1. Prevalence, prevention and addressing hypoglycaemia

2. Why address hypoglycemia in diabetes? Reducing HbA 1c levels associated with prevention or delay in complications and death Hypoglycemia is a limiting factor in achieving glycaemic targets Hypoglycemia is associated with morbidity and rarely even be fatal Optimizing glycaemic control is of obvious importance: $376 billion USD spent to treat diabetes and its complications in 2010; hypoglycemia is cost-intensive 6.8% of global all-cause mortality attributed to diabetes in 2010 (4 million deaths) Cryer et al 2003. Diabetes Care; 26,6: 1902-1912 IDF Diabetes Atlas 4 th ed., 2009 Roglic and Unwin 2010. Diabetes Research and Clinical Practice; 87: 15-19

3. Symptoms of Hypoglycemia Neurogenic (ANS) Symptoms (Caused by Falling Glucose Level) Shakiness Trembling Anxiety Nervousness Palpitations Clamminess Sweating Dry mouth Hunger Pallor Pupil dilation Neuroglycopenic Symptoms (Caused by Brain Neuronal Glucose Deprivation) Abnormal mentation Irritability Confusion Difficulty in thinking Difficulty speaking Paresthesias Headaches Stupor Seizures Coma Death (if untreated)

4. Sequalae of hypoglycaemia Mild symptomatic hypoglycaemia No direct serious clinical effects May impair subsequent hypoglycaemia awareness Severe hypoglycaemia associated with Stroke and transient ischaemic attacks Memory loss/cognitive impairment Myocardial infarction Injury (direct/indirect) Death

5. Hypoglycemia unawareness Patients with long-standing diabetes and onomic neuropathy, might not subjectively sense symptoms of hypoglycemia even in the presence of low glucose concentrations Glycemic targets of therapy should be adjusted upward in these patients because they are at particularly high risk for hypoglycemia

6. Hypoglycemia Risk Factors Missed or delayed meal Eating less food at a meal than planned Vigorous exercise without carbohydrate Compensation Taking too much diabetes medicine (e.g., insulin, insulin secretagogues, and meglitinides) Drinking alcohol

7. SU should be discontinued There is evidence of feedback by exogenous insulin upon endogenous insulin secretion Combining insulin and SU in patients with significant residual endogenous insulin secretion might incur a high risk of hypoglycaemia

8. Hypoglycaemia: a barrier to insulin use? Nakar et al. J Diab Compl 2007;21:220−6 Patients not treated with insulin Physicians Insulin makes one fat Fear of hypoglycaemia Pain from injection Pain from blood tests 100 60 20 10 50 40 30 0 90 70 80 * ** Study participants in agreement (%) *p=<0.001, **p=0.01

9. Keys to addressing hypoglycaemia Patient education Perception vs. reality: rates of hypoglycaemia are much lower in type 2 patients than type 1 patients, even on intensified insulin therapy Educate patients to properly self-monitor blood glucose (SMBG); actively monitoring BG to mitigate fear of hypoglycaemia Regimen selection and dosage Physicians must tailor insulin therapy to the patient, while considering glycaemic level and patient feedback Choice of insulin Modern insulin analogues incur less hypoglycaemia at equivalent levels of glycaemic control, thus offering the possibility of titrating more safely to target Korytkowski M. Int J Obes Relat Metab Disord 2002;26:S18–S24 Danne T. MedscapeCME Diabetes & Endocrinology, 2009-09-21

10. Tips for Preventing Hypoglycemia If blood glucose is < 70 mg/dl, give 15–20 g of quick-acting carbohydrate (1–2 teaspoons of sugar or honey, 5–6 pieces of hard candy glucose gel or tablets as directed, or 1 cup of milk). Test blood glucose 15 minutes after treatment. If it is still < 70 mg/dl, re-treat with 15 g of additional carbohydrate. Keep glucagon injection kit available for patients who are unconscious or unable to take in oral carbohydrate

11. Treatment hints Intravenous glucose (25 g) should be given if the patient is unable or unwilling to take carbohydrates orally. If intravenous therapy is not practical, subcutaneous or intramuscular Glucagon can be used. transientlyThis treatment raise plasma glucose concentrations only transiently, and patients should therefore be urged to eat as soon as is practical to replete glycogen stores.

12. Changing the dose: some general rules Combating hypoglycaemia Reduce insulin dose by at least 20% and review after 1 week Preventing hypoglycaemia correcting hyperglycaemiaPreventing hypoglycaemia takes priority over correcting hyperglycaemia http://www.rcn.org.uk/__data/assets/pdf_file/0009/78606/002254.pdf

13. HYPOGLYCAEMIA & MODERN INSULIN Do modern insulins offer any advantages over traditional insulins?

14. NovoMix ® 30 effectively reduces HbA 1c in T2 patients; low hypo rates OnceMix, Strojek et al 2009. Curr Med Res Opin; 25; 2887-94 1-2-3 Garber A et al. Diab Obesity Metab 2006; 8(1):58-66 EUROMIX, Kann et al. Exp Clin Endocrinol Diabetes 2006; 114:527-532 REFORM Lund S et al. BMJ 2009;339: 2-11 INITIATE Raskin P et al. Diabetes Care 2005; 28:260-5 ACTION Raskin et al. Diabetes Obes Metab. 2009 Jan; 11(1):27-32 PREFER Liebl et al. Diabetes Obes Metab. 2009 Jan; 11(1):45-52

15. Aspart (NovoRapid ® ) maintains glycaemic control † : 3-year data... Home et al. Diabetes Res Clin Pract 2006;71:131–9 8.5 8.0 7.5 0 HbA 1c (%) Months 0612182424 3036 * p=0.035 at 30 months n=753 Insulin aspart (IAsp) Human insulin (HI) † Study conducted in patients with T1 diabetes

16. …and incurs a low risk of hypoglycaemia Hypoglycaemia rate (event/patient-month) RR (IAsp/HI) [95% CI], p-value IAspHI Major0.08 1.00 [0.72–1.39] NS Minor2.462.031.24 [1.09–1.39] p=0.02 Despite significant differences in glycaemic control, the risk of major hypoglycaemia did not differ between the two treatments † Home et al. Diabetes Res Clin Pract 2006;71:131–9 †Study conducted in patients with T1 diabetes; IAsp = NovoRapid ®

17. Aspart significantly reduced major nocturnal hypoglycaemia vs. HI † 0 0.5 1 1.5 2 2.5 3 Total events Nocturnal events Diurnal events Hypoglycaemia event rate (events/patient/year) Heller et al. Diabet Med 2004;21:769–75 IAsp HI n=155 72%* risk reduction with insulin aspart † Study conducted in patients with T1 diabetes * P = 0.001

18. Modern analogues incur fewer hypos at equivalent levels of glycaemic control Hypoglycaemia is a major perceived barrier to insulin use for patients and physicians Modern insulin analogues incur less hypoglycaemia at equivalent levels of glycaemic control, thus offering the possibility of titrating more safely to target These findings have been reported both in clinical trials, and in observational studies