1. HYPOGLYCEMIA IN TYPE 1 DM Presented By: Alaa Monjed

2. OUTLINE Definition of Hypoglycemia in T1DM, incidence and Impact of on DM management How to maintain Glucose Homeostasis and Counterregulaton of Hypoglycemia Counterregulatory failure and hypoglycemia unawareness in T1DM How to Prevent and treat? Different insulin regimens, MDI and CSII

3. Case #1 49 year old male, T1DM for 20 years, on Lantus qhs and NR ac meals. He used to have a tight glycemic control with HbA1c 6- 6.5%. Recently had a hypoglycemia coma resulting in brain injury. Now, runs BG between 9-20 mmol/L. HbA1c > 9.5%.

4. Case#2 45 year old lady, T1DM for 30 years. HbA1c 5.4- 6.5% with no evidence of microvascular DM complications. On NR premaels and NPH twice daily +/- 4 am NR. Has hypoglycemia unawareness and recurrent severe hypoglycemia. Over the last year she had at least 5 – 6 episodes of hypoglycemia induced Seizures.

5. This fear of hypoglycemia influences an individual’s ability to adhere to optimal insulin replacement regimens and to put in place those measures required to achieve near- normal glucose control In this way, hypoglycemia has emerged as a major obstacle to achieving the goals of intensive insulin therapy in everyday clinical practice Hypoglycemia in Type 1 Diabetes DIABETES, VOL. 59, OCTOBER 2010

6. Definition of Hypoglycemia 1.The development of autonomic or neuroglycopenic symptoms 2.A low plasma glucose level (<4.0 mmol/L for patients treated with insulin or an insulin secretagogue) 3.Symptoms responding to the administration of carbohydrate

7. ADA Definition of Hypoglycemia All episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm. The workgroup recommended that people with diabetes become concerned about the possibility of hypoglycemia at a SMBG level ≤3.9 mmol/L. ADA Workgroup on Hypoglycemia (2005)

8. Symptoms of Hypoglycemia

9. Severity of Hypoglycemia

10. INCIDENCE OF HYPOGLYCEMIA Hypoglycemia is a fact of life for most people with type 1 diabetes The average individual with type 1 DM experiences about 2 episodes of symptomatic hypoglycemia/week, a figure that has not changed substantially in the last 20 years Severe hypoglycemia has annual prevalence of 30–40% and annual incidence of 1.0 – 1.7 episodes per patient per year Frier BM. The incidence and impact of hypoglycemia in type 1 and type 2 diabetes. International Diabetes Monitor 2009;21:210–218

11. Hypoglycemia in T1DM It occurs as a consequence of 3 factors: Bahavioral issues Too much insulin Alcohol on an empty stomach Exercise-related Individuals who stack their insulin Impaired counterregulatory system Diabetes complications Autonomic neuropathy gastroparesis Renal failure

12. NOCTURNAL HYPOGLYCEMIA It can lead to disruption of sleep and delays in correction of the hypoglycemia Nighttime is typically the longest period between self-monitoring of plasma glucose, between food ingestion, and the time of maximum sensitivity to insulin It becomes less common using rapid acting insulin analogs before meals and using long acting insulin analogs rather than NPH as the basal insulin

13. IMPACT OF HYPOGLYCEMIA An estimated 2–4% of people with T1DM die from hypoglycemia Prolonged, profound hypoglycemia can cause neurological damage and brain death Hypoglycemia causes a transiently prolonged corrected QT interval It is reasonable to suggest that a fatal arrhythmia triggered by hypoglycemia might explain the “dead in bed syndrome” It is preventing the maintenance of euglycemia over a lifetime

14. GLUCOSE HOMEOSTASIS Insulin acts to restore normoglycemia through: decreasing hepatic glucose production increasing glucose uptake by skeletal muscle and adipose tissue inhibiting glucagon secretion

15. Response to Hypoglycemia in Normal Subjects

16. The mechanisms that normally prevent or rapidly correct hypoglycemia: decreased pancreatic islet β cell insulin secretion increased pancreatic islet α cell glucagon secretion increased adrenomedullary epinephrine secretion the ingestion of food prompted by symptoms of hypoglycemia Cortisol and GH contribute only if the hypoglycemia persists for several hours

19. RESPONSE TO HYPOGLYCEMIA IN DIABETES

20. INSULIN The first defense, the ability to suppress insulin release, cannot occur in patients with absolute beta-cell failure (type 1 diabetes and long-standing type 2 diabetes) Thus, the main defense against hypoglycemia is increased release of counterregulatory hormones, which raise BG concentrations by stimulating glucose production and by antagonizing the insulin-induced increase in glucose utilization

21. GLUCAGON The glucagon response to hypoglycemia, although normal at the onset of diabetes, is lost in parallel with that of insulin in type 1 diabetes and more slowly in type 2 diabetes This may be the result of beta-cell failure and subsequent loss of the hypoglycemia-induced decline in intraislet insulin that normally signals increased glucagon secretion during hypoglycemia

22. EPINEPHRINE The epinephrine response to hypoglycemia also becomes attenuated in many patients, at least in part because of recent antecedent hypoglycemia An attenuated epinephrine response causes defective glucose counterregulation, which is associated with a 25- fold or greater increased risk of severe hypoglycemia

24. Hypoglycemia-Associated Autonomic Failure The concept of hypoglycemia-associated autonomic failure (HAAF) in T1DM and advanced T2DM posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation hypoglycemia unawareness and, thus, a vicious cycle of recurrent hypoglycemia Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. Cryer PE. J Clin Invest. 2006 Jun;116(6):1470-3.

25. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. Cryer PE. J Clin Invest. 2006 Jun;116(6):1470-3.

27. HYPOGLYCEMIA UNAWARENESS With recurrent hypoglycemia, the nervous system adapts to low BG levels and maintains glucose uptake despite hypoglycemia (by upregulating GLUT1 transporters at the BBB) without adrenergic effects, resulting in unawarness to hypoglycemia It is associated with a 6-fold increased risk for severe hypoglycemia

28. Fanelli CS et al. 21 T1DM pts with hypoglycemia unawareness and frequent mild/severe hypoglycemia episodes while on "conventional" insulin therapy intensive insulin therapy which meticulously prevented hypoglycemia (based on physiologic insulin replacement and continuous education, EXP, n = 16), or maintenance of the original "conventional" therapy (CON, n = 5) An increase in glycated Hb by 1% over 1 yr and a significant reduction in the hypoglycemia frequency Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM Diabetologia. 1994 Dec;37(12):1265-76.

29. Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta- adrenergic sensitivity in type 1 diabetes. PATIENTS: 10 men with T1DM and hypoglycemia unawareness (mean age [+/-SD], 46 +/- 16 years; mean duration of diabetes, 20 +/- 10 years). INTERVENTION: Strict avoidance of hypoglycemia. MEASUREMENTS: beta-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L) before and after 4 months of avoidance of hypoglycemia. Fritsche A, Stefan N, Häring H, Gerich J, Stumvoll M Ann Intern Med. 2001;134(9 Pt 1):729.

30. RESULTS: After 4 months, the mean number of episodes of hypoglycemia (glucose level<3.9 mmol/L) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P<0.001). Hemoglobin A(1c) values increased from 6.8% +/- 0.3% to 7.7% +/- 0.3% (P<0.001). CONCLUSIONS: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta-adrenergic sensitivity

31. A two- to three-week period of scrupulous avoidance of hypoglycemia is advisable since that often restores awareness

32. Hypoglycemia in the Diabetes Control and Complications Trial THE DCCT RESEARCH GROUP

33. DCCT Trial Conventional Therapy 1 or 2 daily injections of insulin including mixed insulin No daily adjustments of insulin dosage Goals of therapy: Absence of symptoms due to hyperglycemia or hyperglycosuria Absence of ketonuria Maintenance of IBW No severe/frequent hypoBG Intensive Therapy Insulin 3 or more times daily by injection or pump SMBG qid Dosage adjustment according to SMBG, diet, exercise Goals of therapy: Premeal BG 3.9-6.7 Postprandial BG <10

34. 65% in the intensive group vs 35% in the conventional group had at least one episode of severe hypoglycemia over 6.5 years 30% in each group experienced a second episode within the 4 months following the first episode of severe hypoglycemia Within each treatment group, the number of prior episodes of hypoglycemia was the strongest predictor of the risk of future episodes, followed closely by the current HbA1c value

35. Epidemiology of severe hypoglycemia in the diabetes control and complications trial The DCCT Research Group Severe hypoglycemia occurred more often during sleep (55%); 43% of all episodes occurred between midnight and 8 AM Of episodes that occurred while subjects were awake, 36% were not accompanied by warning symptoms The American Journal of Medicine Volume 90, Issue 4, April 1991, Pages 450–459

37. How to Treat Hypoglycemia?

42. STRATEGIES TO PREVENT HYPOGLYCEMIA Patients at high risk for severe hypoglycemia should be informed of their risk and counseled, along with their significant others, on preventing and treating hypoglycemia (including use of glucagon) Preventing driving and industrial accidents through self- blood glucose monitoring Taking appropriate precautions prior to the activity Documenting BG readings taken during sleeping hours Individuals may need to have their insulin regimen adjusted appropriately to lower their risk

44. 1.Diabetes self-management (supported by education and empowerment) 2.Frequent self-monitoring of blood glucose (and perhaps in some instances continuous glucose sensing) 3.Flexible and appropriate insulin (and other drug) regimens 4.Individualized glycemic goals 5.Ongoing professional guidance and support STRATEGIES TO PREVENT HYPOGLYCEMIA

45. Insulin Regimens Use of long-acting insulin analogs (glargine, detemir) as the basal insulin and rapid-acting insulin analogs (lispro, aspart, glulisine) as the pre-meal bolus insulin reduces the risk of hypoglycemia, particularly nocturnal hypoglycemia. Although many clinicians believe CSII is better, at comparable A1C levels CSII has not been found to consistently result in less hypoglycemia than a basal- bolus regimen with insulin analogs

46. Glargine vs. NPH Pharmacology Heinemann, L et al. Diabetes Care 2000; 23:644

47. Glargine vs. NPH Glargine possesses modest therapeutic advantage over NPH in T1DM HbA1c weighted-mean difference - 0.11% In meta-analysis, no significant difference in any type of hypoglycemia Singh et al. CMAJ 2009; 180: 385

48. Insulin Detemir vs. NPH Similar glycemic control observed in T1DM T1DM - HbA1c weighted change of -0.06% Slightly lower risk of severe and nocturnal hypoglycemia in T1DM but not in T2DM on MDI Severe hypoBG RR 0.74 Nocturnal hypoBG RR 0.92 Singh et al. CMAJ 2009; 180: 385

50. weighted mean difference between HbA1c values was − 0.12% (95% CI, − 0.17% to − 0.07%) for adult T1DM pts

51. Figure 3. Differences in overall hypoglycemic event rate. A, Standardized mean differences (error bars indicate 95% confidence interval [CI]) in overall hypoglycemic event rate during therapy with short-acting insulin (SAI) analogues compared with structurally unchanged SAI in patients with type 1 diabetes mellitus.

52. The standardized mean difference for overall hypoglycemia (episodes per patient per month) was − 0.05 (95% CI, − 0.22 to 0.11) Conclusion: the analysis suggests only a minor benefit to HbA1c values in adult patients with type 1 diabetes mellitus but no benefit in the remaining population with type 2 or gestational diabetes from SAI analogue treatment

54. RCTs and before/after studies of ≥ 6 months’ duration CSII and with severe hypoglycemia frequency > 10 episodes/100 patient years on MDI Severe hypoglycemia was reduced during CSII compared with MDI, with a rate ratio of 2.89 (95% CI 1.45 to 5.76) for RCTs 4.34 (2.87 to 6.56) for before/after studies [rate ratio 4.19 (2.86 to 6.13) for all studies] The reduction was greatest in those with the highest initial severe hypoglycemia rates on MDI ( P < 0.001)

57. 1-year, multicenter, RCT study The efficacy of sensor-augmented pump therapy was compared with that of a regimen of MDI in 485 patients (329 adults and 156 children) with inadequately controlled T1DM. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary endpoint was the change from the baseline glycated hemoglobin level

58. At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the SAP 8.1% in the MDI group (P<0.001) The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the SAP group than in the MDI group The rate of severe hypoglycemia in the SAP group (13.31 cases per 100 person-years) did not differ significantly from that in the MDI group (13.48 per 100 person-years, P = 0.58)

59. Severe hypoBGSAP N=247 MDI N-248 P-value No. of events32270.58 No. of patients2117 Rate per 100 Person-yr 13.3113.480.84 Sensor-augmented CSII has been reported to achieve lower A1C levels without an increase in hypoglycemia

62. Strength of Evidence High indicates high confidence that evidence reflects the true effect; further research is unlikely to change confidence in the estimate of the effect Moderate indicates moderate confidence that evidence reflects the true effect; further research may change confidence in the estimate of the effect and may change the estimate Low indicates low confidence that evidence reflects the true effect; further research is likely to change confidence in the estimate of the effect and is likely to change the estimate Insufficient indicates that evidence is unavailable, does not permit a conclusion, or consists of only 1 study with high risk of bias

65. Limitation: Many studies were small, of short duration, and limited to white persons with type 1 diabetes mellitus Conclusion: CSII and MDI have similar effects on glycemic control and hypoglycemia, except CSII has a favorable effect on glycemic control in adults with T1DM. For glycemic control, rt-CGM is superior to SMBG and sensor-augmented insulin pumps are superior to MDI and SMBG without increasing the risk for hypoglycemia

66. TAKE HOME MESSAGE Treatment-induced hypoglycemia is a common problem It has a significant impact on diabetic patient’s glycemic control At each clinic visit, hypoglycemia and hypoglycemia unawareness should be assessed and the preventing/treating strategies should be discussed Glycemic control should be individualized based on the microvascular complications, duration of DM, autonomic neuropathy, hypoglycemia unawareness and hypoglycemia fears

67. THANKS