Does Hypoglycemia Increase the Risk of Cardiovascular Events? A - PowerPoint PPT Presentation

Does Hypoglycemia Increase the Risk of Cardiovascular Events? A report from Linda G Mellbin Lars Rydén, Matthew Riddle, Jeffrey Probstfield, Julio Rosenstock, Rafael Díaz, Salim Yusuf, Hertzel Gerstein on behalf of The ORIGIN Trial Investigators

Linda G Mellbin Declaration of interest Research grants Swedish Heart-Lung Foundation, Swedish Diabetes Association, Swedish Cardiac Society, Karolinska Institutet, Stockholm County Council MSD, Sanofi Lecture fees MSD, Sanofi, Novartis, Bayer AG, AstraZeneca, Lilly, Roche Consulting fees/Clinical trials Roche, GSK, Sanofi, AstraZeneca

Hypoglycemia in focus when managing people with diabetes Diabetes Care 2013; 36: 1384 From current gaps in knowledge ➸ “Hypoglycemia continues to cause considerable morbidity and even mortality…” ➸ “The impact of hypoglycemia on such outcomes need to be better defined and mechanisms understood…”

Study objectives ➸ To assess the relationship between hypoglycemia and cardiovascular events in people with dysglycaemia at high cardiovascular risk ➸ To analyse whether any such relationship differs in people allocated to glucose lowering with basal insulin glargine versus standard glycaemic care with oral agents

ORIGIN Design Glargine Standard Care Omega 3 FA Glargine + Omega 3 Omega 3 Glargine + Placebo Placebo Placebo In high risk people with IFG, IGT or early diabetes, does insulin replacement therapy targeting fasting normoglycemia (< 5.3 mM or 95 mg/dl) with insulin glargine, reduce CV outcomes more than standard approaches to dysglycemia?

ORIGIN Patient population n=12537 from 573 sites in 40 countries Greenland Iceland Sweden Norway Finland Russia United Kingdom Belarus Canada Denmark Bel. Neth. Ireland Poland Germany Switz. Hungary Romania Italy Ukraine Kazakhstan Mongolia France Bulgaria Georgia Uzbekistan Kyrgyzstan Azerb. N. Korea ATLANTIC Portugal Turkmenistan Tajikistan Spain Turkey S. Korea United States Jordan Greece Syria Cyprus Iran Tunisia China Lebanon Iraq Afghanistan Japan Israel Morocco Algeria Kuwait Pakistan Nepal Bhutan PACIFIC Libya Qatar The Bahamas Western Sahara Egypt Mexico U.A.E. (Occupied by Morocco) Saudi Arabia Myanmar Cuba Bangla- Dom. Rep. Mauritania India Laos (Burma) Jamaica Mali desh Oman Belize Haiti Niger PACIFIC Honduras Thailand Vietnam Philippines Cape Verde Yemen Chad Eritrea Senegal Guatemala Gambia Sudan Cambodia El Salvador Nicaragua Burkina Faso Dijbouti Guinea Bissau Guinea Nigeria Benin Costa Rica Cote Sri Lanka Venezuela Guyana Sierra Leone Ghana Panama Suriname Ethiopia d'Ivoire Central African Republic Somalia French Guiana Togo Brunei Cameroon Liberia Colombia Malaysia OCEAN Equatorial Guinea Uganda INDIAN Sao Tome & Principe Kenya Gabon Rwanda Ecuador OCEAN Burundi Dem. Rep. Papua Congo Tanzania Indonesia Solomon Islands Peru OCEAN Of Congo New Brazil Guinea Timor Leste (East Timor) Angola Zambia Fiji Vanuatu Bolivia Zimbabwe Namibia Mozambique OCEAN Botswana Paraguay Madagascar Australia Chile Swaziland Lesotho South Africa Uruguay Argentina New Zealand Antarctica Mean Age = 63.5 yrs; Females = 35% Diabetes 82%; IFG or IGT 12%

ORIGIN Glycemic control – FPG 8,0 FPG (mmol/l) Glargine 7,5 IQR 5.7 – 7.9 Standard 6,9 6,8 7,0 FPG (mmol/L) 6,6 6,9 6,5 6,0 5,5 5,0 5,3 5,2 5,2 5,2 5,1 5,1 5 5 4,5 IQR 4.4 – 5.8 4,0 0 1 2 3 4 5 6 7 End Follow up (years)

Main outcome Cardiovascular death, myocardial Infarction or stroke Adjusted Hazard Ratio 1.02 (0.94-1.11) Proportion with events P=0.63 by log rank test Insulin glargine Standard care Follow up (years) (Gerstein et al. NEJM 2012;367:319)

Hypoglycemia Definitions ➸ Non-severe hypoglycemia symptoms confirmed by a glucose ≤3.0 mmol/l [≤54 mg/dl ] ➸ Severe hypoglycemia symptomatic hypoglycemia with need for assistance and either a) prompt recovery with oral carbohydrate, intravenous glucose, or glucagon and/or b) documented glucose ≤2.0 mmol/l [≤36 mg/dl]

Outcome measures Definitions ➸ The primary composite outcome cardiovascular death or nonfatal myocardial infarction or stroke ➸ Mortality ➸ Cardiovascular mortality ➸ Arrhythmic death sudden unexpected death, death from documented arrhythmia, unwitnessed death and resuscitated cardiac arrest

Statistical considerations Propensity scores Scores were developed for hypoglycemic episodes including the following independent variables ➸ Demographics age, gender, ethnicity, education, DM, prior CV event, hypertension, depression, current smoking, alcohol >2/wk ➸ Pharmacological treatment metformin, SU, statin, ACE/ARB, beta-blocker, thiazides, antiplatelets ➸ Measurements BMI, WHR, HbA1c, FPG, HDL, LDL, TG, sCr, ACR ≥30 mg/g, MMSE

Hypoglycemic episodes Total number = 3 518 ➸ Any episode of hypoglycemia glargine 2 614 standard 904 ➸ Severe hypoglycemia glargine 359 standard 113

Hypoglycemia during the trial Prevalence by glucose lowering treatment Glargine Standard P (n = 6264) (n = 6273) Episode % /100py % /100py Non severe ≥ 1 episode 42 10 14 3 <0.001 No episode 58 86 <0.001 Severe ≥1 episode 6 1.0 2 0.3 <0.001

Risk for an outcome comparing patients with and without hypoglycemia Unadjusted data Nonsevere hypoglycemia Non-severe hypoglycemia p HR (95% CI) CV death or nonfatal MI or stroke 0.115 1.10 (0.98-1.23) Mortality <0.001 1.21 (1.08-1.35) Cardiovascular death 0.049 1.16 (1.00-1.34) Arrhythmic death 0.091 1.19 (0.97-1.47) Severe hypoglycemia Severe hypoglycemia CV death or nonfatal MI or stroke <0.001 1.77 (1.39-2.25) Total mortality <0.001 2.05 (1.65-2.55) Cardiovascular death <0.001 2.02 (1.52-2.69) Arrhythmic death <0.001 2.14 (1.43-3.18) 0.5 1 1.5 2 2.5 3 3.5

Risk for an outcome comparing patients with and without hypoglycemia Adjusted (propensity score) Nonsevere hypoglycemia Non-severe hypoglycemia p HR (95% CI) CV death or nonfatal MI or stroke 0.938 1.00 (0.88-1.12) Mortality 0.069 1.12 (0.99-1.26) Cardiovascular death 0.701 1.03 (0.88-1.20) Arrhythmic death 0.402 1.10 (0.88-1.36) Severe hypoglycemia Severe hypoglycemia CV death or nonfatal MI or stroke <0.001 1.59 (1.24-2.03) Total mortality <0.001 1.75 (1.39-2.19) Cardiovascular death <0.001 1.71 (1.27-2.30) Arrhythmic death 0.007 1.77 (1.17-2.68) 0.5 1 1.5 2 2.5 3 3.5

Hypoglycemia and outcomes Impact of glucose lowering therapy (adjusted) Outcome Nonsevere Severe Composite Glargine 1.01 (0.88-1.17) 1.38 (1.03-1.86) Standard Care 0.95 (0.76-1.18) 2.39 (1.55-3.70) Standard vs. Glargine 0.93 (0.72-1.20) 1.70 (1.01-2.87) Mortality Glargine 1.09 (0.94-1.26) 1.34 (1.00-1.79) Standard Care 1.18 (0.97-1.45) 3.13 (2.20-4.46) Standard vs. Glargine 1.10 (0.87-1.40) 2.31 (1.47-3.64)

Hypoglycemia and outcomes Impact of glucose lowering therapy (adjusted) Outcome Nonsevere Severe CV Death Glargine 1.08 (0.90-1.31) 1.38 (0.94-2.01) Standard Care 0.95 (0.72-1.25) 2.89 (1.80-4.65) Standard vs. Glargine 0.89 (0.65-1.22) 2.09 (1.15-3.82) Arrhythmic Death Glargine 1.18 (0.91-1.53) 1.24 (0.71-2.17) Standard Care 0.97 (0.66-1.43) 3.66 (1.99-6.76) Standard vs. Glargine 0.86 (0.55-1.35) 2.94 (1.29-6.69)

Severe hypoglycemia and outcomes Proportion of participants with an outcome by treatment Number of severe % hypoglycaemic episodes 30 Glargine ≥ 1 Standard ≥ 1 Glargine none 20 Standard none 10 0 Primary Total Cardiovascular Arrhythmic outcome mortality mortality mortality

Conclusion ➸ There is a relationship between severe hypoglycaemia & CV outcomes in people with dysglycaemia at high CV risk ➸ This relationship was 2-3 times lower in the insulin-glargine compared to the standard group ➸ In light of more frequent severe hypoglycemia in the insulin group, hypoglycemia caused by insulin-glargine mediated glucose lowering is unlikely to be the cause of CV outcomes ➸ The relationship between severe hypoglycaemia & CV outcomes is likely due to confounding by unmeasured riskfactors for CV outcomes