Sitagliptin (Januvia) Treatment for Recurrent Miscarriage

Sitagliptin (Januvia) Treatment for Recurrent Miscarriage

Recent evidence has pointed to the possibility that some miscarriages may be due to defects in the function of the uterine lining. Women with recurrent miscarriage, especially those that have had a miscarriage of a chromosomally normal embryo, have been found to have low levels of a type of stem cell – endometrial mesenchymal stem-like progenitor cells (eMSC) in the basal (bottom) layer of the endometrium (uterine lining). They also appear to have problems converting the cells in the uterine lining (endometrial stromal cells – EnSC) into a form that will support pregnancy (decidual cells – DC ) and away from a type that may cause miscarriage (senescent decidual cells – SASP). Treatments that increase the eMSC and restore a healthy ratio of decidual cells may reduce the risk for miscarriage.

What is sitagliptin?

Sitagliptin, also known as Januvia, belongs to a class of medications called DPP-4 inhibitors. DPP-4 is an enzyme that breaks down certain proteins. One of the proteins that DPP-4 breaks down is called incretin. This prolongs the action of incretin in the body which helps control blood sugar. Thus, the primary use currently for sitagliptin is to treat people with Type 2 diabetes. Sitagliptin is FDA approved in the United States as a treatment for Type 2 diabetes.

How does sitagliptin help the uterus?

Another protein that is broken down by DPP-4 is called SDF-1. By blocking the action of DPP-4, sitagliptin can prolong the action of SDF-1. SDF-1 is produced in the uterine lining. When an follicle / egg is maturing in the ovary, the follicle produces estrogen. Estrogen makes the uterine lining thicker but it also increases the amount of SDF-1 that is produced by the endometrium. SDF-1 circulates in the blood and reaches the bone marrow. As a result, the bone marrow produces a type of stem cell called BMDC (Bone Marrow Derived Cells). The BMDCs lodge in the basal layer of the endometrium and are converted into eMSCs which help with regeneration of the uterine lining.

How does sitagliptin reduce the chance for miscarriage?

It is thought that sitagliptin improves the health of the uterine lining by increasing the eMSCs which are low in some women with recurrent miscarriage, and convert more endometrial stromal cells into healthy decidual cells instead of unhealthy senescent cells. The embryo may therefore have a better chance for survival after implantation.

Is there any evidence that sitagliptin reduces the risk for miscarriage?

Yes. This year (2020), scientists in England recruited a number of women aged 18 to 42 with a history of 3 or more miscarriages. Half the group received sitagliptin and half received a placebo (phony, inactive capsules). Subjects receive this treatment for three months. Neither the doctors nor the patients knew who got the real pills. This is known as a double-blind, randomized, placebo-controlled trial. This is considered this highest quality type of medical study because it reduces the chance for other variable to affect the results.

The researchers found that the women who received sitaglitpin: 1) Increased the number of eMSCs in their endometrium 2) Increased the number of decidual cells compared to senescent cells and 3) were more likely to have live births.

Specifically, in the group who received and completed treatment with sitagliptin, there were 8 live births out of 17, one termination of pregnancy at 16 weeks for a fetal abnormality and 3 spontaneous pregnancy losses before 12 weeks of gestation. A chromosome analysis was performed in 2 of 3 miscarriage cases and both showed a chromosome abnormality.

In the placebo group, there were 7 live births and 6 spontaneous pregnancy losses before 12 weeks out of 19 patients. Chromosome analysis was performed in only one of the losses. The results was normal. No chromosome abnormality.

Conclusion

Sitagliptin appears to be a novel way to improve the uterine lining prior to implantation by recruiting more bone marrow cells to help with endometrial regeneration. Treatment was well tolerated. although the group was very small, there appeared to be a greater chance for a live birth.

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