Q&A: Providers need to shift course with diabetes medications, technology during pregnancy
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Key takeaways:
- GLP-1s and SGLT2s may lead to adverse effects for the baby if not stopped early in pregnancy.
- More data are needed to assess the efficacy of CGM with type 2 or gestational diabetes during pregnancy.
NEW ORLEANS —The rise in use of diabetes medications and continuous glucose monitoring had led to new challenges for treating pregnant women with diabetes.
During a presentation at the American College of Clinical Endocrinology annual meeting, Linda A. Barbour, MD, MSPH, FACP, professor in endocrinology, metabolism and diabetes and maternal-fetal medicine at University of Colorado; Victoria Sandler, MD, clinical assistant professor at University of Chicago Pritzker School of Medicine and clinical endocrinologist at Endeavor Health; and Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, FADCES, FCCP, clinical pharmacy specialist and co-director of endocrine disorders in pregnancy at the Cleveland Clinic Endocrinology & Metabolism Institute and a Healio | Endocrine Today Editorial Board Member, reviewed the latest data and clinical recommendations for managing diabetes during pregnancy.
Barbour discussed how metformin, GLP-1 receptor agonists and SGLT2 inhibitors could lead not only to adverse outcomes for the baby, but to long-term effects as well. Use of metformin, in particular, during pregnancy could lead to nutrient restriction to the fetus, and this has become a large focus of research.
“If you restrict nutrients in utero and then expose this nutrient-restricted offspring to an obesogenic environment later on life, that is a significant risk factor for later childhood obesity,” Barbour told Healio.
Sandler said findings have been inconclusive as to how maternal exposure to GLP-1 receptor agonists affects babies.
“Additional studies are needed to further elucidate the impact of maternal GLP-1 agonists on neonatal and offspring outcomes and to characterize whether the effect is mitigated by gestational age at the time of exposure,” Sandler told Healio.
The use of diabetes technology also presents challenges. An increasing number of pregnant women with type 2 diabetes and gestational diabetes are using CGM, even though data are limited.
“Clinically, it's been challenging without having guidance for type 2 and gestational diabetes,” Isaacs told Healio. “Time in range alone is probably not enough because we have to still be looking at the average glucose and overnight. There’s still a lot to be learned.”
Healio spoke with the presenters about controversies regarding the use of certain diabetes medications and CGM during pregnancy and whether hybrid closed-loop systems are ready for use by pregnant women.
Healio: What are some controversies related to the use of metformin in pregnancy?
Barbour: The big controversy with metformin use is not so much the short-term effects, but the long-term effects. The biggest concern with metformin is that it readily crosses the placenta, and fetal concentrations are higher than maternal concentrations. There are many pleotropic effects of this drug that we worry about.
Metformin crosses the placenta, but not well in the first trimester. It’s the second trimester that it’s concentrated in the mitochondria. Fetal levels are even greater than maternal levels because of a placental cation transporter. Metformin appears to cause some nutrient restriction to the fetus, but not only by lowering glucose levels. It affects nutrient transfer and nutrient sensing. It has anti-cancer drug properties, it decreases cell cycle proliferation and then it inhibits mitochondrial respiratory complex I.
There were two major randomized trials in which metformin vs. placebo was added to insulin in type 2 diabetes during pregnancy: the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial published in 2020 and then MOMPOD trial that was published in 2023. In the MiTy trial, there was no difference in the primary composite neonatal outcomes compared with placebo. With metformin there was a decrease in large for gestational age, a significant decrease in insulin required, a small decrease in HbA1c and about a 2 kg decrease in weight gain. There was also an increase in small for gestational age babies. That’s a concern because small-for-gestational age babies, like large for gestational age babies, have an increased risk later on in life for childhood obesity.
In MOMPOD, there was again no difference in primary composite neonatal outcomes, maternal weight gain or insulin use compared with placebo. With metformin there was a decrease in large for gestational age babies and no difference in small for gestational age. A limitation with MOMPOD was the study did not collect HbA1c information in the vast majority of the women before delivery, so it is not clear whether glycemic control was equivalent in both arms.
The biggest concern we have with metformin is that the long-term offspring data and the only outcome trials that were randomized are in pregnancies complicated by gestational diabetes and polycystic ovary syndrome. In the Metformin in Gestational Diabetes (MiG) trial published in 2008, in which patients were randomized to insulin versus metformin, there was a signal that there was an increased risk for elevated BMI and childhood overweight later in life at age 7 to 9 years in one of the cohorts. The same increased risk of a higher weight was found at 5 to 10 years in the PCOS (Ped-Met) trials, but no increased risk was found in a follow-up study at 9 years in two open-label trials in gestational diabetes performed in Finland. It is important to look that far out, because if you only look at 2 years, it is difficult to pick up abnormal growth trajectories so early in life.
Healio: What do we know about the impact of GLP-1 receptor agonists in pregnancy, and what research still needs to be conducted?
Sandler: GLP-1 receptors are present on human placental tissue at the time of delivery. Additionally, umbilical total and active GLP-1 levels were found to be positively correlated with fetal birth weight.
The effect of maternal GLP-1 agonist exposure on fetal outcomes in the real world is still being determined. In one case report, early antenatal exposure to GLP-1 therapy was associated with neonatal macrosomia, shoulder dystocia and neonatal hypoglycemia. Additional studies have shown mixed results and were limited by study design — for example, exposure was based on prescription history — and lack of data on fetal outcomes like miscarriage or pregnancy loss.
Barbour: We have almost no data on extended GLP-1 use throughout pregnancy. These medications are almost always stopped during the first trimester, and they are a very high molecular weight, so they are not likely to cross the placenta. However, the placenta has GLP-1 receptors that may stimulate nutrient-sensing pathways. They're unlikely to cause any major malformations.
But what we are concerned about is that women who stop using GLP-1s immediately before pregnancy may not have good glycemic control without them. We have to switch them over to insulin and try to gain optimal glycemic control immediately. By the time we do that, it's often after 5 to 8 weeks when organogenesis is completed and the risk for hyperglycemic-associated malformations has already occurred.
Also, we have seen some pretty significant weight rebound with GLP-1s once they're stopped. When women stop using a GLP-1 in pregnancy in the first trimester, rapid weight regain is possible. There is a case report of maternal weight regain in excess of 75 lb and delivery of an infant who weighed more than 11 lb.
Isaacs: We’re dealing with this in practice because so many people are taking GLP-1s, and it's likely helping women become pregnant. They’re coming to us on these medications and our practice is typically to discontinue it. But of course, there’s exposure already in that first trimester. We just need to continue to monitor. This is going to be something that affects practice for years to come as these agents become even more widely used.
Healio: What are some concerns with SGLT2 inhibitor use during pregnancy?
Sandler: Given that SGLT2 inhibitors are of a smaller molecular weight, they have the potential to cross the placenta. In human case reports, exposure to SGLT2 inhibitors was associated with a higher than expected incidence of congenital malformations, such as hydrocephalus, encephalocele, renal aplasia and esophageal atresia, as well as miscarriages. In contrast, animal studies showed relative safety when exposure was during early gestation, whereas exposure in later in pregnancy was associated with dilation of renal pelvis and tubules.
Healio: What benefits can CGM provide for women with diabetes during pregnancy?
Isaacs: For type 1 diabetes, we have good quality data showing that there's benefit to utilizing CGM in pregnancy in terms of improved glycemic outcomes as well as maternal and fetal outcomes compared with blood glucose monitoring. The challenge is that we don't have so much data in type 2 diabetes and gestational diabetes. We have so little data that there's not even consensus about what the targets should be and what the percent time in range should be. For type 1 diabetes, we have established a 63 to 140 mg/dL range, aiming for at least 70% or more time in that target range.
That being said, we're seeing a huge increase in CGM use in type 2 diabetes and gestational diabetes populations. One reason is coverage and access has expanded, especially for pre-existing type 2 diabetes. We also have FDA-approved devices in pregnancy, which is something we did not have before. The Abbott FreeStyle Libre 2, the Abbott FreeStyle Libre 3, and the Dexcom G7 are all now cleared for use in pregnancy.
Barbour: Time in range in pregnancy may need to be a lot higher, or tighter ranges may be required, to make a significant difference in pregnancy outcomes in type 2 diabetes or in gestational diabetes, perhaps because there are so many other contributors to fetal overgrowth. Maternal insulin resistance, obesity and lipid levels also contribute, and it may be more of a challenge to be able to demonstrate that CGM will improve outcomes.
Healio: What challenges are there to implementing a hybrid closed-loop insulin delivery system during pregnancy, and what further research do we need to conduct?
Isaacs: We have the AiDAPT study, which was a randomized controlled trial with a hybrid closed-loop pump compared with standard therapy. That trial showed that there were improved glucose outcomes and a trend toward improved maternal and fetal outcomes as well. But that was in the CamAPS FX system, which is available in the U.K. That system can go down to a target glucose of 81 mg/dL. In the U.S., we don't have the CamAPS, and we don't have any system that goes down to 81 mg/dL. Our lowest currently available system is the Medtronic MiniMed 780G system, which goes down to 100 mg/dL.
It’s very challenging to achieve the 70% time in range target in type 1 diabetes with injections and even with a manual pump, so we’re using these systems off-label in various ways. For example, sometimes turning them on just during the day and trying to use manual settings overnight, or using them in the first trimester to prevent hypoglycemia and then going to manual.
More recently, the Sequel Twiist received FDA approval. That’s going to work with the Tidepool algorithm, and that algorithm goes down to 87 mg/dL. That may offer more customization. I have some patients that are looping with open-source algorithms that can go much lower.
I’ll just add that this is all in type 1 diabetes. There's very little we know about using these hybrid closed-loops in type 2 diabetes.
References:
- Boggess KA, et al. JAMA. 2023;doi:10.1001/jama.2023.22949.
- Feig DS, et al. Lancet Diabetes Endocrinol. 2020;doi:10.1016/S2213-8587(20)30310-7.
- Hanem LGE, et al. Lancet Child Adolesc Health. 2019;doi:10.1016/S2352-4642(18)30385-7.
- Lee TTM, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2303911.
- Muller DRP, et al. Front Endocrinol. 2023;doi:10.3389/fendo.2023.1215356.
- Paavilainen E, et al. Diabetes Obes Metab. 2022;doi:10.1111/dom.14589.
- Rowan JA, et al. BMJ Open Diabetes Res Care. 2018;doi:10.1136/bmjdrc-2017-000456.
- Szmuilowicz ED, et al. J Diabetes Sci Technol. 2024;doi:10.1177/19322968241239341.
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