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Hypo- glycemia NOT an innocent side effect S. Gentile

Hypo- glycemia NOT an innocent side effect S. Gentile Department of Clinical and Experimental Medicine Second University of Naple s. Frequency. Quality of life . Adherence. Direct Complications. Chronic complications. ?. Economic burden.

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Hypo- glycemia NOT an innocent side effect S. Gentile

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  1. Hypo-glycemia NOT an innocent side effect S. Gentile Department of Clinical and Experimental Medicine Second University of Naples

  2. Frequency Qualityof life Adherence DirectComplications Chroniccomplications ? Economicburden

  3. The incidence of severe hypoglycaemic episodes increases with duration of treatment UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.

  4. GLUCOSE-LOWERING AGENTS AND RISK OF HYPOGLYCAEMIA • Hypoglycaemia has been associated with: • Activation of adrenergic response1 • Impaired flexibility in substrate shift in the diabetic myocardium2 • QTcprolongation and cardiac rate/rhythm disturbances3 • Excessive glucose fluctuations with marked activation of oxidative stress4 1. Hilsted J. Clin Physiol. 1993;13:1-10. 2. Avogaro A, et al. Am J Cardiol. 2004;93:13A-16A. 3. Landstedt-Hallin L, et al. J Intern Med. 1999;246:299-307. 4. Monnier L, et al. JAMA. 2006;295:1681-87. 1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Cefalu WT. Nature. 2007;81:636-49. 1. Amiel SA, et al. Diabetic Med. 2008;25:245-54. 2. Melander A. Diabetic Med. 1996;13:S143-7

  5. Factors associated with hypoglycaemia • Advancingage • Restricting or reducedmealingestion (especiallycarbohydrateintake) • Longerdiabetesduration • Deterioration of renal and hepaticfunction • Potentiatingeffects of alcohol and drug use • Excessivephysicalactivity 1. Amiel SA, et al. Diabetic Med. 2008;25:245-54. 2. Melander A. Diabetic Med. 1996;13:S143-7.

  6. Increasedincidenceofseverehypoglycaemiceventswith intensive therapy in ADVANCE, ACCORD and VADT Intensive glucose lowering contributes to an increased risk of hypoglycaemia by 2- to 3-fold, particularly at later stages of type 2 diabetes ADVANCE1 ACCORD2 VADT3 Per 100-patients per year 15 15 15 12.0 12 12 12 9 9 9 Severehypoglycaemicevents Severe hypoglycaemic events Severe hypoglycaemic events 6 6 6 4.0 3.0 3 3 3 1.0 0.7 0.4 0 0 0 Standard Intensive Standard Intensive Standard Intensive P<0.001 P<0.001 P<0.01 1. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2545-59. 2. ACCORD Study Group. N Engl J Med. 2008;358:2545-59. 3. Duckworth W (VADT). N Engl J Med. 2009;360:129-39.

  7. Hypoglycaemia: a majorpredictorof CV-death in the VADT study Hazard Ratio (HR lower CL, HR upper CL) P Value Hypoglycaemia 4.042 (1.449,11.276) 0.01 HbA1c 1.213 (1.038,1.417) 0.02 HDL 0.699 (0.536, 0.910) 0.01 Age 2.090 (1.518, 2877) <0.01 Prior event 3.116 (1.744, 5567) <0.01 0 2 4 6 8 10 12 Duckworth W.(VADT): results. 2008. Available from http:// webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?type=0&lid=3853, In the ACCORD study and VADT, a clear association between severe hypoglycaemia and CV events was found1,2 (although no cause-effect relationship was proven) Hypoglycaemia may be of particular concern in Individuals with a long duration of T2DM, elderly patients, especially with previous CV events3,4 Byington RP ACCORD Study Group: 9 Oct 2009. 2. Duckworth W, N EJ M 2009;360:129 3. Del Prato S. Diabetologia. 2009;52:1219. 4. Mannucci E, NutrMetabCardi Dis. 2009;19:604

  8. Recent hypoglycaemia is associated with a higher risk of MI in diabetes patients Casesof MI(%) Any hypoglycaemiain specific periods Controls(%) Adjusted risk of MI(95% CI) Index date or day before Prior 2 weeks Previous 5.5 months Previous 6 months Previous year 2.9 1.1 6.0 4.8 9.6 0.1 0.3 2.5 2.1 4.2 — 1.65 (1.50–1.81) 1.20 (1.15–1.25) 1.11 (1.06–1.15) 1.12 (1.08–1.16) Risk of MI associated with episodes of hypoglycaemia within a given prior period Miller DR, et al. Poster Presentation at 45th EASD. Sep 29 – 2 Oct 2009, Vienna, Austria.

  9. Verylow and increasingbloodglucoselevelsatadmission are associated with a higherrisk of deathaftermyocardialinfarction* *Subjectswerestratifiedbythrombolysis in myocardialinfarction (TIMI) score The relationship betweenadmissionbloodglucose <81 mg/dLandincreaseddeath was not seen in subjectswith a TIMI risk score <4 25 22.6% 20 15 Riskofdeathat 30 days (%) P<0.001 10 8.7% 8.0% 4.3% 5 3.2% 2.5% 0 < 81 81-99 126-150 151-199 >199 100-125 n=62 n=123 n=280 n=186 n=200 n=196 Blood glucoselevel (mg/dL) Pinto DS, et al. J Am Coll Cardiol. 2005;1:178-83.

  10. Hypoglycaemia and AutonomousNervous System abnormalities Cardiovascular impairment is associated with increased mortality1–5 Impaired baroreflex sensitivity is a predictor of cardiac mortality in post-MI patients4,5 Cardiovascular autonomic function is attenuated after antecedent hypoglycaemia6 A B C P<0.04 20.0 5.0 70 60 17.5 0.0 50 P<0.01 Sympathetic Burst Frequency (bursts/minute) Change in BaroreflexSensitivity (ms/mmHg) BaroreflexSensitivity (ms/mmHg) 40 15.0 -5.0 30 12.5 -10.0 20 0.0 -15.0 0 5.0 2.8 5.0 2.8 Baseline Post- Nitroprusside Antecedent Clamp Glucose (mmol/L) Antecedent Clamp Glucose (mmol/L) A:Baroreflex sensitivity after antecedent euglycaemic ( ) or hypoglycaemic ( ) clamp studies. B:Change in baroreflex sensitivity in individual subjects after antecedent hypoglycaemia versus antecedent euglycaemia. C:MSNA assessed at baseline and after nitroprusside in subject after antecedent euglycaemia ( ) or antecedent hypoglycaemia ( ). 1. Maser RE, et al. Diabetes Care. 2003;26:1895-901. 2. Vinik AI, Ziegler D. Circulation. 2007;115:387-97. 3. Bigger JT, et al. Circulation. 1993;88:927-34. 4. De Ferrari GM, et al. J Am Coll Cardiol. 2007;50:2285-90. 5. La Rovere MT, et al. 1998; Lancet 351:478-84. 6. Adler GK, et al. Diabetes 2009;58:360-6.

  11. Patientswhoreported severe hypoglycemiahad 3.4-fold highermortality (p<0.005) comparedwiththosewhoreportedmild/no hypoglycema

  12. Diabetes Care 36:894–900, 2013 Symptomatic hypoglycemia (clinically mild or severe) is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality • Mild/Severe Hypoglycemia • HRs • cardiovascular diseases 2.09 • all-cause hospitalization 2.51 • total mortality 2.48

  13. SUs may increase mortality and CV risk vs metformin: • In a Danish study of 107,806patients, monotherapy with glimepiride, glibenclamide, glipizide, and tolbutamide was associated with significantly increased all-cause mortality vs metformin in patients with and without previous MI • Results were similar for CV mortality and the composite CV end point Schramm TK, et al. Eur Heart J. 2011;32:1900-1908 Risk for All-Cause Mortality No Previous MI Previous MI Hazard Ratio (95% confidence interval) Hazard Ratio (95% confidence interval) Risk for Overall Mortality 13 Cleveland Clinic: 23,915 T2DM patients Pantalone KM,, et al. Diabetes Obes Metab. 2012;14(9):803-809.

  14. Intern J ClinPrac2013; 67(4), 307–316 Incidence of hypoglycaemic AEs was generally similar for saxagliptinand placebo across groups 6.7 vs 6.32%) Allen, et al. Presentedat EASD 2012; poster #838 Incidence of all reported hypoglycaemic AEs were similar in patients: with a history of CVD (7.2% vs 6.2%) and without (7.8% vs 6.9%) Cook, et al. Presentedat EASD 2012; poster #837

  15. Systematic review and meta-analysis of SGLT2 inhibitors in patients with T2DM SGLT2-i have a favourable effect on HbA1c, systolic blood pressure weight and incidence of hypoglycaemia (RR=0.24 [95% CI: 0.06, 0.98] versus active competitors) v SBP=systolic blood pressure; WMD=weighted mean difference; I2=heterogeneity • SGLT2-i are associated with an increased risk for urinary tract infections compared with active comparators (RR=1.51 [1.08, 2.09]) and for genital infections compared with both placebo (RR 3.28, 95% CI 2.19 to 4.90)or other hypoglycaemic medications (RR=4.57 [2.80, 7.45]) • ADA/EASD algorithm considerations RR=relative risk; CI=confidence interval Tsapas, et al. Presented at EASD; OP #241

  16. Hypoglycaemic coma requiring hospitalisationis more common in elderly people with type 2 diabetes 40 35 30 25 Number of subjects 20 15 10 5 0 17–20 21–30 31–40 41–50 51–60 61–70 71–80 81–90 Age range (Years) Retrospective medical record review of individuals with diabetes who were admitted with DIHC or developed DIHC during hospitalisation. Ben-Ami H, et al. Arch Intern Med. 1999;159:281-4.

  17. THE HYPOGLYCAEMIA IN ELDERLY • In the elderly, hypoglycaemia can have serious, sometimes life-threatening, consequences for the heart or brain • Elderly patients have a HIGHER RISK OF COMPLICATIONS: • Falls and injury, cognitive decline, depression, degraded quality-of-life • SYMPTOMS MAY BE DIFFERENT from younger patients: • Blurred vision, instability • Often blunted by an autonomous neuropathy or impaired cognitive function (‘silent’ hypoglycaemia) • FAVOURING FACTORSfor hypoglycaemia other than age are: • Multiple co-morbid conditions • Renal impairment • Multiple medications • More frequent, poorly-adapted behaviour response • Rare use of self monitoring • Absence of patient and caregiver education Lecomte P. Diabetes Metab, 2005;31:5S105-5S111.

  18. Impairedrenalfunctionenhances the risk of hypoglycaemia in elderlypeople with T2DM • Subjectswith T2DM hospitalised with severe hypoglycaemia and loss of consciousness, 24 out of 35 casespresented with renal failure1 • Those with renalfailurewereolderthanthose with normalrenalfunction (74.3 vs 32.8 years) • Impairedrenalfunctionenhances the risk of drug-inducedhypoglycaemia in individualstreated with insulinsecretagogues or exogenous insulin2 1. Hasslacher C, Wittmann W. DtschMedWochenschr. 2003:128:253-6. 2. Snyder RW, Berns JS. Semin Dial. 2004;17:365-70.

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