Cardiovascular Risk While Using Insulin

The use of insulin to treat type 2 diabetes patients is growing, but does its risk for hypoglycemia impact cardiovascular health?

While insulin is the treatment for type 1 diabetes, this medication is not the first choice for patients with type 2 diabetes. Despite this, the percentage of type 2 patients treated with insulin increases ~7.5% per year. The use of insulin in patients with type 2 diabetes is encouraged by guidelines when patients cannot reach a glycemic target. As the prevalence of insulin use increases over the years, it is crucial to determine the impact of this medication on patients’ outcomes. Type 2 diabetes was linked in the past with cardiovascular events. Literature has shown that cardiovascular events can lead to death in patients with type 2 diabetes.  

Insulin has a high risk for the development of hypoglycemia, and severe hypoglycemia is one of the strongest predictors of macrovascular events. Some macrovascular events include cardiovascular and cerebrovascular diseases. Severe hypoglycemia, if not treated correctly, can lead to death. Previous studies studied the relationship between hypoglycemia events and cardiovascular conditions like stroke and myocardial infarction. Researchers believed that hypoglycemia events alone do not lead to cardiovascular diseases, but can trigger these events in patients with a high risk of cardiovascular complications.  Now, researchers are looking for the link between insulin and cardiovascular morbidity and mortality risk. 

Researchers looked at all-cause mortality in patients with type 2 diabetes as the primary outcome in a recent systemic review using meta-analysis and sequential trial analysis. Secondary effects include cardiovascular mortality, myocardial infarction, stroke, or severe hypoglycemia in the use of basal insulin to treat patients with type 2 diabetes. The study used 26 studies with a total of 24,382 participants, age range from 45 to 66 years. Researchers performed pair-wise comparisons of insulin versus other agents, and comparisons between agents other than insulin. They used relative risk (R.R.) and a power of 80% to analyze the results.  

The study used 21 studies to analyze data of all-cause mortality in 23,096 patients and 2,386 events. Also, researchers determined the cardiovascular mortality from 15 studies with 17,896 patients and 1,166 events. Moreover, 1,010 of 21,243 participants developed myocardial infarction from data published in 15 reviews. On the other hand, data from 11 studies showed that 794 of 20,014 participants developed a stroke.  

In the main comparison, there was no increase in the risk of the primary outcome of all-cause mortality with an R.R. of 0.99 (95% CI: 0.92-1.06). Researchers evaluated the effect in the study duration, insulin dose, HgA1C, and weight and showed no association between these factors and all-cause mortality. Insulin was not associated with increased risk of cardiovascular mortality R.R.: 1.01 (95% CI: 0.91-1.13). Identical results were reported for myocardial infarction and stroke with an R.R.: 1.02 (95% CI: 0.92-1.15) and RR:0.86 (95% CI: 0.66-1.13), respectively. The only result that shows an association with insulin as a side effect was the increased risk of severe hypoglycemia while using basal insulin with an R.R.: 2.92 (95% CI: 2.41-3.54).  

The systematic review had a large sample size which is a primary advantage for the study. On the other hand, most of the clinical studies used did not assess cardiovascular events, and getting this data from those trials was challenging, presenting a limitation for them. Most of the data reported on this review are based on two clinical trials, even though they used 26 studies.  

Overall, the systematic review results reflect that the use of basal insulin is not associated with all-cause mortality or cardiovascular events. The results do show that insulin can lead to severe hypoglycemic events compared to other anti-diabetic medications. Given the condition and its complications, it is hard to perform a prospective study to analyze cardiovascular complications in patients with type 2 diabetes who use insulin. Further studies are needed to determine if hypoglycemic events due to insulin use affect these results.  

Practice Pearls:  

• The prevalence of insulin use in patients with type 2 diabetes increases ~7.5% per year. 
• The use of insulin in patients with type 2 diabetes does not increase cardiovascular events nor mortality risks.  
• Insulin use was associated with an increased risk of severe hypoglycemic events in type 1 and type 2 diabetes.  

Varvaki, Dimitris Et Al. “All-Case Mortality And Cardiovascular Safety Of Basal Insulin Treatment In Patients With Type 2 Diabetes Mellitus: A Systematic Review With Meta-Analysis And Trial Sequential Analysis“ Diabetes Res Clin Pract. February 4, 2021.  

Lee, Alexandra et al. “The Association of Severe Hypoglycemia with Incident Cardiovascular Events and Mortality in Adults with Type 2 Diabetes“ Diabetes Care January 2018.  

Price, Hillary et al. “Comparative Cardiovascular Morbidity and Mortality in Patients Taking Different Insulin Regimens for Type 2 Diabetes: A Systematic Review“ BMJ Open 5(3). February 2015.  

Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy