Joanna Khatib, MD: Insulin Use Raises Risk of Severe Cardiovascular Events

A meta-analysis of several well-known cardiovascular outcome trials has found that insulin, when combined with other treatments for type 2 diabetes, was associated with an increased risk of severe cardiovascular outcomes.

Data from the analysis examined insulin combined with a variety of different study drugs including SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and was presented during the American Diabetes Association 2019 Scientific Sessions in San Francisco, CA.

Investigators examined data from 7 studies examining efficacy of cardiovascular drugs, including EXSCEL, SUSTAIN6, SAVORTIMI, EMPAREG, LEADER, EXAMINE, and DECLARE. When comparing participants from those studies who received concomitant insulin in addition to the study drug, investigators found the group who received insulin had a risk ratio of 1.43 (95% CI; 1.32, 1.55).

Investigators noted they were unable to determine the mechanism behind the increased risk. Lead author Joanna Khatib, MD, of Tulane University, sat down with MD Magazine® at ADA 2019 to dive further into the details of the study and offer perspective on what the findings mean clinically.

MD Mag: What did you find when examining the impact of insulin treatment on outcomes in cardiovascular outcome trials?

Khatib: So, there has been multiple cardiovascular outcome trials. Since 2013, there's been around 11 and a few more coming out during this meeting and they've mostly have shown really exciting data — showing that those new diabetes type 2 drugs, they provide cardiovascular benefit but we didn't really know how this relationship is affected when patients are treated with these new diabetes drugs and with insulin, which is a combination that we see very frequently in clinic.

So, that was the aim of our study — to look at the cardiovascular outcomes in patients who use these drugs in those cardiovascular trials and they were on insulin. Lucky for us, there was a good amount of patients in those trials where they were at baseline they were on insulin. So, we were able to look at those numbers.

Now, this was a meta-analysis so the trials are known, like I said there are 11. So, we look at them up on PubMed, Google Scholar but they're very well-known trials. Six of them actually had shown cardiovascular benefit they were mostly the SGLT2 inhibitors then the GLP-1 agonist drugs. So, we looked at all 11.

Now, not all 11 had the data that we needed to do our analysis so ended up taking out 4. Two were DPP-4, one SGLT2, and one GLP-1. So, that left us with 7 trials and we also did a sensitivity analysis for that one we took out the DPP-4 trials, which there was one left because we had already taken out 2, and we used the static program and then when we looked at the results of those.

So, we had multiple analyses. We looked at first just using the drugs versus placebo without any insulin. So, patients who had not been in any insulin that I showed us that the group that used the drugs, they had less cardiovascular outcomes which is kind of what we already knew going into this. Then, we looked at patients who were on the drug with insulin versus just drug. Now, the group of patients who are using drug with insulin did have more cardiovascular events.

So, that was the main thing that we were looking at. What we did see from our results is that patients who were using those drugs, even though they had more cardiovascular outcomes when they were using insulin, there was still benefit.

So, giving those drugs with insulin still provided cardiovascular benefit. So, implication wise, what we're saying is that maybe those drugs should be started a bit earlier than when we usually do use them because we do know they provide cardiovascular benefit and also even when they're used with insulin. If patient is needing insulin and the new drugs, they usually have worse control of their diabetes, so it kind of puts them at higher risk for cardiovascular or disease. That was our thought maybe behind our results but it's still a combination even when the drugs are used with insulin there is still benefit.