1 NICE 2015 guidelines to help us treat T2 diabetes in 2016? Paul Newrick Consultant Physician WAHNHST 2016

2 Achieving normal blood glucose levels – still remains key to reducing diabetic complications Relative Risk (%) HbA 1c (%) Retinopathy Nephropathy Neuropathy Microalbuminuria Diabetes Control and Complications Trial % decrease per 1% decrement in HbA1c p< UKPDS

3 Choosing the HbA1c target Cardiovascular safety is the issue Mortality HbA1c 7.5% 6.4% 10.5% Hazard ratio = 1 HR 1.52 HR 1.79

4 What are the challenges for diabetes care in 2016? Numbers! Toxic environment…obesity Converting knowledge into behaviour Multiple therapeutic choices/decisions Integrated care

5 NICE CG the management of type 2 diabetes Issued May 2009 National Institute for Health and Clinical Excellence. Type 2 diabetes: The management of type 2 diabetes. London: NICE, 2009.

6 ADA/EASD position statement 2015: when the goal is to avoid weight gain

7 Effect of glucose lowering agents on HbA 1c when added to metformin All classes of second-line agents added to metformin significantly reduced HbA 1c from baseline relative to metformin alone; there were no statistically significant differences between drug classes Results of a MTC based on 40 RCTs (n=17,795) DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon like peptide-1; MTC=mixed treatment comparison; RCT=randomised controlled trial; SU=sulphonylurea; TZD=thiazolidinedione. Results of a MTC of the effect of adding second-line antidiabetes treatment versus placebo in adults with type 2 diabetes taking metformin on change from baseline in HbA 1c. The authors conducted meta-regression and sensitivity analyses to test the robustness of the reference case analysis. Overall, meta-regression and sensitivity analyses yielded minimal differences from the reference case. Adapted from: McIntosh B et al (2011) Open Med 5:e35–48 SUs–0.79 (–0.95, –0.63) Meglitinides–0.64 (–0.93, –0.37) TZDs–0.82 (–1.00, –0.66) DPP-4 inhibitors–0.80 (–0.95, –0.65) α-glucose inhibitors–0.74 (–0.98, –0.50) GLP-1 receptor agonists–0.82 (–1.05, –0.59) Basal insulin–0.82 (–1.16, –0.47) Biphasic insulin–0.97 (–1.33, –0.61) Difference in change from baseline in HbA 1c, % (95% CI) TreatmentMTC estimate (95% CI) Favours treatment Favours placebo

8 T2DM in 2009 – choices, choices, choices…

9 Effect of glucose lowering therapies on body weight Change in bodyweight was similar in the metformin and conventional control groups, and less than the increase in bodyweight observed in patients assigned intensive control with sulphonylureas or insulin n=at baseline. Conventional treatment; diet initially, then SUs, insulin and/or metformin if fasting plasma glucose (FPG) >15 mmol/L (>270 mg/dL). SU=sulphonylurea; UKPDS=UK Prospective Diabetes Study. Adapted from UKPDS Group (1998) Lancet 352: 854–65 UKPDS: up to 8 kg in 12 years 1 Insulin (n=409) Conventional (n=411) SU (glibenclamide) (n=277) Metformin (n=342) Change in weight from baseline (kg) Baseline weight: 85 kg Years 12

Sitagliptin vs SU Add-on Therapy to Metformin Hypoglycaemia P< % 5% Week 52 Incidence (%) LS mean change in body weight over time Body weight (kg ± SE) Glipizide 5-20 mg/day + metformin* (n=588) Sitagliptin b 100 mg o.d + metformin* (n=584) Glipizide 5-20 mg/day + metformin* (n=416) Sitagliptin b 100 mg o.d + metformin* (n=389) Weeks

11 NICE final updated guidance Dec 2015 Type 2 diabetes in adults – updated areas Patient-centred care Lifestyle and diet Education – structured, group preferred, annually Aspirin/Clopidogrel – not for 1ary prevention BP – aim for <140/80 unless high risk aim for <130/80 SMBG – assess annually if being used Glycaemic management - drugs Glycaemic management - insulin

12 NICE final updated guidance Dec 2015 Type 2 diabetes in adults Patient-centred care ‘Adopt an individualised approach to diabetes care that is tailored to the needs and circumstances of adults with T2 diabetes…’ Consider older patient’s broader health and social care needs and potential to benefit All patients should have opportunity to make informed choices about treatment, and treatment should take into account their needs and preferences

13 NICE final updated guidance Dec 2015 Type 2 diabetes in adults Glycaemic management Measure HbA1c 6-monthly (3-monthly if unstable/regimen changes) Target HbA1c 48 (53-58 at Step 2; higher if needed for optimum risk: benefit ratio) No routine offer of SMBG Drug treatment – complex network and health-economic analysis with many unresolved issues and incomplete evidence base Start - Metformin (stop if eGFR<30) – try MR if not tolerated – otherwise DPP-4, Pioglitazone or SU 1 st intensification (HbA1c ≥58 target 53) – Add DPP-4 – otherwise Pioglitazone or SU or SGLT 2 nd intensification (HbA1c ≥58 target 53) – Add a 3 rd oral agent or GLP-1 agonist or insulin (depending on psychological and/or BMI issues) Treatment should take into account patient preferences SGLT-2 may be appropriate add-on No guidance on statins

14 NICE final updated guidance Dec 2015 Type 2 diabetes in adults Insulin Start with NPH od (HbA1c<75) or pre-mix bd (HbA1c 75+) Detemir or Glargine if would reduce frequency of injections to 1 if otherwise needing NPH bd + OHAs if recurrent hypoglycaemia if would reduce need for outside assistance if not at target

15 NICE and cardiovascular safety A vital constituent of holistic diabetes care In the long term at least no harm should accrue Data on CVS safety not included but we have some reassurance from trials: Sitagliptin – TECOS Alogliptin - EXAMINE Saxagliptin – SAVOR-TIMI (heart failure signal) Empagliflozin – EMPA-REG (CVS mortality RR 0.62) Lixisenatide - ELIXA

16 Integration with usual diabetes care 1ary Objective To demonstrate that the risk of cardiovascular events in patients treated with sitagliptin in addition to usual care was non-inferior to that in patients treated without sitagliptin in addition to usual care TECOS 16 Green JB et al. NEJM 2015; DOI: /NEJMoa

17 For the primary composite cardiovascular outcome (CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina) sitagliptin, compared with placebo, was noninferior, and not superior For the secondary composite cardiovascular outcome (CV death, nonfatal MI, or nonfatal stroke) sitagliptin, compared with placebo, was noninferior, and not superior The rate of hospitalization for heart failure did not differ between sitagliptin and placebo treatment groups The incidence of severe hypoglycemia did not differ between sitagliptin and placebo treatment groups The utility of sitagliptin as a glucose-lowering agent was confirmed by the more frequent initiation of insulin therapy and the greater need for additional antihyperglycemic agents in the placebo group compared with the sitagliptin group Summary of Results Green JB et al. NEJM 2015; DOI: /NEJMoa

18 Your average patient… Average age Average weight Average lifestyle Average cardiovascular risk profile What is your 1st choice drug? What is your 2 nd choice drug? and why?!

19 T2DM in 2016 – choices, choices… but possibly clearer?

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