Heavy! Sulfonylureas can increase serum free fatty acids in diabetics!

Background: The global epidemic of type 2 diabetes mellitus (T2DM) is an important public health issue
.
It is predicted that the number of diabetics will increase to 642 million
by 2040.
In 2015, about 5 million people aged 20-79 died from diabetes, accounting for 12.
8%
of all-cause mortality worldwide.
Sulfonylurea (SU) drugs are widely used in T2DM therapy
.
Its mechanism of action is based on enhancing insulin release
from pancreatic β cells by binding to ATP-sensitive K+ channels.
There is also some evidence that hepatic glucose production
can be limited by sensitizing β cells to glucose.
However, SU drugs have limitations, such as not being effective
for type 1 diabetes or after pancreatectomy.
Several studies have shown that treatment with SU may increase the risk of cardiovascular disease-related death and stroke
in patients with T2DM.
SU drugs include certain generations of drugs
.
First-generation drugs include acetylhexanamide, glycine cyclamide, carbamide, etc
.
The second generation of drugs includes gliclazide, glibenclamide, glipizide, glibenclamide, etc
.
Third-generation drugs include glimepiride, which is occasionally considered a second-generation drug
.
Circulating free fatty acids (FFAs), also known as non-esterified fatty acids, are released from phospholipids and adipocyte triglycerides after hydrolysis by phospholipase and lipolysis
, respectively.
Free fatty acids are a key factor
in the link between obesity and T2DM.
Free fatty acids play a key role in a
variety of metabolic processes.
They can work by promoting the production of very low-density lipoproteins and the release of triglycerides, which can lead to the development of
atherolipidemia.
In addition, higher VLDL levels may increase serum FFA flow to the liver, leading to inflammation and hepatic insulin resistance
.
In addition, they inhibit the production and release of insulin, which is the cornerstone
of the etiology of T2DM.
In recent years, a growing body of research has confirmed the link between FFA and heart disease, and serum FFA has been accompanied by an increased
risk of coronary heart disease.
High free fatty acid levels reflect the severity
of myocardial ischemia and necrosis.

Fatty acid metabolism is considered an effective factor
in SU-mediated T2DM treatment.
However, the exact effect of SU treatment on serum FFA concentrations remains unclear
due to the presence of different SUs and their different combinations with other antidiabetic drugs such as metformin, rosiglitazone, or pioglitazone.

Objective: Current meta-analysis to investigate a possible link
between SU therapy and serum FFA concentration.
This analysis contributes to a better understanding of the impact
of SU-mediated therapy on FFA in T2DM patients.

Methods: Systematic search
of relevant literature from January 1, 1991 to July 30, 2021 was carried out using computer searches of PubMed, EMbase, Cochrane Library, Reference Citation Analysis ( and Web of Science databases.
According to the heterogeneity test, the relationship between
SU treatment and FFA concentration was investigated using a fixed-effect model and a random-effects model.
Two investigators independently extracted
the data.
Mean difference (MD) and corresponding 95% confidence intervals (CI) were used to measure effect size
.
R3.
5.
1 software was used for statistical analysis
.

Results: Thirteen studies with 2273 people
were included.
The results showed a slight increase in FFA concentration after SU treatment (MD=0.
08, 95% CI: 0.
03-0).

P<0.
01).

In addition, we found that SU in combination with other antidiabetic drugs also increased serum FFA concentrations (MD = 0.
14, 95% CI: 0.
01-0).

P<0.
01).

For the type of SU, there was no significant difference
in FFA concentrations between glimepiride and glibenclamide.
FFA concentration was higher at ≥12wk (MD=0.
0 9, 95%CI:0.
0 4~0.
13), but there was no significant change at <12 wk (MD=0.
0 1,95%CI:-0.
0 7~0.
0 9).

Table 1 summarizes population and subgroup analyses

Figure 1 Estimates of study quality included in the meta-analysis
.

Figure 2 Forest diagram
.
A: To assess the overall effect of sulfonylureas on the concentration of free fatty acids; B: Subclass analysis was performed according to different sulfonylureas to evaluate the effect of sulfonylureas on the concentration of free fatty acids; and forest communities to assess the effect of
combination drugs on free fatty acid concentrations.
CI: confidence interval; MD: Mean difference
.

Sensitivity analysis in Figure 3 of the included studies reported the effect of
sulfonylurea therapy on free fatty acid concentrations.
CI: confidence interval; MD: Average difference

Conclusion: SU treatment can increase the serum FFA concentration in
diabetic patients.
The underlying internal mechanisms need further research
.

Yu M, Feng XY, Yao S,et al.
Certain sulfonylurea drugs increase serum free fatty acid in diabetic patients: A systematic review and meta-analysis.
World J Clin Cases 2022 Sep 16; 10(26)