1. Should we be using the new insulins in T2DM? Ian Gallen MD FRCP Community Diabetologist Royal Berkshire Hospital

2. Purpose of Insulin Therapy Prevent and treat fasting and postprandial hyperglycemia Permit appropriate utilization of glucose and other nutrients by peripheral tissues Suppress hepatic glucose production Prevent acute complications of uncontrolled diabetes Prevent long term complications of chronic diabetes

4. Questions which need to be asked Which insulin regime is most likely to achieve good control in T2DM Does analogue basal insulin offer advantages over NPH? Does biphasic Analogue insulin offer advantages over biphasic human insulin? What is the rational way forward?

5. Reasons for poor diabetic control Delay in commencing insulin treatment Insufficient dose titration Failure to control fasting blood sugar Inappropriate insulin mix False concerns about maximum insulin dose None of these are improved with analogues

6. Why do patients delay insulin treatment? Concern about injections Stigma of insulin injections Concern about employment False previous family experience Strong negative cultural beliefs Worry over hypoglycaemia Fears for weight gain New insulins might help

7. Why do patients delay insulin?

8. Helping Patient Accept Insulin Therapy Address patient concerns –Dispel fear by countering misconceptions –Review rationale for insulin use –Explain that insulin –Can be incorporated into lifestyle –Causes only modest weight gain –Is a common course of treatment for this progressive disease Promise patient support and close follow-up –Monitoring can prevent hypoglycemia –Today’s technology can facilitate daily injections and readings

9. Choice of insulin treatments Once daily NPH/Analogue Basal with oral agents – T2DM and some T1 patients dependant on others for care Twice daily – Either Combination did/tid Biphasic insulin (Human or Analogue) T1 or T2 or bd (NPH/Analogue T2DM) Basal Bolus – T1 or T2DM (Human-NPH/Analogue Bolus-Basal) Insulin pump treatment – T1DM only

10. Which insulin regime in T2DM? The 4 T study

11. Low Skills and Capabilities High Review @30 units Review @30 units Review @60u BD Review @60u BD Review @60u BD Review @60u BD Review @60u BD Review @60u BD Review @60u BD Review @60u BD Patient able toself titrate & havecarb awareness Recommend initiation on human basal insulin Consider alternatives if ; District Nurse to Administer Steroid Patients Nursing Home Patients Erratic Eating Patterns In these cases contact DSN team for advice Once Daily Human Basal Basal Bolus BD Mix 50/50 BD Human Basal BD Human or Analogue Mix TDS Mix 50/50 DSN Referral Recommended Berkshire West Insulin Optimisation Framework for Type 2 Diabetes

12. Hypoglycaemia is frequent in T1DM

13. Hypoglycaemia is infrequent in T2DM Total of 3.5 episodes/patient/year Nocturnal hypoglycaemia 1.9 episodes/patient/year). An inverse relationship is seen between all confirmed hypoglycaemia and HbA(1c) at endpoint; – for every 1% reduction in HbA(1c), the increase is 1.4 episodes/patient/year. Patients with confirmed hypoglycaemia had lower HbA(1c) than patients without hypoglycaemia (7.39 vs. 7.64%, respectively). Diabetes Metab Res Rev. 2009 Mar;25(3):224-31.

14. Possible Limitations of Human Insulin S Slower onset of action – Requires inconvenient administration: 20 to 40 minutes prior to meal – Risk of hypoglycemia if meal is further delayed – Mismatch with postprandial hyperglycemic peak Long duration of activity – Up to 12 hours’ duration – Increased at higher dosages – Potential for late postprandial hypoglycemia 6-26

15. Rapid-acting Insulin Analogues: Lispro and Aspart 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 120180210150240 Lispro Regular Human 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Aspart Regular Human Plasma Insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506. 6-28

16. What are the problems with basal insulin treatment? Insufficient length of action requiring twice daily dosage Large intra-dose variability leading to increased hypoglycaemia or loss of daytime control Excess basal insulin treatment, leading to weight gain High dose volumes in insulin resistant and obese patients

17. Rapid-acting Analogues : Clinical Features Insulin profile more closely mimics normal physiology Convenient administration immediately prior to meals Faster onset of action Limit postprandial hyperglycemic peaks Shorter duration of activity – Reduced late postprandial hypoglycemia – But more frequent late postprandial hyperglycemia Need for basal insulin replacement revealed 6-27

18. Insulin levels following injection in T1DM Lepore. Diabetes, 49:2142–8.

19. Characteristics of basal insulins Insulin nameDurationIntra- dose variability Cost (5x3ml) (cost/day 40u) NPH8 to 16 hours+++£19.80 (£0.53) Detemir8 to 16 hours++£44 (£1.70) Glargine16 to 20 hours++£41 (£1.01) Toujeo20 to 30 hours+£41 (£1.01) Degludec30++£72 (£1.92)

20. Glargine and Hypoglycaemia in T2DM

21. Glargine causes less hypoglycaemia in insulin naive T2DM DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003

22. Int J Clin Pract. 2009 Apr; 63(4): 574–582. Rates of major (left) and minor (right) hypoglycaemia were lower at the final visit compared with the baseline visit in the main cohort. ***p < 0.0001 vs. baseline Reduced hypoglycaemia with NM30 in T2 DM

23. Type of documented symptomatic hypoglycemia Insulin glargine (% of patients) NPH insulin (% of patients) pInsulin glargine significant % risk reduction Overall54.261.20.000611 Nocturnal28.438.2<0.000126 Non-nocturnal49.651.70.2553– Severe1.42.60.042246 Severe nocturnal0.71.70.023159 Severe non-nocturnal0.80.90.7296– Abbreviations: NPH, neutral protamine Hagedorn. Meta-analysis of episodes of hypoglycemia with insulin glargine versus NPH insulin. Rosenstock et al 2005.

24. Reduced hypoglycaemia when compared with Glargine

25. Fewer episodes of hypoglycaemia

26. Small reduction in severe hypoglycaemia

27. Slightly reduced weight gain than with Glargine

28. What about insulin degludec? Diabetes Research and Clinical Practice DOI: (10.1016/j.diabres.2015.04.002) 1.Clinical Diabetes October 2013vol. 31 no. 4 166-170 NNT Study B = 50 patients to avoid 1 event at the cost of £16000

29. Where is the appropriate place of analogue basal insulin therapy? Use in T1DM (NICE Guidelines 2015) Patients who are demonstrated have problems with basal insulin treatment Patients with nocturnal hypoglycaemia ?? Patients with excess weight gain Patients requiring third party administration of insulin treatment

30. Where is the appropriate place of rapid acting analogue insulin therapy? Use in T1DM (NICE Guidelines 2015) That’s about it!

31. Where is the appropriate place of biphasic analogue insulin therapy? There isn’t one!

32. What are the real unmet needs in insulin therapy Early recognition of failure of oral therapy Strong positive recommendation of benefits of insulin treatment to patients Reassurance concerning potential negative consequences in therapy Intense support to optimise insulin dosage Regular expert clinic review to identify problems with insulin therapy

33. What you need to do in practice tomorrow Do a search for all your patients with HbA1C is >85 mmol per mole – Refer those patients to X-pert and – For those on tablets, move them either to basal insulin and tablets, premixed insulin, or basal insulin and GLP1 combination therapy if they are obese For those refusing insulin treatment, reassure on the safety of insulin treatment, demonstrate injection, and explain that poor diabetic control is not an option For those already on insulin treatment, ask the diabetes specialist nurses to come work with you to titrate insulin doses. For those patients who are gaining weight, consider adjunctive therapy with SGLT/GLP1 For those with body mass index greater than 35 and less than 65 years old suggest refer to bariatric service Analogue insulin is expensive, so only use in clinically justified situations