

15. Cost of various agents

16. Yearly cost

18. NHSBA spend on DM agents. To insert