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Hypo- glycemia NOT an innocent side effect S. Gentile

This study explores the frequency, quality of life, adherence, and direct/chronic complications of hypoglycemia, along with the economic burden it poses. It also discusses the factors associated with hypoglycemia and its association with cardiovascular events and mortality. The study concludes that hypoglycemia is not an innocent side effect and should be managed carefully in diabetic patients.

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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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