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ORIGIN: Association between Hypoglycemia and Risk of Cardiovascular Events with Titrated Insulin Glargine or Standard Care


Presenter abstract
Discussant report
All the Scientific resources on ESC Congress 365


By Linda Mellbin
Other authors: Professor Lars Rydén Sweden,  Professor Matthew Riddle US, Professor Jeff Probstfield US, Professor Julio Rosenstock US, Professor Salim Yusuf Canada and Professor Hertzel Gerstein Canada for the ORIGIN trialists
Hypoglycemia is an adverse effect of glucose lowering therapy suggested to be linked to cardiovascular (CV) morbidity and mortality. Whether this relationship is causal or due to factors related to the propensity for hypoglycemia is unknown.  The ORIGIN trial of insulin-mediated normoglycemia vs. standard care offers an opportunity to assess such relationships.
Material and methods:
Patients with impaired fasting glucose, impaired glucose tolerance or early type 2 diabetes and at increased CV risk due to established CV-disease or the presence of CV risk factors were randomised to basal insulin glargine titrated to a fasting plasma glucose of ≤95 mg/dl (5.3 mmol/l; n= 6264) or standard glycemic care (n=6273). Confirmed nonsevere hypoglycemia was defined as symptoms/signs associated with a concurrent glucose level ≤54 mg/dl (3.0 mmol/l). Severe hypoglycemia required external assistance plus either prompt recovery with therapy or a concurrent glucose ≤36 mg/dl (2.0 mmol/l). Outcomes assessed were: 1) a composite of CV death or nonfatal myocardial infarction or stroke; 2) all-cause mortality; 3) CV mortality and 4) arrhythmic death.  Hazards were estimated before and after adjustment for a hypoglycaemia propensity score (among variables were age, gender, ethnicity, education level, prior CV event, hypertension, depression, current smoking, alcohol intake, albumin /creatinine ratio, pharmacological treatment, BMI, HbA1c, fasting glucose, lipid levels, creatinine and prior diabetes).
During follow-up (median 6.2 years; IQR 5.8-6.7) 3518 patients had at least one episode of confirmed nonsevere hypoglycemia (2614/6264 [41,7%] in the glargine and 904/6273 [14.4%] in the standard care group) while 472 patients had at least one episode of severe hypoglycemia (359/6264 [5.7%] in the glargine and 113/6273 [1.8%] in the standard care group). Combining both arms confirmed nonsevere hypoglycemia was, following adjustment, not significantly associated with any of the outcomes. Conversely, severe hypoglycemia increased the risk for the primary outcome (HR 1.59; 95% CI 1.24-2.03, p<0.001), mortality (HR 1.75; 95%CI 1.39-2.19, p<0.001), CV death (HR 1.71; 95%CI 1.27-2.30, p<0.001) and arrhythmic death (HR 1.77; 95%CI 1.17-2.68, p=0.007). The severe hypoglycemia hazard for these outcomes was 2-3 times higher in standard care than among glargine participants (p for interaction <0.05). Similar findings were noted for nocturnal hypoglycemia with respect to the primary outcome and mortality.
Severe, but not non-severe, hypoglycemia increases the risk for CV outcomes in people at high CV risk and dysglycemia. This risk did not relate to insulin glargine-mediated normoglycemia, but was apparent in the presence of standard glucose lowering therapy.  Nocturnal hypoglycemia did not predict arrhythmic or CV death.

Discussant Report

Peter J Grant
Diabetes is characterised by the presence of hyperglycaemia and the development of micro- and macro-vascular complications. Prospective studies have evaluated the effects of intensive glycaemic control on cardiovascular (CV) outcomes with differing results.
The ACCORD study was stopped prematurely because of increased mortality in the intensively treated group, whilst VADT indicated no effect on CV outcomes (1,2,).
It has been suggested that strict control is associated with worse CV outcomes in diabetes of long duration with poorer control and underlying CV disease. However, analysis of ACCORD did not support the view that the differences in mortality between the groups were due to severe hypoglycaemia (3).
The results of the ORIGIN trial (4) provide important evidence to indicate that severe hypoglycaemia and nocturnal severe hypoglycaemia independently predict cardiovascular outcomes. Although more hypoglycaemic episodes occurred with intensive glargine therapy, it appeared that worse outcomes occurred with hypoglycaemia associated with standard therapy (mostly sulphonylurea based). The results are important because they indicate a role for hypoglycaemia in adverse CV outcomes and support the need for individualizing intensified glycaemic control. Important questions persist regarding the possible additive effects of hypoglycaemia on a background of sulphonylurea therapy and the potential for impaired renal function to affect this.
Additionally, there remains a suspicion that a single severe episode of hypoglycaemia may cause adverse CV outcomes and sudden death and this may affect the interpretation of the results.
The data presented from ORIGIN confirm the clinical view that hypoglycaemia is an important indicator of poor CV outcomes and highlight the need to consider these risks when intensifying glycaemic control.

1 - The Action to Control Cardiovascular Risk in Diabetes Study Group: Effects of intensive glucose lowering in type 2 diabetes. New Engl J Med 2008; 358: 2545-59.
2 - Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward RWarren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD. Clucose control and vascular complications in veterans with type 2 diabetes. New Engl J Med 2009;360: 129-39
3 - Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, Dudl RJ, Ismael-Beigi F, Kimel AR, Hoogwerf B, Horowitz KR, Savage PJ, Seaquist ER, Simmons DL, Sivitz WI, Speril-Hillen JM, Sweeney ME. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. Br Med J, 2010; 340: b4909 doi:10.1136/BMJ.b4909
4 - ORIGIN Trial Investigators: Does hypoglycaemia increase the risk of cardiovascular events ? A report from the ORIGIN trial.  Eur Heart J  2013 , in press.




ORIGIN: Association between Hypoglycemia and Risk of Cardiovascular Events with Titrated Insulin Glargine or Standard Care

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.