SLIDE 1 Linda G Mellbin
Lars Rydén, Matthew Riddle, Jeffrey Probstfield, Julio Rosenstock, Rafael Díaz, Salim Yusuf, Hertzel Gerstein
The ORIGIN Trial Investigators
Does Hypoglycemia Increase the Risk
A report from
SLIDE 2 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
Linda G Mellbin
Declaration of interest
SLIDE 3 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…”
SLIDE 4 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
SLIDE 5
Glargine Standard Care Omega 3 FA Glargine + Omega 3
Omega 3
Placebo
Glargine + 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
Design
SLIDE 6 ORIGIN
Patient population
Spain Norway Portugal Turkey Ukraine Greece Ireland Greenland Iceland United States Canada Mexico The Bahamas Cuba Panama El Salvador Nicaragua Costa Rica Jamaica Haiti
Argentina Bolivia Colombia Venezuela Peru Brazil Guyana Chile Ecuador Kenya Ethiopia Eritrea Sudan Egypt Niger Mauritania Mali Nigeria Somalia Namibia Libya Chad Tanzania
Of Congo Angola Algeria Madagascar Zambia Gabon Tunisia Morocco Swaziland Lesotho Liberia Sierra Leone Guinea Gambia Congo Senegal Guinea Bissau Israel Lebanon Georgia Kyrgyzstan Yemen Iraq Iran Oman Saudi Arabia Russia India China Kazakhstan Nepal Vietnam Sri Lanka Papua New Guinea Brunei Philippines Malaysia Indonesia Japan Mongolia
Australia New Zealand United Kingdom Fiji Zimbabwe Vanuatu Uzbekistan Uruguay U.A.E. Uganda Turkmenistan Togo Thailand Tajikistan Syria Sweden Suriname South Africa Antarctica Solomon Islands Sao Tome & Principe Rwanda Qatar Poland Paraguay Pakistan Neth. Mozambique Laos Kuwait Honduras Guatemala Ghana Germany French Guiana France Finland Equatorial Guinea Dijbouti Denmark Cyprus Cote d'Ivoire Central African Republic Cape Verde Cameroon Cambodia Burundi Burkina Faso Bulgaria Botswana Bhutan Benin Belize Bangla- desh Azerb. Afghanistan Western Sahara (Occupied by Morocco) Timor Leste (East Timor) Myanmar (Burma)
ATLANTIC PACIFIC PACIFIC INDIAN OCEAN OCEAN OCEAN OCEAN
Bel. Belarus Hungary Romania Switz. Italy Jordan
n=12537 from 573 sites in 40 countries Mean Age = 63.5 yrs; Females = 35% Diabetes 82%; IFG or IGT 12%
SLIDE 7 ORIGIN
Glycemic control – FPG
6,9 5,2 5 5 5,1 5,1 5,2 5,2 5,3 6,9 6,6 6,8
4,0 4,5 5,0 5,5 6,0 6,5 7,0 7,5 8,0 1 2 3 4 5 6 7 End
FPG (mmol/L) Follow up (years)
Glargine Standard IQR 4.4 – 5.8 IQR 5.7 – 7.9
FPG (mmol/l)
SLIDE 8 Main outcome
Cardiovascular death, myocardial Infarction or stroke
(Gerstein et al. NEJM 2012;367:319)
Adjusted Hazard Ratio 1.02 (0.94-1.11) P=0.63 by log rank test
Standard care Insulin glargine
Proportion with events Follow up (years)
SLIDE 9
➸ 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]
Hypoglycemia
Definitions
SLIDE 10
➸ 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
Outcome measures
Definitions
SLIDE 11
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
Statistical considerations
Propensity scores
SLIDE 12
➸ Any episode of hypoglycemia glargine 2 614 standard 904
Hypoglycemic episodes
Total number = 3 518 ➸ Severe hypoglycemia glargine 359 standard 113
SLIDE 13
Glargine (n = 6264) Standard (n = 6273) P
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
Hypoglycemia during the trial
Prevalence by glucose lowering treatment
SLIDE 14 Non-severe hypoglycemia CV death or nonfatal MI or stroke Mortality Cardiovascular death Arrhythmic death Severe hypoglycemia CV death or nonfatal MI or stroke Total mortality Cardiovascular death Arrhythmic death p 0.115 <0.001 0.049 0.091 <0.001 <0.001 <0.001 <0.001
HR (95% CI)
1.10 (0.98-1.23) 1.21 (1.08-1.35) 1.16 (1.00-1.34) 1.19 (0.97-1.47) 1.77 (1.39-2.25) 2.05 (1.65-2.55) 2.02 (1.52-2.69) 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
Nonsevere hypoglycemia Severe hypoglycemia
Unadjusted data
SLIDE 15 0.5 1 1.5 2 2.5 3 3.5
Non-severe hypoglycemia CV death or nonfatal MI or stroke Mortality Cardiovascular death Arrhythmic death Severe hypoglycemia CV death or nonfatal MI or stroke Total mortality Cardiovascular death Arrhythmic death p 0.938 0.069 0.701 0.402 <0.001 <0.001 <0.001 0.007
HR (95% CI)
1.00 (0.88-1.12) 1.12 (0.99-1.26) 1.03 (0.88-1.20) 1.10 (0.88-1.36) 1.59 (1.24-2.03) 1.75 (1.39-2.19) 1.71 (1.27-2.30) 1.77 (1.17-2.68)
Nonsevere hypoglycemia Severe hypoglycemia
Risk for an outcome comparing patients with and without hypoglycemia
Adjusted (propensity score)
SLIDE 16 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)
SLIDE 17 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)
Hypoglycemia and outcomes
Impact of glucose lowering therapy (adjusted)
SLIDE 18 30 20 10
Primary
Arrhythmic mortality Total mortality Cardiovascular mortality Glargine none Standard ≥ 1 Glargine ≥ 1 Standard none
Severe hypoglycemia and outcomes
Proportion of participants with an outcome by treatment %
Number of severe hypoglycaemic episodes
SLIDE 19 Conclusion
➸ There is a relationship between severe hypoglycaemia & CV
- utcomes 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
- utcomes is likely due to confounding by unmeasured
riskfactors for CV outcomes
