Counterpoint from ORIGIN Hypoglycemia Subanalysis

Conclusions from Medical Media regarding this subanalysis:

• When patients with dysglycemia had severe hypoglycemia while on treatment with basal insulin glargine, the episodes did not trigger as many adverse cardiovascular outcomes as did severe hypoglycemia during standard care with oral glucose-lowering drugs but no insulin.
• "Hypoglycemia caused by insulin glargine–mediated glucose lowering is unlikely to cause cardiovascular outcomes," Dr. Linda G. Mellbin said at the European Society of Cardiology Congress 2013. 
• "What was reassuring was that while insulin glargine caused more hypoglycemic events" compared with standard treatment in these patients, "the absolute number of fatal events was still lower with insulin, showing insulin is a very safe treatment," said Dr. Lars Rydén, professor of cardiology at the Karolinska Institute and a coinvestigator with Dr. Mellbin.

Counterpoints:

This subanalysis does very little to answer the following paradox.  Despite having more severe hypoglycemias(76% vs 24%)-consistent and robust relationship to all primary and secondary endpoints-in the glargine treated arm, there is no excess mortality in the treatment arm.  They are offering the commentary that glargine is a safe insulin regimen and that people should not be reluctant to start insulin early.

1. This study highlights the clear relationship between severe hypoglycemias with death and cardiovascular mortality.  There are more severe hypoglycemias with lantus than standard oral therapy. [This highlights the clear added risk when you introduce lantus for therapy.]  There is a 3 fold risk of inducing symptoms so severe that you need assistance.   
2. People had been supporting glargine through claiming that it is a smooth, peakless insulin.  In this study, it shows that glargine is not better than stardard of care sulfonureas.  It does not provide any cardiovascular advantage nor is it safer than sulfonureas.  
3. We know from the UKPDS that early aggressive control can provide cardiovascular benefit.  We know from previous subanalysis of the ORIGIN trial, that patients on glargine had better durable glycemic control.  Another substudy from Diabetes Care show that the IMT carotids were a bit better in the glargine group.  The question that needs to be asked is:  "Is hypoglycemia is so bad with the lantus group that it is negating the positive benefit of glycemic control."
4. How can you draw conclusions about nocturnal hypoglycemia.  The absolute numbers between the lantus and control is 100 vs 18.  18!!
5. If you treat your stable diabetics with lantus and titrate them to 95, you will get a high report of nonsevere and severe hypoglycemia, which obliterates any metabolic benefit you achieve using this regimen.  You will also expect weight gain of 1.6kg of weight gain and more reports of new angina pectoris. 
   
   
   
   
   
   
   
   
   
   
   
   
   

Points: Origin Hypoglycemia Subanalysis

Points

1. 12,537 patients with known CV disease recruited into prospective study from 573 centers from around the world. Randomized to standard care vs glargine. With glargine titrated to fasting glucose <=95 by self-measurement. Study powered to detect 18% and 16% relative risk reduction in primary outcome and secondary outcome. All patients self-monitored and logged glucose levels. Median follow up 6.2 yrs. 99% outcome status known. Primary outcome: composite non-fatal MI, non-fatal CVA, or death from CV cause. Secondary outcome: any of primary events, a revascularization procedure, or hospitalization for heart failure. Points in favor of the Origin study are the power of study, prospective, randomized and using patients who had known CV disease and therefore at higher risk for an event. The subanalysis included all patients and data from the original study.

2. From table 2: Significant elevated hazard score in severe hypoglycemia for each endpoint shown: CV death or non-fatal MI or stroke 1.77, Total mortality 2.05, CV death 2.02, Arrhythmic death 2.14. Unadjusted hazard for severe nocturnal hypoglycemia was also significantly elevated in all 4 categories.  The unadjusted hazard for non-severe mortality was also significantly elevated at 1.21.

3. From table 3: Incidence of hypoglycemia both non-severe and severe is higher in insulin glargine group versus standard care.

4. Although the crude incidence of mortality, cv death, arrhythmic death, and CV death-non-fatal MI-CVA in both severe and non-severe hypoglycemia is higher in the glargine group than the standard group, overall there was no difference in mortality or cv events between the two groups if one includes both hypoglycemia and absence of hypoglycemia.

5. The findings of an association between severe hypoglycemia and CV outcomes is consistent with prior studies showing a similar association.

Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial

Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial

Abstract

Aims Hypoglycaemia caused by glucose-lowering therapy has been linked to cardiovascular (CV) events. The ORIGIN trial provides an opportunity to further assess this relationship.

Methods and results A total of 12 537 participants with dysglycaemia and high CV-risk were randomized to basal insulin glargine titrated to a fasting glucose of ≤5.3 mmol/L (95 mg/dL) or standard glycaemic care. Non-severe hypoglycaemia was defined as symptoms confirmed by glucose ≤54 mg/dL and severe hypoglycaemia as a requirement for assistance or glucose ≤36 mg/dL. Outcomes were: (i) the composite of CV death, non-fatal myocardial infarction or stroke; (ii) mortality; (iii) CV mortality; and (iv) arrhythmic death. Hazards were estimated before and after adjustment for a hypoglycaemia propensity score. During a median of 6.2 years (IQR: 5.8–6.7), non-severe hypoglycaemic episodes occurred in 41.7 and 14.4% glargine and standard group participants, respectively, while severe episodes occurred in 5.7 and 1.8%, respectively. Non-severe hypoglycaemia was not associated with any outcome following adjustment. Conversely, severe hypoglycaemia was associated with a greater risk for the primary outcome (HR: 1.58; 95% CI: 1.24–2.02, P < 0.001), mortality (HR: 1.74; 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: 1.17–2.67, P = 0.007). Similar findings were noted for severe nocturnal hypoglycaemia for the primary outcome and mortality. The severe hypoglycaemia hazard for all four outcomes was higher with standard care than with insulin glargine.

Conclusion Severe hypoglycaemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycaemia. Although allocation to insulin glargine vs. standard care was associated with an increased risk of severe and non-severe hypoglycaemia, the relative risk of CV outcomes with hypoglycaemia was lower with insulin glargine-based glucose-lowering therapy than with the standard glycaemic control. 

Point Counterpoint

Point Counterpoint

Idea:

Find a study which is relevant to clinical practice and has a new/unexpected outcome.

One expert takes the "point" position the other takes the "counterpoint" position.

Each expert independently dissects the paper and comes up with 5 points. One will have five points in favor of supporting why we should believe the outcome. The other will have 5 points showing why the outcome is probably not valid.

Essentially what we're trying to find out is should our practice change in some way based on the findings?

We will do 3 papers per month and alternate the point counterpoint positions.

The first will be Dr. Lee and Dr. Laidlaw with the paper "Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial".

The program will work as follows:

1. 3 papers chosen per month

2. The person choosing the paper for that week will be "point". (The person choosing the next week's paper will be counterpoint).

3. Upload the paper to Zotero and notify via the blog (title of paper and abstract ideally).

4. On Thu each expert will separately post their 5 points and counterpoints.

5. Then anyone can chime in with comments and potentially come to some consensus thought on the matter.

Let the games begin!