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Hypoglycaemia – the hidden problem

Hypoglycaemia – the hidden problem. Professor Anthony Barnett University of Birmingham and Heart of England NHS Foundation Trust United Kingdom. Hypoglycaemia – the hidden problem. Hypoglycaemia basics.

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Hypoglycaemia – the hidden problem

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  1. Hypoglycaemia – the hidden problem Professor Anthony Barnett University of Birmingham and Heart of England NHS Foundation Trust United Kingdom

  2. Hypoglycaemia – the hidden problem Hypoglycaemia basics

  3. “The major limiting factor to achieving intensive glycaemic control for people with type 2 diabetes” Hypoglycaemia Briscoe VJ, et al. Clin Diab 2006;24:115-121.

  4. Plasma glucose <3.9mmol/l based on activation of counter-regulatory responses In clinical trials threshold ranges between 3-3.9 mmol/l Others “classify” into “mild” and “severe” Result: difficult to pinpoint exact incidence! Definition of hypoglycaemia Briscoe VJ, Davis SN. Clin Diabetes 2006;24:115-21.

  5. Hypoglycaemia – the hidden problem Epidemiology and consequences of hypoglycaemia

  6. Hypoglycaemia in type 2 diabetes • Hypoglycaemia symptoms are common in type 2 diabetes (38% of patients)1 • Associated with: • Reduced quality of life • Reduced treatment satisfaction • Reduced therapy adherence • More common at HbA1c < 7% 1. Diabetes, Obesity and Metabolism 2008 Jun;10 Suppl 1:25-32.

  7. Asymptomatic episodes of hypoglycemia may go unreported • In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose monitoring1 • Other researchers have reported similar findings2,3 100 75 62.5 55.7 46.6 50 Patients, % 25 n=70 n=40 n=30 0 All patients with diabetes Type 1 diabetes Type 2 diabetes Patients with ≥1 unrecognized hypoglycemic event, % 1. Chico A, et al. Diabetes Care 2003;26(4):1153-1157. 2. Weber KK, et al. Exp Clin Endocrinol Diabetes 2007;115(8):491-494. 3. Zick R, et al. Diab Technol Ther 2007;9(6):483-492.

  8. Risk factors for hypoglycaemia • Use of insulin and sulfonylureas1 • Older people2,3 • Long duration diabetes2 • Irregular eating habits3 • Exercise3 • Have lower HbA1c4 • Periods of fasting e.g. Ramadan • Prior hypoglycemia5,6,7 • Hypoglycemia unawareness8 • Alcohol9 See notes for references.

  9. Effects of hypoglycaemia on quality of life (RECAP-DM study) • Hypoglycaemia significantly more likely in patients with macrovascular complications • Associated with lower treatment satisfaction scores (p<0.0001) • Such patients more likely to report barriers to adherence (p=0.0057) Alvarez Guisasola F, et al. Diabetes Obes Metab 2008;10(Suppl.1):25-32.

  10. Hypoglycaemia significantly reduces patients’ quality of life P<0.0001 Vexiau P, et al. Diabetes Obes Metab 2008;10(S1):16-24. Reproduced with permission

  11. Hypoglycaemia increases healthcare costs • In the UK, the estimated cost of hypoglycaemia due to type 2 diabetes is about £7.4 million1 • Probably an underestimate £330 £287.50 £105.60 £92 Amiel SA, et al.Diabetic Medicine 2008; 25: 245-254.

  12. Recognition of warning symptoms is fundamental for self-treatment and to prevent progression to severe hypo1 Even mild hypoglycaemia induces defects in counter-regulatory responses and impaired awareness2 Impaired awareness predisposes to six-fold increase in the frequency of severe hypoglycaemia3 Only 15% of type 2 diabetes patients who experienced a hypoglycaemic event reported the incident to their doctor1,4 Patients have low awareness of hypoglycaemia 1. McAulay V, et al.Diabet Med. 2001;18:690-705. 2. Amiel SA, et al. Diabetic Medicine 2008;25:245-254. 3. Gold AE, et al. Diabetes Care 1994;17:697-703. 4. Leiter LA, et al. Can J Diab. 2005;29(3):186-192.

  13. Fear of hypoglycaemia:1 Is an additional psychological burden on patients May limit the aggressiveness of drug therapy Can decrease adherence to diet May reduce compliance with therapy Influences: Patient health outcomes2 Post-episode lifestyle changes2 Other family members-disrupts domestic life3 A severe hypoglycaemic event is associated with a greater fear of hypo in the future4 Blood glucose awareness training can reduce levels of fear5 Fear of hypoglycaemia is a burden for patients 1. Can J Diab. 2005;29:186-192; J Diab Complic 2004;18:60-68; 2. Leiter LA, et al.Can J Diab. 2005;29:186-192; 3. Frier BM et al. IJCP Supplement. 2001;123:30-37; 4. Currie CJ, et al.Curr Med Res Opin 2006;22:1523-1534; 5. Wild D, et al. Patient Educ Couns. 2007;68:10-15.

  14. Clinical consequences of hypoglycaemia • Hospital admissions: • In a prospective study1 of well-controlled elderly T2D patients, 25% of hospital admissions for diabetes were for severe hypos • Increased mortality: • 9% in a study2 of severe SU-associated hypoglycaemia • Road accidents caused by hypos3: • 45 serious events per month 1. Diab Nutr Metab 2004;17(1):23-26. 2. Horm Metab Res Suppl 1985;15:105-111. 3. BMJ 2006;332:812.

  15. Hypoglycaemia – the hidden problem Hypoglycaemia in patients undergoing intensive glucose control

  16. Recent studies investigating intensive glycaemic control have highlighted the problem of hypoglycaemia CAD, coronary artery disease; CHF, congestive heart disease; CVD, cardiovascular disease; MI, myocardial infarction a Conventional vs intensive b p=0.04

  17. Severe hypoglycaemia was more common with intensive therapy in three recent trials of intensive glucose control 25 20 Intensive control 15 % Patients with at least one event during the trial Standard control 10 5 0 ACCORD ADVANCE VADT

  18. ACCORD – requirement for medical assistance amongst patients with hypoglycaemia 18 16.2 Requiring any assistance 15 Requiring medical assistance 12 10.5 Patients (%) 9 6 5.1 3.5 3 0 Intensive therapy(target HbA1c <6%) Standard therapy(target HbA1c 7.0 to 7.9%) ACCORD study. N Engl J Med 2008;358(24): 2545-2559.

  19. ACCORD Trial – intensive glucose lowering may be harmful in patients at high CV risk • 22% relative increase in mortality for intensive over standard treatment 25 20 15 Intensive therapy Mortality (%) 10 Standard therapy 5 0 0 1 2 3 4 5 6 Years No. at Risk Intensive therapy 5128 Standard therapy 5123 4972 4971 4803 4700 3250 3180 1748 1642 523 499 506 480 Action to Control Cardiovascular Risk in Diabetes N Engl J Med 2008;358:2545-59. Reproduced with permission

  20. ACCORD: higher mortality in participants who experienced severe hypoglycaemia 3.3% 3.5 3.0 2.5 2.0 Overall mortality rate (%) 1.2% 1.5 1.0 0.5 0.0 Experienced SH Never experienced SH The cause of the increased mortality could not be proven; severe hypoglycaemia was implicated SH = severe hypoglycaemia

  21. Reduced endogenous insulin secretion leading to Unstable free insulin concentrations Impaired glucagon response Impaired sympathoadrenal responses with antecedent hypoglycaemia The same factors which influence hypoglycemic risk in type 1 diabetes operate in advanced type 2 diabetes Explaining the increased hypoglycaemic risk in intensively treated type 2 diabetes

  22. Cardiac arrhythmias due to abnormal cardiac repolarization in high-risk patients (IHD, cardiac autonomic neuropathy) Increased thrombotic tendency/decreased thrombolysis Cardiovascular changes induced by catecholamines Increased heart rate Silent myocardial ischaemia Angina and myocardial infarction Potential mechanisms of hypoglycaemia-induced mortality

  23. Effect of experimental hypoglycaemia on QT interval A B QTc= 456 ms QTc= 610 ms HR= 66 bpm HR= 61 bpm 5.0mM 2.5mM International Diabetes Monitor 2009; 21(6): 234-241. Reproduced with permission

  24. Hypoglycaemia – the hidden problem Impact of drug treatment on hypoglycaemic risk

  25. Pooled hypoglycaemia results for randomized trials, by drug comparison Bolen S, et al. Ann Intern Med 2007;147:386-399. Reproduced with permission

  26. Agents with increased hypoglycaemic potential Those which enhance insulin secretion/β-cell function in non-glucose dependent manner Sulfonylureas Short-acting secretagogues (rapaglinide/nateglinide) Agents with minimal/low hypoglycaemic risk Improve insulin resistance Biguanide-metformin Thiazolidinediones (pioglitazone/rosiglitazone) Incretin-based therapies-enhance insulin secretion in glucose-dependent manner Incretin enhancers: DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) Reduce glucose absorption Alpha-glucosidase inhibitors (acarbose, voglibose) ? Bile-acid sequestrants (colesevelam) Oral antidiabetic agents and hypoglycaemic risk in type 2 diabetes

  27. Agents with high hypoglycaemic potential Human insulin preparations Regular insulin NPH insulin Pre-mixed formulations Agents with moderate hypoglycaemic potential Insulin analogue preparations Rapid-acting – aspart, glulisine, lispro Long-acting – glargine, determir Amylin analogue – pramlintide Agents with minimal/low hypoglycaemic potential Glucagon-like peptide-1 analogue/receptor agonists Exenatide Liraglutide Injectable agents and hypoglycaemic risk in type 2 diabetes

  28. Rates of hypoglycemia increase as A1C levels decrease in patients with type 2 diabetes on OADs 40 30 Annual rate (%) 20 10 0 0 4 5 6 7 8 9 10 11 Most recent A1C (%) Wright et al. J Diabetes Complications. 2006;20:395-401. Reproduced with permission

  29. UKPDS 33. Lancet 1998;352:837-853. Hypoglycaemia with sulphonylureas versus insulin(UKPDS) Any Severe 3.0 40 36.5 2.5 2.3 30 2.0 Mean (%) Mean (%) 1.5 20 17.7 1.0 11 0.6 10 0.4 0.5 0.1 1.2 0.0 0 Diet Chlorpropamide Glibenclamide Insulin

  30. Hypoglycaemia with secretagogues vs sensitizers (the ADOPT study) All hypoglycemia Severe hypoglycemia Percent of patients with episodes Glyburide Metformin Rosiglitazone Glyburide Metformin Rosiglitazone ADOPT Study N Engl J Med 2006;355:2427-2463.

  31. In an observational study over 9-12 months in six UK secondary care diabetes centres: 39% of patients receiving an SU described mild hypoglycaemia 7% of patients receiving an SU described severe hypoglycaemia 14% of patients receiving an SU experienced a blood glucose <2.2 mmol/l The incidence of hypoglycaemia was similar in insulin- and SU-treated patients Hypoglycaemic events occur frequently in patients treated with sulphonylureas UK Hypoglycaemia Study Group. Diabetologia. 2007;50(6):1140-7.

  32. Increased risk of hypoglycaemia1,2,3 The UKPDS noted 4.8kg weight gain over a three year period2 Tolerability issues with long-acting insulin secretagogues 1. UKPDS 13 BMJ 1995;310:83-8. 2. UKPDS 28 Diabetes Care 21(1):87-92. 3. Adverse Drug React Toxicol. Rev 2002;21(4):205-17.

  33. Hypoglycaemia increases with biphasic or prandial versus basal insulin Patients reporting grade 2 or grade 3 hypoglycaemic events Holman RR, et al. N Engl J Med 2007;357:1716-1730. Reproduced with permission

  34. Metformin is associated with a very low risk of hypoglycaemia when used as a monotherapy There is an increased risk of hypoglycaemia when using sulphonylurea plus metformin that when using either agent alone Symptomatic hypoglycemia (incidence) Metformin: No events Repaglinide: 0.97 events/patient-year Combination: 3.20 events/patient-year Severe hypoglycemic episodes None reported Hypoglycaemic risk with sulphonylurea combination therapy Moses R et al.Diabetes Care 1999;22(1):119-124.

  35. Patient receive little information on the adverse events of oral medication: In a UK survey, only 10% of people treated with an SU knew that it could cause hypos1 GPs and practice nurses may not be aware of the prevalence of hypos with SUs Sulphonylureas - lack of awareness and education 1.Browne et al. Diabetes Med 2000;17(7):528-531.

  36. Severe hypoglycaemia more likely with longer insulin treatment 8 7 No severe hypos 6 Severe hypos 5 Median duration of insulin therapy (years) 4 3 2 1 0 Type 2 diabetes Type 1 diabetes Hepburn et al. Diabetic Med 1993; 10(3): 231-7.

  37. Hypoglycaemia – the hidden problem Reducing hypoglycaemic risk in type 2 diabetes

  38. UK NICE guidelines recommend adding a DPP-4 inhibitor or glitazone to metformin instead of SU if significant risk of hypoglycaemia and its consequences1 Alternatives to sulphonylureas to reduce hypoglycaemic risk 1. National Institute of Health and Clinical Excellence. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes NICE clinical guideline (May 2009).

  39. Pioglitazone with metformin showed sustained efficacy over 2 years and a low incidence of hypoglycaemia Weeks of treatment 0 10 20 30 40 50 60 70 80 90 100 110 0.0 -0.25 -0.50 HbA1c (%)1 -0.75 -1.00 -1.25 -1.50 Pioglitazone + metformin Gliclazide + metformin n=317 received PIO + MET; n=313 received GLIC + MET; n=10 not eligible for this analysis2 1. Matthews et al. Diabetes Metab Res Rev 2005;21:167-174. 2. Charbonnel et al. Diabetologia 2005;48:1093-1104. Reproduced with permission

  40. Vildagliptin add-on to insulin: fewer hypoglycaemic events No. of events No. of severe events† ** 185 Vildagliptin + insulin 200 Placebo + insulin 10 160 8 * 113 120 6 Number of events 6 Number of severe events 80 4 40 2 0 0 0 †Severe defined as grade 2 or suspected grade 2 hypoglycaemia. *p<0.05; **p<0.001 between groups. Fonseca V et al. Diabetologia 2007;50:1148-1155.

  41. Hypoglycaemia – the hidden problem Hypoglycaemia - conclusions

  42. Hypoglycaemia is the major factor limiting intensive control in T2D May explain mortality associated with intensive treatment in ACCORD Costs of hypoglycaemia are grossly underestimated Can cause severe morbidity and mortality and lower health-related quality of life Patient awareness of the risk of hypoglycaemia with some antidiabetic therapies is low Occurs in a significant proportion of patients on OADs Sulphonylureas are associated the highest risk of hypoglycaemia, both alone and in combination Insulin therapy is associated with a significant incidence of hypoglycaemia Addition of a thiazolidinedione to insulin has been shown to reduce the incidence of hypoglycaemic events Replacement of sulphonylureas with alternative OADs may significantly reduce the risk of hypoglycaemia NICE recommends adding a DPP-4 inhibitor or glitazone to metformin instead of a sulphonylurea if there is a significant risk of hypoglycaemia Hypoglycaemia - conclusions

  43. Hypoglycaemia – the hidden problem Professor Anthony Barnett University of Birmingham and Heart of England NHS Foundation Trust United Kingdom

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