XR vs. IR Form of Metformin − It’s Not Just About Gastrointestinal Tolerability
It is well known that the XR form of metformin shows better gastrointestinal tolerability. However, research suggests that the two forms of metformin − XR and IR − differ in other aspects as well. In what ways? We will attempt to summarize this in the following text.
XR vs. IR Metformin
Extended-release metformin (XR) is typically prescribed to improve the gastrointestinal tolerability of this medication. However, differences between the XR form and immediate-release metformin (IR) have also been observed in their impact on laboratory and clinical outcomes.
What did the study comparing the two forms show?
From 2014 to 2016, a randomized clinical trial was conducted in Italy comparing the results of 253 individuals with type 2 diabetes inadequately controlled by diet (HbA1c > 7.0 to < 8.5%). Study participants were randomized to treatment with metformin XR or IR for 6 months. In both cases, the maximum tolerated doses were administered, averaging 2000 ± 1000 mg for the IR form, while the doses for the XR form were on average half as much. The study evaluated the following parameters:
- Pre- and postprandial glucose levels
- Glycated hemoglobin
- Fasting insulin and insulin resistance according to the HOMA-IR model
- Cholesterol levels
- Levels of certain adipokines (visfatin, vaspin)
- Values of inflammatory markers − C-reactive protein measured by high-sensitivity method (hsCRP) and tumor necrosis factor alpha (TNF-α)
- Body weight, BMI, and waist circumference
Glycometabolic Control
Both IR metformin and XR metformin showed significant improvement in glycometabolic control in the monitored parameters after 3 months. However, users of the XR form had a greater effect on reducing glycated hemoglobin after 6 months compared to the IR form (XR: 6.8 ± 0.3; IR: 7.3 ± 0.4%; p < 0.05). Similarly, lower values of fasting and postprandial glucose, fasting insulin, and HOMA-IR were also observed with the XR form.
Body Weight
Both formulations showed similar effects on reducing body weight, BMI, and waist circumference. Participants lost approximately 3 kg over 6 months.
Lipid Profile
The XR metformin showed a greater effect on reducing total and LDL cholesterol compared to the IR form. Neither formulation affected HDL cholesterol levels. A reduction in triglyceride levels was observed only with the XR form, this effect was not seen with the IR form.
Adipokines
In the group taking XR metformin, a reduction in vaspin and an increase in visfatin were observed. This effect was not seen with the IR form of metformin.
Vaspin
Vaspin acts as an insulin sensitizer. Elevated levels of this adipokine are associated with obesity and insulin resistance. Most studies in humans have shown a positive correlation between vaspin and the parameters of metabolic syndrome. Vaspin likely plays a role in the development of atherosclerosis in obese individuals and could be used as a predictor of coronary and cerebrovascular disease.
Visfatin
Visfatin is produced and expressed not only by adipose tissue but also by leukocytes, hepatocytes, myocytes, and cardiac tissue. The autocrine effects of visfatin likely play an important role in regulating insulin sensitivity not only in the liver.
Inflammatory Markers
Hyperglycemia induces the development of endothelial inflammation. Elevated CRP values can also be related to the process of atherosclerosis and cardiovascular risk. In users of XR metformin, a reduction in inflammatory markers TNF-α and hsCRP was observed compared to baseline.
What is the explanation for the different effects of XR and IR forms?
The reason for the differences in the effects of various formulations of metformin could be the more stable glycemia levels in the case of the XR form, as well as better compliance in the case of the better-tolerated XR form. Interestingly, for example, the parameters of glycometabolic control were comparably affected by both forms of metformin after 3 months of treatment, while after 6 months, the results already differed in favor of the XR form. The explanation might be long-term compliance. The cited study further investigated treatment satisfaction through a questionnaire, which also favored the XR form.
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Sources:
1. Derosa G., D'Angelo A., Romano D., Maffioli P. Effects of metformin extended release compared to immediate release formula on glycemic control and glycemic variability in patients with type 2 diabetes. Drug Des Devel Ther 2017; 11: 1481−1488, doi: 10.2147/DDDT.S131670.
2. Dimova R., Tankova T. The role of vaspin in the development of metabolic and glucose tolerance disorders and atherosclerosis. Biomed Res Int 2015; 2015: 823481, doi: 10.1155/2015/823481.
3. Saddi-Rosa P., Oliveira C. S. V., Giuffrida F. M. A., Reis A. F. Visfatin, glucose metabolism and vascular disease: a review of evidence. Diabetol Metab Syndr 2010; 2: 21, doi: 10.1186/1758-5996-2-21.
4. Soška V. Commentary on the article “What is C-reactive protein and how to correctly interpret its elevated values?” Internal Medicine 2016; 18 (1): 49–51.
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