Abstract
Background/Aim: Tirzepatide has been shown to improve glycemic control, improve insulin sensitivity, increase adipocyte lipoprotein lipase (LPL) activity and decrease apolipoprotein C3 levels. We previously reported that a patient who had type 2 diabetes (T2DM), persistent chylomicronemia and heterozygosity for LPL deficiency had resolution of his chronic chylomicronemia and near normalization of serum triglycerides in response to tirzepatide therapy. Therefore, the aim of this study was to perform a case series using tirzepatide treatment in a group of patients with T2DM or metabolic syndrome, chylomicronemia and multiple genetic variants affecting LPL to verify similar results in a larger group of patients with Metabolic Chylomicronemia Syndrome.
Method: 61 patients with chylomicronemia who were referred to our lipid clinic were screened. Fiftyeight out of 61 patients had identifiable genetic variations in one of the 7 genes associated with chylomicronemia and 57/61 had T2DM. Twenty of these chylomicronemic patients (19 with T2DM and 1 with prediabetes) were able to be treated with tirzepatide and 17/20 had a genetic variant associated with a decrease in LPL: 5 having heterozygosity for LPL deficiency, 10 having variants of apolipoprotein A5, 1 with a variant of the LMF-1 gene and one patient with prediabetes who was a compound heterozygote having LPL heterozygosity plus an apolipoprotein A5 variant. Three patients had no identifiable genetic variation associated with chylomicronemia and all were treated with tirzepatide given to maximum tolerated dose.
Results: In all patients, there was a resolution of their chylomicronemia. In patients who had a history of chylomicronemia induced pancreatitis or abdominal pain, there were no episodes of pancreatitis or abdominal pain while on tirzepatide. Pre-/post lipid profile averages as follows: total triglyceride decreased from 9.25 to 3.19 mmol/L (-65%, P value < 0.006), total cholesterol decreased from 5.12 to 3.72 mmol/L (-27%, P < 0.0013), LDL cholesterol decreased from 2.14 to 1.72 mmol/L (-20%, P<0.40), non-HDL cholesterol decreased from 4.09 to 2.97 mmol/L (-27%, P <0.002). HDL cholesterol increased from 0.74 to 0.84 mmol/L (+13%, P <0.023). In addition, the average A1c decreased from 7.6% to 6.0% (-15%, P <0.0001) and body weight decreased from 98.0 to 91.8 kg (-6.5%, P <0.0001).
Conclusion: In this case series of patients with a history of chylomicronemia, T2DM/ metabolic syndrome and multiple gene variants affecting LPL, tirzepatide caused a resolution of chylomicronemia with a significant decrease in total triglyceride, total cholesterol and non-HDL cholesterol levels as well as an increase of HDL cholesterol. Tirzepatide resulted in a significant improvement of A1C as well as a decrease in body weight. The mechanism(s) underlying these effects is(are) not completely understood but warrants further investigation. The results of this case series suggest that tirzepatide may be an agent useful for the treatment of patients with T2DM and chylomicronemia who have genetic variants affecting LPL.