1. Insulin initiation OPTIMISING Glycaemic control and Weight Dr C Rajeswaran Consultant Physician Diabetes & Endocrinology Mid Yorkshire NHS Trust

2. UKPDS: A 1% decrease in HbA 1c is associated with a reduction in complications Stratton IM et al. BMJ 2000; 321: 405–412. 12% Stroke** * p<0.0001 ** p=0.035 1% HbA 1c Microvascular complications e.g. kidney disease and blindness * 37% Amputation or fatal peripheral blood vessel disease* 43% Deaths related to diabetes* 21% Heart attack* 14%

3. Glycaemic control and body weight Weight gain appears unavoidable when patients with Type 2 diabetes are commenced on insulin Calculations of average weight gain are that for every 5 mmol/l reduction in fasting glucose, or a 2.5% fall in HbA1c, approximate weight gain is 5 kg (Makimattila et al, 1999) Body weight increases by 2Kg for each percentage point decrease in HbA1C during the first year 1 1.Makimattila et al Diabetologia 1999;42;406-412

4. Glycosuria is known to occur once fasting glucose levels reach around 10-12 mmol/l, and if treatment with insulin is delayed until this time, weight gain is likely to occur. Gain in weight mainly represents an increase in fat mass, which enhances insulin resistance and increases the risk of obesity related complications. Makimattila S, Nikkila K. Yki-Jarvinen H (1999) Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia 42: 406-12

5. Insulin in Type 2 Diabetes is aimed at inhibition of hepatic glucose output And improvement of peripheral glucose utilisation

6. Causes of weight gain with treatment ?

7. Insulin and weight Reduced glycosuria Anabolic action of insulin Fluid retention Hypoglycaemia and increased calorie consumption Excess insulin administration Combination of obesity and muscle impairment: 'sarcopenic obesity'.

8. Metabolic Consequences of Weight Gain Patients with T2 DM often have many other comorbid conditions increasing their risk for macrovascular events. Weight gain may have further deleterious metabolic consequences, such as worsening hypertension, lowering HDL-C, and raising LDL-C. [1,2] Blood pressure control and lipid control have both been shown to reduce cardiovascular events in patients with type 2 DM. 1.Yki-Jarvinen H, Ryysy L, Kauppila M, et al. Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:4037-4043. 2.United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713.

9. Adjusted odds ratio for death, by metabolic category for 51- 61years age group Diabetes 2.63 Obesity 0.78 Obesity and diabetes 6.81 Oldridge et al, Jr of clinical Epidemiology 54(2001);928-934

10. Insulin secretion

11. Adapted from Riddle et al. Diabetes Care. 1990;13:676-686. Contribution of Postprandial Glucose (PPG) to 24 hour hyperglycaemic profile Mainly target Basal hyperglycaemia: Metformin Secretagogues TZD’s Basal insulin Mainly target Postprandial hyperglycaemia: Repaglinide Nateglinide Acarbose Rapid-acting insulin Glucose (mmol/l) 10.0 5.0 0 06001200 Hours 180000000600 7.5 12.5 2.5 Basal Hyperglycemia Postprandial Hyperglycemia

12. As patients get closer to HbA 1c target, the need to manage PPG increases Monnier L, et al. Diabetes Care. 2003;26:881-885. 30% 40% 45% 50% 70% 60% 55% 50% 70% 30% >10.210.2-9.39.2-8.58.4-7.3<7.3 % Contribution to HbA 1c HbA 1c Range (%) 0 20 40 60 80 100 Fasting Plasma Glucose (FPG) Post Prandial Glucose (PPG)

13. How Do We Minimize Weight Gain Associated With Insulin Therapy? Patients who are started on insulin treatment may take away mixed messages about dietary control and think that they can increase their calorie intake on insulin; this results in excessive weight gain. Lifestyle intervention should be reinforced with initiation of insulin therapy. Medical Nutrition therapy

14. Metformin and insulin Metformin appears to have an insulin-sparing effect and reduces weight gain with insulin treatment. Studies using a combination of 2g metformin with bedtime isophane insulin, as opposed to twice-daily isophane insulin, showed that the insulin requirements in the metformin group were reduced by 47% and there was 45% less weight gain (Makimattila et al, 1999). This reduction in weight gain seemed to be due to reduced energy intake in those on metformin. Patients with T2DM should remain on metformin when they convert to treatment with insulin.

15. Repaglinide with insulin In a RCT, use of repaglinide resulted in a reduction in HbA1c compared to twice daily insulin group (1.8% versus 1% drop) and weight gain (2.2 kg versus 2.9 kg), but less insulin was required in the repaglinide group (Davies et al, 2002). Repaglinide in combination with bedtime insulin and metformin produces a significantly greater fall in HbA1c compared with the twice-daily insulin or night time insulin and metformin. Davies MJ, Howe J, Jarvis J at al (2002) Use of the combination of insulin and the prandial glucose regulator repaglinide in patients with type 2 diabetes mellitus. Diabetic Medicine 19(2): 25

16. One injection Intermediate-acting insulin or long-acting analog at bedtime Premixed formulation before dinner Two injections Breakfast and dinner: premixed formulation Breakfast and dinner: short-acting or rapid-acting plus NPH or long-acting insulin analog Three injections Add a short- or rapid-acting insulin injection at lunchtime to a 2-injection premixed regimen Add a third premix injection at lunchtime to a 2-injection premixed regimen Move the intermediate- or long-acting insulin analog to bedtime with short-acting or rapid- acting insulin analog at breakfast and dinner Multiple injections Short-acting or rapid-acting insulin analog at each meal with an intermediate- or long-acting at bedtime Insulin pump Insulin regimes: Multiple options

17. If FPG is elevated, start with long-acting (basal) insulin; If PPG is elevated, rapid-acting (prandial or bolus) can be used; and If FPG and PPG are elevated, any of the following would be appropriate: Oral agents with basal insulin Premixed insulin analogs Basal/bolus as in multiple daily injections (MDI) or an insulin pump. Initiating Insulin: Basic Recommendations No set formula......