Questionable Claims and Obesity Stigma in Breastfeeding Promotion

Image from the Center for Disease Control

It's World Breastfeeding Week ─ time to highlight the importance of breastfeeding! But not in the way this poster is doing.

I'm all for increasing breastfeeding rates. I've attended La Leche League meetings. I nursed my own four children for several years each. I've promoted breastfeeding on my website and my blog. I've helped other women with breastfeeding issues. It's hard to find a more ardent breastfeeding supporter than me.

However, today I'm going to be a heretic and offer up some criticism of breastfeeding advocacy. In particular, I have concerns with people trying to increase breastfeeding rates by promoting its potential for maternal weight loss or obesity prevention in children.

One press release from 2012 shows a typical example of hyperbole from the U.K.:

Breast-feeding may help mothers reduce the risk of obesity later in life, according to a study of 740,000 post-menopausal women in the U.K. 

For every six months women breast-fed, their body mass index was 0.22, or 1 percent, lower, even decades after giving birth, according to the research

A 1 percent reduction in BMI may seem small, but spread across the population of the U.K., that could mean about 10,000 fewer premature deaths per decade from obesity-related conditions, such as diabetes, heart disease and some cancers,” Valerie Beral, co-author of the study and director of the Cancer Epidemiology Unit at the University of Oxford, said in a statement.

Similarly, many breastfeeding advocates try to raise breastfeeding rates by promoting its potential for obesity prevention in children. The United States Breastfeeding Committee, for example, has a huge campaign promoting breastfeeding as the first step to preventing obesity in children (see graphic from the CDC above). 

These two approaches go unquestioned among many breastfeeding advocates, but they are problematic for several reasons.

First, the evidence is not that strong, and second, public health campaigns using breastfeeding to promote obesity prevention are often highly stigmatizing and full of negative stereotypes. In fact, they may alienate some of the very people they want to reach out to.

A Closer Look at the Evidence

Unfortunately, if you really look at the research, evidence for breastfeeding as obesity prevention in either mother or baby is modest at best.

Maternal Effects

Care providers are concerned about the potential for postpartum weight retention to increase a woman's weight long-term. I understand the concern. Long-term retention of pregnancy weight gain can be a factor in obesity for some women.

But although long-term breastfeeding after birth does result in quicker loss of pregnancy weight for some women, the effect tends to be modest in the research, and not all women find breastfeeding is helpful in postpartum weight loss. A few even find that they don't really lose those final pregnancy pounds until after weaning.

A large research review from the USDA's Center for Nutrition Policy and Promotion (Evidence Analysis Library Division) found:

A moderate body of consistent evidence shows that breastfeeding may be associated with maternal post-partum weight loss. However this weight loss is small, transient, and depends on breastfeeding intensity and duration.

Other meta-analyses have found that the relationship between breastfeeding and post-partum weight retention is very complicated, and definitive proof of benefit is difficult to show.

For maternal weight loss, breastfeeding can be helpful for some women, but in large groups, the effect is not particularly strong.  

The 2012 press release quoted above argues that a 1% reduction in BMI across the board could prevent 10,000 deaths per decade. This is highly speculative. A 1% reduction of BMI is very small and its effects would also probably be small. Their conclusion likely inflates the impact by using questionable data on the relationship between weight and mortality. Note they don't defend their statement or back it up with data; they just make broad, sweeping proclamations about the amount of lives it would save. This is the kind of overreach that is typical of these campaigns.

Furthermore, promoting breastfeeding for weight loss can backfire. A 2011 study found:

Belief that breastfeeding could aid postpartum weight loss was initially high, but unrelated to breastfeeding initiation or intensity. Maintenance of this belief over time, however, was associated with lower lactation scores. BMI was negatively correlated with breastfeeding initiation and intensity. Among overweight and obese women, unrealistic expectations regarding the effect of breastfeeding on weight loss may negatively impact breastfeeding duration.

If you promote breastfeeding as THE way to control weight and then that effect doesn't appear, there is likely to be a backlash. Stop creating unrealistic expectations in women and focus on breastfeeding's other benefits to them.

Effects on Offspring Obesity

Some studies do link breastfeeding with lower obesity rates in children later in life, especially in children at higher risk. While I believe this effect is real to some extent, I have real reservations about touting these studies.

There is more than a tinge of fat-phobia and mother-blaming in the media spin on these studies. The implication is that if you would just breastfeed your baby, it's very unlikely he'll be fat. And that just doesn't match the experience of many people.

Anecdotally, many high-BMI women have breastfed children for a year or more and still have children with weights considered "above normal." Unlike what researchers assume, this is not because we are force-feeding our children junk food or letting them play video games all day. Clearly, there are multiple influences on a child's weight, but genetics is one of the strongest. Breastfeeding does not overcome a strong genetic predisposition to obesity.

Yes, there are some studies that suggest that breastfed babies tend to be less heavy on average, but there are so many other confounding variables in these studies that it's hard to draw definitive conclusions. When other variables are controlled for, not all studies show that breastfeeding is protective against obesity.

For example, a recent large study from the Netherlands shows that breastfeeding did not protect against higher body weight. Although the study did the usual hyperventilating about the "dangers" of pediatric obesity, the authors did acknowledge the weaknesses of promoting breastfeeding for obesity prevention. One of the authors stated:

"It's important not to say things like, 'if you breast-feed your baby, he will not become obese.' " 

This is not the only study that found that breastfeeding was not protective against overweight status. A 2007 study found that having been breastfed as a child did not significantly influence women's adult weight status.

In addition, a randomized controlled trial in Belarus aimed to examine whether increasing breastfeeding rates at the population level prevented pediatric obesity. They succeeded in substantially raising the breastfeeding rates, yet this did not translate into reduced childhood obesity rates. The authors concluded:

Breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic.

This study has been criticized because it increased breastfeeding only modestly and mostly short-term. It still had low long-term breastfeeding rates and did not compare fully formula-fed babies with fully breastfed babies. These are legitimate criticisms. It may be that more differences between the groups would become clear with higher rates of extended breastfeeding and more clear delineations between exclusive formula use and exclusive breastfeeding. Yet the fact that little effect was found despite increased rates is troubling. You would think there would have been some impact.

Another unique study attempted to correct for other variables by looking at siblings within the same family who were fed differently. The strength of this study is that by using siblings in the same family, it corrects for education and socio-economic status and other variables which can strongly influence outcomes. Tellingly, it found virtually no difference in adiposity levels between breastfed and formula-fed siblings.

The majority of the research seems to suggest that while breastfeeding might be somewhat protective against obesity, this effect is small, may not last throughout life, and might be less important than other factors. One very pro-breastfeeding review concluded:

From current available data, any effects of breastfeeding on childhood obesity are likely not large, and tend to be most noted when formula feeding is compared with longer durations of breastfeeding.

The research picture on the effect of breastfeeding on obesity rates is far more muddled than clear. We need to be careful about overstating its effects, and we need to be careful about the language we use when we talk about certain benefits. In particular, its promotion for obesity prevention is questionable. A more accurate description is that breastfeeding may lower the risk for obesity. Although even that is not proven, this phrasing is much more defensible.

From my own review of the research, I believe that breastfeeding probably is associated with a modestly reduced risk of obesity on a population-wide basis, but that most of this effect is due to other variables and probably only short-term. Whatever the impact of exclusive breastfeeding on weight is, it's debatable how important that really is for public health.

Since breastfeeding has many other benefits that are quite clear, it seems more logical to be promoting these, rather than touting breastfeeding as a cure-all for obesity. 

Obesity Bias in Research 

Why might breastfeeding lower the risk for obesity at all? No one knows for sure, but even in the speculations obesity bias rears its ugly head.

The reasoning from the experts is filled with fat-phobic assumptions. For example, experts often imply that bottle-fed babies develop "unnaturally large" appetites because of passive intake vs. breastfed babies' self-regulated intake. This plays into the stereotype that fat kids have little self-control and over-consume food.

Or they state that breastfed babies are more likely to be willing to try new foods like fruits and vegetables. This plays into the stereotype that that obese kids don't eat fruits and vegetables. Because everyone knows that fat kids mostly eat junk food, right?

It's hard to separate researchers' fat-phobic stereotyping from plausible biological mechanisms. The best size-neutral guess is that breastfeeding lowers the risk for insulin resistance among children (which may in turn blunt the risk for diabetes and lower the tendency to gain weight), and it may promote a healthier gut microbiome, which in turn might lead to a lower risk for obesity. That seems quite plausible without relying on obesity stereotypes of over-consumption and poor eating habits.

So there could a biological foundation to the argument that breastfeeding might lower the risk for obesity. But prevent obesity completely? Probably not. There are too many other factors at work. It's far too simplistic to say that breastfeeding protects against obesity.

Furthermore, we need to watch the parent-blaming in these studies. For example, a short-term recent study found that longer breastfeeding was more protective in infants at the most risk for obesity, but that the effect wasn't as strong as hoped. An analysis of the study pointed out that maternal smoking and low education levels were also associated with higher weight, and that there was a lack of information about other feeding behaviors. The implication is that breastfeeding is not enough to overcome bad behavior in the parents. The author concludes:

So, does breastfeeding lower the risk of childhood obesity? My conclusion is yes; but only in infants at higher risk for obesity and [who] are breastfed for longer durations. In addition, as obesity is multifactorial, breastfeeding alone is unlikely to entirely prevent it.

Another author, writing about breastfeeding and childhood obesity, concludes:

The overall consensus is that breastfeeding provides protective factors, but can be mitigated by other factors (i.e. maternal health, environmental, SES, etc.) and should not be considered as an independent factor for obesity prevention.

In other words, those ignorant fat parents can overcome the benefits of breastfeeding by providing an unhealthy home environment and being too uneducated to change their own obesity or develop better health habits. Genetics? Total excuse. Any obesity must be the parents' fault, even if they breastfeed.

Yeah. As a fat parent, that sure makes me want to breastfeed.

Public Health Campaign Stigma

Another problem with promoting breastfeeding to prevent obesity is the biased attitudes these campaigns reinforce and the highly stigmatizing images they use.

(Because formula-feeding your baby is like feeding him candy bars.
And heaven knows that all formula-fed babies are fat and all
breastfed babies are skinny, right?)

Here is an image from a doctor's presentation that basically compares formula use with feeding your baby multiple candy bars a week. The apparent result is a chubby-cheeked sumo baby with multiple fat folds. What, no breastfed baby has ever had chubby cheeks and fat dimples?

And if the figure cited at the bottom is true, surely 30,000 more calories would ensure that all formula-fed babies would be fat and all breastfed ones would be thin. Unless perhaps there are other factors at work too? But heaven forbid those be acknowledged.

Even the articles that admit that a breastfed baby can be at the top of the weight charts usually then blame the baby's weight on the mother's nursing too much and suggest restricting nursing or giving a pacifier. Always a child's weight is blamed on over-consumption and restriction is promoted as the answer. Yet the answers are usually far more complex.

Image from article called
"Breastfeeding is the First Defense Against Obesity"

Here is another image from an article about breastfeeding for preventing obesity. The image has since been taken off of the article, but the fact that it was ever on there in the first place says a great deal about the assumptions and biases of the people promoting these campaigns.

Notice how the little boy (wearing too-small clothes) is gleefully surrounded by cake, ice cream, and lots of candy. Articles like this often use troubling images that strongly reinforce stereotypes about obesity and which likely increase obesity stigma and discrimination.

The image used for a blog post about preventing obesity
through breastfeeding, written by a lactation consultant (IBCLC)

Here's another image from a similar article ─ written by an influential professional lactation consultant, no less! Notice the too-small shirt, the hanging belly, and the prominent sweets (not one but TWO ice cream cones). Because you know that all obese children are that way because they are gorging on sweets and stuffing themselves to the max.

Here is an image from an article about a U.S. breastfeeding promotion campaign. It has the image of a breastfeeding woman of size, which is so rare that it should be a positive thing ─ but it's not. How typical that one of the very few images you can find of a woman of size breastfeeding is from a campaign that assumes that the diet of a high-BMI woman couldn't possibly be normal or healthy. The fact that the woman of size is also a woman of color makes it even more stigmatizing.

As a fat mother, I can tell you that these kinds of ads and articles make me want to breastfeed less, not more. In fact, they piss me off no end.

My Experience

In defiance of images like these, I breastfed my four kids for about 2.5 to 4 years each. That's a cumulative total of somewhere around 10 years. So if anyone should have seen a reduction in maternal BMI due to breastfeeding, it should have been me! Yet I didn't. I know many other women of size who also had a similar experience.

But surely all that breastfeeding reduced obesity in my children, right? I did all the "right" things. Not only was each child breastfed for multiple years (not months), I don't smoke, I am highly educated, I had a very small weight gain in pregnancy, we are in a higher socio-economic group, I didn't work outside the home for years, and I didn't introduce solids before 6 months. According to the research, they should be close to average-sized, right?

Nope. My first three children have a BMI near the top of the Class I obesity range, about where I was at their ages. I'm sure that critics will blame me by claiming that an obesogenic environment trumps everything (no doubt believing I force-fed them chocolate-covered french fries), but really, we did a great deal to promote healthy eating and exercise. Their habits were better than many of the children around them, but they were still fat.

On the other hand, my fourth child is skinny as the day is long, despite eating the same food and having the same genetic background as the rest of the kids. She didn't breastfeed longer or exercise more than the others; she simply seems to have benefited from a lucky throw of the genetics dice. She just took after a different branch of the family tree, apparently.

Same parents, same gene pool, same food, same environment, similar basic breastfeeding period ─ yet they have far different outcomes. Sure, that's only one family's experience, but I think it demonstrates that there are no simple answers here. And that's what I object to ─ the simplistic and stigmatizing messages that experts are putting out about breastfeeding and obesity.

Conclusions

Breastfeeding is amazing. So many health benefits come along with breastfeeding! It has a lot of short-term benefits in lowering the risk for illness in young children. It has a lot of long-term benefits in terms of metabolic improvements, lower risk for breast cancer, ovarian cancer, diabetes, heart disease etc. in mothers.

In this country (and many others), far too few babies are breastfed. Even among those whose mothers do nurse, breastfeeding last only a few months, instead of the years it was biologically designed for. The public health implications from such low rates of breastfeeding are perfectly valid topics for discussion.

But when breastfeeding is promoted as a well-intentioned but biased bludgeon to "prevent" obesity, I start getting cranky. I've held my tongue about it for too long. It's time to call out the breastfeeding advocates who distort the science and promote obesity stigma in trying to increase breastfeeding rates.

Look at the following breastfeeding advocacy poster.

Lowering the risk of obesity is the top benefit listed. Really? If there is an effect on obesity, it's quite small. Frankly, other benefits are FAR more important. (At least the poster does use the phrase, "lowers the risk for." That's something. Too many campaigns are using words like "prevent" or "protect from" obesity.)

Let's be clear about what needs to change in breastfeeding advocacy:

1. Breastfeeding campaigns need to stop overstating the evidence. The research shows that breastfeeding is unlikely to prevent obesity. We can mention that it might lower the risk somewhat, but even then most of the difference is attributable to other variables
2. We need to de-emphasize weight loss or obesity prevention as motivations in breastfeeding advocacy materials. Focus instead on other benefits that are far more clear and evidence-based
3. We need to be very careful about the language and images we use to discuss weight and breastfeeding. We need to eliminate the assumptions and stereotyping about obesity in breastfeeding research and drop the stigmatizing images used in breastfeeding campaigns

I'm ALL for promoting breastfeeding, but the truth is that weight is complex. A lot of fat women breastfeed and never lose weight, and a lot of fat women breastfeed for years and still have fat children. There are also plenty of formula-fed children who are thin. Breastfeeding is just not the weight cure-all that authorities want it to be and we need to stop telling people that it is. 

Stop using "obesity prevention" as a way to promote breastfeeding. Focus on the MANY other benefits which are far more clear in the research. And stop playing on societal fears and obesity stigma in breastfeeding advocacy materials. 

Can Inositol Prevent Gestational Diabetes?

We have written before about the use of inositol (either myo-inositol or d-chiro-inositol) to reduce insulin resistance in women with Polycystic Ovarian Syndrome (PCOS). It's a promising therapy, one that deserves far more research attention than it is getting so far.

But one of the pressing questions so far is whether or not it can reduce a woman's chance for raised blood sugar during pregnancy (Gestational Diabetes, or GD). Several recent studies from Italy have addressed this question.

How Inositol Works

Inositols are a group of carbohydrate compounds that exist in nine chemical orientations called stereoisomers; the two most important ones are myo-inositol and d-chiro-inositol. Your body uses bacteria from the gut to convert the phytic acid found in found in fruits, vegetables, legumes, whole grains, nuts, and other foods into inositols. They then play an important role inside the cell in insulin signaling.

In PCOS, this pathway does not seem to function properly. While most people can get the inositol they need from foods, women with PCOS may have difficulty converting naturally-occurring inositols into d-chiro-inositol (DCI). Or they may convert it reasonably well but excrete it too quickly and therefore do not have enough in the body to help utilize its insulin properly. Supplementing with exogenous (outside the body) sources of inositol is thought to help restore proper signaling function.

So, basically, the idea is that women with PCOS are not able to utilize the natural forms of inositol in their food and this causes insulin metabolism to be inefficient. This leads to a build-up of insulin in the body, which leads to the hormone imbalances of PCOS. And in pregnancy, it may lead to an increased risk for gestational diabetes. The hope is that treatment with inositol may help reduce these problems. 

Inositol and GD

During pregnancy, a temporary state of increased insulin resistance occurs because diabetogenic hormones are produced by the placenta in order to provide the fetus with more energy in case of famine or nutritional challenges. This happens in all women.

In normal pregnancies, the mother's insulin levels are able to respond enough to keep her blood sugar in the normal range, but in some women, the pancreas can't respond with enough insulin (or the body becomes too resistant to the insulin) to keep the blood sugar normal. These women are at high risk for getting GD in pregnancy, which in turn may lead to a higher rate of big babies, pre-eclampsia, and other problems. The women most at risk for GD include those with PCOS, those with a strong family history of diabetes, and high-BMI women.

As a result, a number of researchers have proposed using insulin-sensitizing medications routinely during pregnancy in these groups to reduce the risk of GD and other problems.

Or course, some insulin-sensitizing drugs cannot be used because they cross the placenta and can cause birth defects or low blood sugar in the newborn. Metformin is the usual drug of choice in recent years and seems relatively safe, but its performance has been mixed. So now researchers are proposing using inositols (usually myo-inositol) to reduce the risk for GD.

And indeed, some research has shown that women who develop GD in pregnancy tend to excrete high levels of inositol in their urine, suggesting their bodies are unable to convert/utilize it properly. And there is at least one small study that suggests that some women with already-diagnosed cases of GD can be effectively treated with inositols.

So might prophylactic treatment with inositol help prevent GD in women at high risk for the condition?

Studies on Inositol for GD Prevention

So far, the studies on using inositol to prevent or lower the incidence of GD are promising.

An April 2013 study found that myo-inositol lowered the rate of GD in non-obese women with a history of Type 2 diabetes in a close relative. The GD rate was 15.3% in the placebo group vs. 6% in the myo-inositol group.

A July 2013 study found that administering myo-inositol to women who had elevated fasting glucose levels in early pregnancy also lowered the rate of the development of GD.

A December 2015 study found that myo-inositol lowered the rate of GD in a population of "overweight" (BMI 25-30) women. The GD rate was 27.4% in the placebo group vs. 11.6% in the myo-inositol group.

An August 2015 study found that myo-inositol cut the rate of GD incidence in obese women (BMI 30 and over) in half; the GD incidence was 33% in the placebo group vs. 14% in the myo-inositol group.

Most significant of all, a small June 2012 study found that myo-inositol dramatically lowered the rate of GD in women with PCOS. The control group (treated with metformin until conception was confirmed, when it was stopped) had a 54% GD rate, whereas the myo-inositol group (treated before and throughout the entire pregnancy) had a 17.4% rate.

These are all very significant findings and some researchers are getting very excited about the use of inositols in pregnancy. We will undoubtedly see many more studies on this in the future.

Weaknesses of the Studies

However, some cautions are warranted in looking at these studies. One prominent GD researcher wrote a mostly-positive editorial on the use of myo-inositol for preventing GD, but noted a number of problems with the studies, echoing the reservations that I had as I reviewed the abstracts.

Generally, the study groups are pretty small. You need much larger studies to be sure there is a true benefit happening. Also, most serious complications are rare in pregnancy; you need really large study groups to confidently rule out potential safety issues like birth defects or perinatal mortality.

Also, the studies are all done in Italy; most of the inositol research these days is being done there. When all the research on a substance is being done in one particular area or by one set of doctors, that raises the question of bias. It will be very important to see this work replicated in other places and other populations.

The Italian hospitals have also concentrated mostly on myo-inositol. I'd also like to see researchers compare myo-inositol and d-chiro-inositol to see which has greater efficacy.

And of course, the potential for harm in pregnancy is always high because there is a baby involved. Since inositol is a substance your own body produces from food, you would think the risk should be low, but even nutrients that are beneficial in small doses (like vitamin A) can be harmful to fetuses in large doses. More research is needed to look for any possible neonatal effects, as well as to clarify optimal and safe dosages.

Furthermore we need to clarify when usage of inositols is safe. In most of these studies, myo-inositol was only given after the first trimester, so we don't really know if it has any effect on the development of babies early in the first trimester. In the study on obese women, myo-inositol was started in the first trimester but likely this occurred after organogenesis. People in the PCOS study took it throughout the whole pregnancy; no harm was found, but the study was quite small and much larger studies would be needed to see possible impact on rare outcomes.

Some animal models have suggested that large doses of myo-inositol can trigger uterine contractions, so that is another concern that must be addressed. No increase in prematurity was noted in the PCOS pregnancy study, but again, that study was too small to be definitive. Obviously, research that looks specifically at premature labor is needed.

One intriguing finding has been that inositol use (especially d-chiro-inositol) has lowered the risk for Neural Tube Defects (NTDs) in folate-resistant mouse models. A defect in insulin-signaling pathways might be a plausible explanation for why obese women have a somewhat higher risk for neural tube defects than other women. Although no research on obese women has been done, preliminary research on inositol supplementation in women who are at high risk for a NTD because of a prior NTD-affected fetus has been promising. On the other hand, because NTDs are rare, it will probably be a very long time before we know for sure whether inositol use lowers the risk of NTDs in obese women. 

In addition, as a Cochrane Review noted, studies were inconsistent in reporting neonatal outcomes, and the overall quality of studies were judged to be of low or very low quality. The review found the preliminary GD results quite favorable, but strongly encouraged larger, more diverse, and better-designed research.
So while the initial results from these inositol in pregnancy studies are quite promising, there is definitely room for reservations too.

Final Thoughts

Personally, I am very intrigued by the potentials of inositol use. I find the research around the use of inositols outside of pregnancy to be very promising so far, and I'm intrigued by the anecdotal benefits many women with PCOS have reported. To me the mechanism of action seems quite plausible and it is logical that inositol supplementation might be useful. Since myo-inositol is very inexpensive and easy to find, inositols have tremendous potential as a therapy ─ if they are effective and safe.

However, I'm always a little bit leery when researchers start experimenting with interventions during pregnancy. History is littered with examples of things we thought were a good idea in pregnancy, were adopted without adequate research, and which actually turned out to be ineffective or even harmful.

I also have mixed feelings about the fact that doctors are pushing this treatment with high-BMI women regardless of glycemic status or PCOS diagnosis. Some researchers have pushed the envelope of ethical behavior at times to try to reduce possible complications in obese women, and I'm deeply concerned doctors will start pushing these treatments before they are truly proven to be effective and without harm.

On the other hand, high-BMI women clearly do have increased risks for some complications, including gestational diabetes. If a way to prevent GD could be found, that might improve outcomes in some women. As long as this is treated as experimental research, done with proper protocols and truly informed consent, it is important that these studies go forward ─ but it's equally important that women have the right to opt out of them without penalty if they decide they are uncomfortable with the potential risks. Nor should inositols be incorporated into routine care at this point.

As we have written about before, metformin was thought to be the miracle drug for preventing problems in women with a high potential for insulin resistance. However, more thorough research has shown its usefulness to be mixed.

Metformin has certainly been shown to be useful in managing gestational diabetes once it is diagnosed. And in women with PCOS, a number of small initial studies showed that metformin was helpful in reducing miscarriage, pre-term birth, and perhaps GD and blood pressure issues.

However, a recent randomized study did not show that metformin was useful in preventing GD among women with PCOS, although researchers noted the need for further large studies to confirm this. It should also be noted that metformin does seem to lower the rate of miscarriage pretty consistently, so it still may be a useful drug for PCOS, even if it doesn't prevent GD.

But outside of PCOS and GD treatment, metformin's use in pregnancy is more doubtful. Two recent large studies have found that metformin was not useful in preventing GD or lowering birth weight in babies of high-BMI women with normal glucose tolerance. The authors concluded that metformin should not be be used routinely to prevent complications in obese women.

So there is plenty of precedent for a promising therapy that looked like THE cure-all for prevention of complications associated with insulin resistance in pregnancy. Yet so far, none of these therapies have proven to be useful across the board. Useful under certain conditions, yes, but not for routine use.

Still, the recent research on inositols in pregnancy is very interesting. The inositols are an intriguing, plausible possible treatment, and anecdotally some women with PCOS have achieved great results with them, but this is not the same as having quality research on its use and safety in pregnancy. More research is vitally needed, with larger study groups, more varied populations, and stricter study designs.

Keep your eyes peeled for future developments, as research into the inositols is expanding. Until then, use of the inositols in pregnancy should remain a matter of individual decision-making between a woman and her provider, with full informed consent.

References

Inositol and High-BMI Pregnant Women

Obstet Gynecol. 2015 Aug;126(2):310-5. doi: 10.1097/AOG.0000000000000958. Myo-inositol Supplementation for Prevention of Gestational Diabetes in Obese Pregnant Women: A Randomized Controlled Trial. DʼAnna R1, Di Benedetto A, Scilipoti A, Santamaria A, Interdonato ML, Petrella E, Neri I, Pintaudi B, Corrado F, Facchinetti F. PMID: 26241420

OBJECTIVE: To evaluate whether myo-inositol supplementation, an insulin sensitizer, reduces the rate of gestational diabetes mellitus (GDM) and lowers insulin resistance in obese pregnant women. METHODS: In an open-label, randomized trial, myo-inositol (2 g plus 200 micrograms folic acid twice a day) or placebo (200 micrograms folic acid twice a day) was administered from the first trimester to delivery in pregnant obese women (prepregnancy body mass index 30 or greater). We calculated that 101 women in each arm would be required to demonstrate a 65% GDM reduction in the myo-inositol group with a statistical power of 80% (α=0.05). The primary outcomes were the incidence of GDM and the change in insulin resistance from enrollment until the diagnostic oral glucose tolerance test. RESULTS: From January 2011 to April 2014, 220 pregnant women at 12-13 weeks of gestation were randomized at two Italian university hospitals, 110 to myo-inositol and 110 to placebo. Most characteristics were similar between groups. The GDM rate was significantly reduced in the myo-inositol group compared with the control group, 14.0% compared with 33.6%, respectively (P=.001; odds ratio 0.34, 95% confidence interval 0.17-0.68). Furthermore, women treated with myo-inositol showed a significantly greater reduction in the homeostasis model assessment of insulin resistance compared with the control group, -1.0±3.1 compared with 0.1±1.8 (P=.048). CONCLUSION: Myo-inositol supplementation, started in the first trimester, in obese pregnant women seems to reduce the incidence in GDM through a reduction of insulin resistance.

J Matern Fetal Neonatal Med. 2015 Dec 23:1-4. [Epub ahead of print] Myo-inositol may prevent gestational diabetes onset in overweight women: a randomized, controlled trial. Santamaria A1, Di Benedetto A2, Petrella E3, Pintaudi B2, Corrado F1, D'Anna R1, Neri I3, Facchinetti F3. PMID: 26698911

OBJECTIVE: To evaluate whether myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) rate in overweight women. METHODS: In an open-label, randomized trial, myo-inositol (2 g plus 200 μg folic acid twice a day) or placebo (200 μg folic acid twice a day) was administered from the first trimester to delivery in pregnant overweight non-obese women (pre-pregnancy body mass index ≥ 25 and < 30 kg/m2). The primary outcome was the incidence of GDM. RESULTS: From January 2012 to December 2014, 220 pregnant women were randomized at two Italian University hospitals, 110 to myo-inositol and 110 to placebo. The incidence of GDM was significantly lower in the myo-inositol group compared to the placebo group (11.6% versus 27.4%, respectively, p = 0.004). Myo-inositol treatment was associated with a 67% risk reduction of developing GDM (OR 0.33; 95% CI 0.15-0.70).  CONCLUSIONS: Myo-inositol supplementation, administered since early pregnancy, reduces GDM incidence in overweight non-obese women.

Inositol and Pregnant Women at Strong Risk for Diabetes

Diabetes Care. 2013 Apr;36(4):854-7. doi: 10.2337/dc12-1371. Epub 2013 Jan 22. myo-Inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study. D'Anna R1, Scilipoti A, Giordano D, Caruso C, Cannata ML, Interdonato ML, Corrado F, Di Benedetto A. PMID: 23340885

OBJECTIVE: To check the hypothesis that myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) onset in pregnant women with a family history of type 2 diabetes. RESEARCH DESIGN AND METHODS: A 2-year, prospective, randomized, open-label, placebo-controlled study was carried out in pregnant outpatients with a parent with type 2 diabetes who were treated from the end of the first trimester with 2 g myo-inositol plus 200 µg folic acid twice a day (n = 110) and in the placebo group (n = 110), who were only treated with 200 µg folic acid twice a day...RESULTS: Incidence of GDM was significantly reduced in the myo-inositol group compared with the placebo group: 6 vs. 15.3%, respectively (P = 0.04). In the myo-inositol group, a reduction of GDM risk occurrence was highlighted (odds ratio 0.35). A statistically significant reduction of fetal macrosomia in the myo-inositol group was also highlighted together with a significant reduction in mean fetal weight at delivery. In the other secondary outcome measures, there were no differences between groups. CONCLUSIONS: myo-Inositol supplementation in pregnant women with a family history of type 2 diabetes may reduce GDM incidence and the delivery of macrosomia fetuses.

J Matern Fetal Neonatal Med. 2013 Jul;26(10):967-72. doi: 10.3109/14767058.2013.766691. Epub 2013 Mar 1. Effect of dietary myo-inositol supplementation in pregnancy on the incidence of maternal gestational diabetes mellitus and fetal outcomes: a randomized controlled trial. Matarrelli B1, Vitacolonna E, D'Angelo M, Pavone G, Mattei PA, Liberati M, Celentano C. PMID: 23327487

OBJECTIVE: To test the hypothesis that dietary myo-inositol may improve insulin resistance and the development of gestational diabetes mellitus (GDM) in women at high risk of this disorder. DESIGN: A prospective, randomized, double-blind, placebo controlled clinical trial, pilot study. PARTICIPANTS: Non-obese singleton pregnant women with an elevated fasting glucose in the first or early second trimester were studied throughout pregnancy...RESULTS: Thirty-six women were allocated to receive myo-inositol and 39 placebo. The incidence of GDM in mid-pregnancy was significantly reduced (p = 0.001) in women randomized to receive myo-inositol compared to placebo (relative risk 0.127). Women randomized to receive myo-inositol also required less insulin therapy, delivered at a later gestational age, had significantly smaller babies with fewer episodes of neonatal hypoglycemia. CONCLUSIONS: Myo-inositol supplementation in pregnancy reduced the incidence of GDM in women at high risk of this disorder. The reduction in incidence of GDM in the treatment arm was accompanied by improved outcomes.

Inositol Use in Pregnant Women with PCOS

Gynecol Endocrinol. 2012 Jun;28(6):440-2. doi: 10.3109/09513590.2011.633665. Epub 2011 Nov 28. Myo-inositol may prevent gestational diabetes in PCOS women. D'Anna R1, Di Benedetto V, Rizzo P, Raffone E, Interdonato ML, Corrado F, Di Benedetto A. PMID: 22122627

To evaluate retrospectively the prevalence of gestational diabetes (GD) in pregnancies obtained with myo-inositol administration in women with polycystic ovary syndrome. A total of 98 pregnancies in PCOS women obtained in a 3-year period, either with myo-inositol (n. 54), or with metformin (n. 44) were considered. While myo-inositol was assumed through the whole pregnancy, the group of women treated with metformin stopped the drug assumption after pregnancy diagnosis, and was considered as a control group. After having eliminated cases of miscarriages and twin pregnancies, a definitive number of 46 women in the myo-inositol group and 37 in the control group was taken in account to be retrospectively evaluated. The primary outcome measure was GD occurrence in both groups; whereas secondary outcome measures were pregnancy outcomes: hypertensive disorders, pre-term birth, macrosomia and caesarean section occurrence. Prevalence of GD in the myo-inositol group was 17.4% versus 54% in the control group, with a highly significant difference also after adjusting for covariates. Consequently, in the control group the risk of GD occurrence was more than double compared to the myo-inositol group, with an odds ratio 2.4 (confidence interval 95%, 1.3-4.4). There was no difference between the groups in relation to secondary outcome measures. This study suggests a possible effect of myo-inositol in the primary prevention of GD in PCOS women.

Meta-Analysis on Inositol for Preventing GD

Cochrane Database Syst Rev. 2015 Dec 17;12:CD011507. doi: 10.1002/14651858.CD011507.pub2. Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes. Crawford TJ1, Crowther CA, Alsweiler J, Brown J. PMID: 26678256

BACKGROUND: ...Myo-inositol, an isomer of inositol, is a naturally occurring sugar commonly found in cereals, corn, legumes and meat. It is one of the intracellular mediators of the insulin signal and correlated with insulin sensitivity in type 2 diabetes. The potential beneficial effect on improving insulin sensitivity suggests that myo-inositol may be useful for women in preventing gestational diabetes...MAIN RESULTS: We included four randomised controlled trials (all conducted in Italy) reporting on 567 women who were less than 11 weeks' to 24 weeks' pregnant at the start of the trials. The trials had small sample sizes and one trial only reported an interim analysis. Two trials were open-label. The overall risk of bias was unclear. For the mother, supplementation with myo-inositol was associated with a reduction in the incidence of gestational diabetes compared with control (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.29 to 0.64; three trials; n = 502 women). Using GRADE methods this evidence was assessed as low with downgrading due to unclear risk of bias for allocation concealment in two of the included trials and lack of generalisability of findings...AUTHORS' CONCLUSIONS: Evidence from four trials of antenatal dietary supplementation with myo-inositol during pregnancy shows a potential benefit for reducing the incidence of gestational diabetes. No data were reported for any of this review's primary neonatal outcomes. There were very little outcome data for the majority of this review's secondary outcomes. There is no clear evidence of a difference for macrosomia when compared with control.The current evidence is based on small trials that are not powered to detect differences in outcomes including perinatal mortality and serious infant morbidity. All of the included studies were conducted in Italy which raises concerns about the lack of generalisability of the evidence to other settings. There is evidence of inconsistency and indirectness and as a result, many of the judgments on the quality of the evidence were downgraded to low or very low quality...Further trials for this promising antenatal intervention for preventing gestational diabetes are encouraged and should include pregnant women of different ethnicities and varying risk factors and use of myo-inositol (different doses, frequency and timing of administration) in comparison with placebo, diet and exercise or pharmacological interventions. Outcomes should include potential harms including adverse effects.

Recent Studies on Inositol for PCOS

Here are the abstracts of some new studies on the use of inositol (d-chiro-inositol or myo-inositol) in women with Polycystic Ovarian Syndrome (PCOS).

Inositol is a naturally-occurring substance in our foods that helps us process insulin properly. Normally, our bodies convert substances in plants and animals into several different forms of inositol. Two of these inositols are used in insulin-signaling pathways. However, some research suggests that women with PCOS do not use inositol properly, leading to insulin-signaling problems. 

These defects in insulin signaling means that the body has to over-produce insulin to compensate. The insulin that is produced does not get used properly, causing excess amounts to stay in the body.

This in turns stimulates the production of androgens ("male" hormones), leading to an imbalance in hormones in the body and many of the distressing symptoms of PCOS (including hirsutism, alopecia, acne, and difficulty ovulating).

And because the body struggles to use its insulin properly, this can lead to increased blood sugar issues over time. This is why many women with PCOS become diabetic at some point in their lives.

Now, however, emerging research suggests that supplementing the body with these inositols may help insulin signaling, thus lowering insulin resistance and improving blood sugar. It may even help lessen PCOS symptoms.

We've discussed inositols before in detail, here, which can be read for a good start on the subject. But right now let's take a look at some of the latest thinking on inositols, as well as on studies that have been released since that original post or were not cited in it.

How Inositols Work in Insulin Signaling

First, a little background for those new to the topic.

Inositols act as "second messengers" in insulin signaling. They play a very important role in how we use insulin.

Insulin produced by the body binds to insulin receptors on the cell walls. From there, the receptor generates second messengers (inositolphosphoglycans, or IPGs) to relay and amplify the signal to help the body use the insulin effectively.

But women with PCOS seem to have a defect in their second messenger pathway. This could explain why they have such strong insulin resistance. One PCOS resource simplifies it this way:

When we eat foods (mostly carbohydrates), they get converted into glucose in our blood stream. We need the glucose to enter our cells to be used for energy. When blood glucose levels rise, a signal (imagine a doorbell is rung) is sent from the cell door to the nucleus telling it to open up. However, with PCOS, the doorbell on the cell door may be defective. This means that it takes longer for the cells to open its doors to glucose resulting in higher amounts of insulin needing to be secreted. Secondary messengers acts to repair the doorbell so that the cell doors open in response to glucose, resulting in less insulin needing to be secreted. 

Improving this second messenger pathway could also become a radical new way of treating PCOS. As one review noted:

The discovery that the impairment in the insulin signalling could be due to a defect in the inositolphosphoglycans (IPGs) second messenger pathway opened a new horizon in the clinical management of PCOS. IPGs are known to have a role in activating enzymes that control glucose metabolism. In PCOS women, a defect in tissue availability or altered metabolism of inositol or IPGs mediators may contribute to insulin resistance

So the problem in PCOS may simply be errors in the second messenger insulin signaling pathway, and treating women with some form of inositol may help bridge the errors in this pathway.

The question is, which is the most effective form of inositol and should the type/dosage used depend on its purpose?

Which Form of Inositol Works Best?

Two forms of inositol get the most attention in PCOS research:

• myo-inositol (MI or MYO)
• d-chiro-inositol (DCI)

Both are forms of inositol, just slightly different stereoisomers. Both play important roles in insulin signaling; their roles are different but complementary.

MI is usually seen as a precursor to DCI; evidence suggests that the body converts myo-inositol to d-chiro inositol. Another inositol stereoisomer, d-pinitol, is also thought to convert into DCI in the body, but MI is thought to be the more important source.

However, many women with PCOS seem to have difficulty with the conversion from MI to DCI, suggesting that PCOS may be caused (or at least influenced) by errors in inositol metabolism. 

So, the theory goes, if we supplement the body directly with inositol, that might help help replace what's missing or make it work more efficiently.

As a result, people have been experimenting with inositol supplements, either myo-inositol or d-chiro-inositol. And the results of these experiments have been promising so far, both in research and anecdotally.

One of the most important questions that has yet to be answered is whether myo-inositol or d-chiro inositol (or some combination of the two) is the best treatment for women with PCOS and what the best dosage/treatment regimen would be.

MI is the form of inositol that is cheapest and easiest to use. It can be bought in capsules over the counter in many health food stores or in bulk powder over the internet. The thought is that if you take enough of it, then the body will convert more of it into DCI and improve insulin signaling, thus decreasing PCOS symptoms and health issues.

On the other hand, DCI is the form that seems to work best on improving hyperandrogenism and possibly insulin resistance. If some women have difficulties converting MI to DCI, why not skip to the chase and supplement directly with DCI?

Early studies on DCI had excellent results and so DCI was the focus of most research at first. However, subsequent studies were not able to replicate these results, so the drug companies largely abandoned DCI as a line of inquiry in 2002. DCI seemed discredited at that point.

What the research since then has suggested is that the initial follow-up studies didn't replicate the studies exactly ─ they increased the dosage in hopes of even better effect. But it seems that they increased the DCI dosage too much ─ apparently, there is a point of diminishing returns with DCI, beyond which it ceases to be helpful, particularly with fertility concerns. So the reason the follow-up studies didn't validate the original studies was because they used a too-high dosage, not because DCI was not potentially useful.

After the supposed "discrediting" of DCI, research on inositols was minimal and mostly focused on MI. Once researchers realized that a too-high DCI dosage was counter-productive and that MI also had benefits, research began to increase on both inositols.

Since myo-inositol is much cheaper and easier to produce, research still often focuses on MI. But some providers still feel that a moderate dose of DCI is a better choice. Still others feel that a combination of MI and DCI should work better, since both work on insulin signaling in different ways.

So what we do know is that there is no clear consensus on inositols yet but that data is emerging and it's important to keep up on the latest research.

Current research seems to suggest that MI is the inositol of choice for PCOS women with fertility issues (it especially seems to improve egg quality) and that MI works better than DCI for fertility treatment.

On the other hand, DCI may be better for those PCOS women with major hyperandrogenism issues and for whom fertility is not a major concern.

The jury is still out on which form is better for significant blood sugar/insulin resistance issues; there is research to support either MI and DCI (or both) for this purpose.

The very latest trend seems to be having women with PCOS take both MI and DCI in a 40:1 ratio (MI to DCI). This usually translates to MI (2-4 grams) and DCI (50-100 mg), but exact dosages will vary from person to person.

Recent research suggests this combination seems to be more effective than either MI or DCI alone. This is logical if they do indeed work on insulin signaling in different ways.

But it may be that the best treatment regimen may differ from woman to woman because the degree of impaired conversion may differ from person to person.

Remember, PCOS tends to have a spectrum of severity. Some have only mild symptoms while others have very severe symptoms. This may reflect a spectrum of efficiency in conversion of MI to DCI. As one resource speculates:

Considering the spectrum of human genetic diversity (take height for example), why should this trait be black/white, yes/no, or on/off? With a little imagination, we can see this impaired conversion of myo-inositol to D-chiro-inositol as a spectrum. Some women make the conversion efficiently, and they have no symptoms of PCOS. Others may make the conversion with some degree of efficiency, but not quite enough to have an optimal MYO/DCI ratio. Their symptoms may be mild. At the other end of the spectrum some people would be completely unable to make this conversion, and they would consequently present with the most severe symptoms. And, as part of the human tapestry, there would be everything in between as well.

Which brings us to the question of which inositol is right for me? Along this spectrum, people who are completely unable to convert myo-inositol to D-chiro-inositol are only going to benefit from supplementation with D-chiro-inositol. Other people who make the conversion, but with less than optimal efficiency, may benefit from large doses of myo-inositol. And, folks in between, might see the best results from a blend of the two.

In other words, some women with PCOS seem to convert MI to DCI pretty well, in which case they probably don't need to take supplemental DCI, just MI. However, others probably do not convert MI to DCI very well and may benefit more from just DCI. Still others may do best with a combination of both.

How are we to know which treatment regimen to try? As always, we need bigger and more qualitative studies to guide our choices.

But in the end, it may also be that each woman (in concert with her care provider) has to experiment and find the right regimen and dosage for her unique needs. 

Summary

More and more research is being done on the use of the inositols for PCOS, and most of this research so far is very encouraging. Some researchers are even suggesting that:

...the combined administration of MI and DCI in physiological plasma ratio (40:1) should be considered as the first line approach in PCOS overweight patients.

As we have seen, the most important benefit of inositols may be in improving insulin signaling, thus reducing insulin resistance and lessening PCOS symptoms. If insulin resistance is the major issue with PCOS and research continues to be promising, then inositols may become the key element to treating it. They may be especially useful for those who cannot tolerate metformin.

But there may be other benefits beyond improving the insulin-signaling pathway. For example, inositols are thought to also help the liver to metabolize fat, which may be helpful to those PCOS women with NAFLD (Non-Alcoholic Fatty Liver Disease).

In addition, inositols act as "signal transduction systems" in ways beyond insulin signaling pathways. They may also be related to the activation of serotonin receptors. Some research suggests that high doses of MI may reduce the risk of depression, which may be more common in people with PCOS.

There is only limited data on the use of inositols during pregnancy but some research suggests that use of myo-inositol may significantly lower the risk for the development of gestational diabetes in women with PCOS, in women with diabetic relatives, or in those who are at otherwise high risk for gestational diabetes.

However, keep in mind that most of the research trials on inositols have been very small, quite short-term, and are highly variable in methodological quality. Most are done in Italy and are not taken very seriously by many care providers in the U.S. or U.K. As a result, some researchers don't feel that any of the inositols have been adequately proven yet. And some care providers haven't even heard of inositols, so it can be difficult to find a provider supportive of trying this therapy.

Bottom line, we need more and better trials to know if long-term use of the inositols is safe and effective and to help care providers feel more comfortable with their use.

In particular, there are a few pressing safety questions that need to be addressed:

• Some sources suggest that women who are on anti-depressants or medications for bipolar disorder may need to avoid inositols or use them only with great care since inositols may affect serotonin receptors
• Some resources recommend that DCI not be used in conjunction with anti-androgen medications like spironolactone because the two together may be too effective against androgens and a certain amount of androgens are actually needed by the body
• We need more data proving conclusively that inositols are safe in pregnancy
• We need more data examining potential interactions with other drugs since many women with PCOS take other medications as well

In short, research on the use of inositols for PCOS is emerging and it behooves us to keep a close watch on emerging research to keep up with the latest developments.

The good news is that the results so far are promising. Below are the abstracts from some of the more important recent studies on inositol use.

*You can read more about the use of the inositols for treatment of PCOS here, here, here, and here. My original blog post about the use of inositols for PCOS can be found here. 


References

Overview

Eur Rev Med Pharmacol Sci. 2014 Jul;18(13):1896-903. Inositol: history of an effective therapy for Polycystic Ovary Syndrome. Bizzarri M1, Carlomagno G. PMID: 25010620 Free full text here.

Inositol is a physiological compound belonging to the sugar family. The two inositol stereoisomers, myo-inositol and D-chiro inositol are the two main stereoisomers present in our body. Myo-inositol is the precursor of inositol triphosphate, a second messenger regulating many hormones such as TSH, FSH and insulin. D-chiro inositol is synthetized by an insulin dependent epimerase that converts myo-inositol into D-chiro-inositol...In [PCOS] patients myo and/or D-chiro-inositol administration improves insulin sensitivity while only myo-inositol is a quality marker for oocytes evaluation. Myo-inositol produces second messengers for FSH and glucose uptake, while D-chiro inositol provides second messengers promoting glucose uptake and glycogen synthesis. The physiological ratio of these two isomers is 40:1 (MI/DCI) and seems to be an optimal approach for the treatment of PCOS disorders.

d-chiro inositol

Gynecol Endocrinol. 2014 Jun;30(6):438-43. doi: 10.3109/09513590.2014.897321. Epub 2014 Mar 7. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Genazzani AD1, Santagni S, Rattighieri E, Chierchia E, Despini G, Marini G, Prati A, Simoncini T. PMID: 24601829

...Since it has been demonstrated a high incidence of insulin resistance in PCOS patients, our study aimed to evaluate the efficacy of the integrative treatment with D-chiro-inositol (DCI) (500 mg die, per os, for 12 weeks) on hormonal parameters and insulin sensitivity in a group of overweight/obese PCOS patients (body mass index; BMI > 26). After the treatment, interval several endocrine parameters improved (luteinizing hormone [LH], LH/follicle stimulating hormone [FSH], androstenedione and insulin), insulin response to oral glucose tolerance test reported the significant improvement of insulin sensitivity as well as the gonadotropin-releasing hormone (GnRH)-induced (10 µg, in bolus) LH response. BMI decreased, though no lifestyle modification was requested. When data were analyzed according to the presence or absence of first-grade diabetic relatives, PCOS patients with diabetic relatives showed greater improvement after DCI administration. In conclusion DCI administration is effective in restoring better insulin sensitivity and an improved hormonal pattern in obese hyperinsulinemic PCOS patients, in particular, in hyperinsulinemic PCOS patients who have diabetic relatives.

Arch Gynecol Obstet. 2014 Nov 22. [Epub ahead of print] Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol. Laganà AS1, Barbaro L, Pizzo A. PMID: 25416201

...We enrolled 48 patients, with homogeneous bio-physical characteristics, affected by PCOS and menstrual irregularities. These patients underwent treatment with 1 gr of D-Chiro-Inositol/die plus 400 mcg of Folic Acid/die orally for 6 months...We evidenced a statistically significant reduction of systolic blood pressure, Ferriman-Gallwey score, LH, LH/FSH ratio, total Testosterone, free Testosterone, ∆-4-Androstenedione, Prolactin, and HOMA Index; in the same patients, we noticed a statistically significant increase of SHBG and Glycemia/IRI ratio. Moreover, we observed statistically significant (62.5 %; p < 0.05) post-treatment menstrual cycle regularization. CONCLUSIONS: D-Chiro-Inositol is effective in improving ovarian function and metabolism of patients affected by PCOS.

Gynecol Endocrinol. 2015 Jan;31(1):52-6. doi: 10.3109/09513590.2014.964201. Epub 2014 Sep 30. The menstrual cycle regularization following d-chiro-inositol treatment in PCOS women: a retrospective study. La Marca A1, Grisendi V, Dondi G, Sighinolfi G, Cianci A. PMID: 25268566

...The objective of this study was to retrospectively analyze the effect of DCI on menstrual cycle regularity in PCOS women. This was a retrospective study of patients with irregular cycles who were treated with DCI. Of all PCOS women admitted to our centre, 47 were treated with DCI and had complete medical charts. The percentage of women reporting regular menstrual cycles significantly increased with increasing duration of DCI treatment (24% and 51.6% at a mean of 6 and 15 months of treatment, respectively). Serum AMH levels and indexes of insulin resistance significantly decreased during the treatment. Low AMH levels, high HOMA index, and the presence of oligomenorrhea at the first visit were the independent predictors of obtaining regular menstrual cycle with DCI. In conclusion, the use of DCI is associated to clinical benefits for many women affected by PCOS including the improvement in insulin resistance and menstrual cycle regularity. Responders to the treatment may be identified on the basis of menstrual irregularity and hormonal or metabolic markers.

myo-inositol 

Gynecol Endocrinol. 2014 Sep 26:1-5. [Epub ahead of print] Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance. Kamenov Z1, Kolarov G, Gateva A, Carlomagno G, Genazzani AD. PMID: 25259724

...The aim of the present study is to evaluate the effectiveness of myo-inositol alone or in combination with clomiphene citrate for (1) induction of ovulation and (2) pregnancy rate in anovulatory women with PCOS and proven insulin resistance. Patients and methods: This study included 50 anovulatory PCOS patients with insulin resistance. All of them received myo-inositol during three spontaneous cycles. If patients remained anovulatory and/or no pregnancy was achieved, combination of myo-inositol and clomiphene citrate was used in the next three cycles. Ovulation and pregnancy rate, changes in body mass index (BMI) and homeostatic model assessment (HOMA) index and the rate of adverse events were assessed. Results: After myo-inositol treatment, ovulation was present in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 myo-inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant. During follow-up, a reduction of body mass index and HOMA index was also observed. Conclusion: Myo-inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients.

Gynecol Endocrinol. 2013 Apr;29(4):375-9. doi: 10.3109/09513590.2012.743020. Epub 2013 Jan 22. Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Artini PG1, Di Berardino OM, Papini F, Genazzani AD, Simi G, Ruggiero M, Cela V. PMID: 23336594

...50 overweight PCOS patients...underwent hormonal evaluations and an oral glucose tolerance test (OGTT) before and after 12 weeks of therapy (Group A (n¼10): MYO 2 g plus folic acid 200 mg every day; Group B (n¼10): folic acid 200 mg every day). Ultrasound examinations and Ferriman-Gallwey score were also performed... RESULTS: After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the patients treated with folic acid. CONCLUSIONS: MYO administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.

Combined Therapy (MI plus DCI)

J Clin Pharmacol. 2014 Oct;54(10):1079-92. doi: 10.1002/jcph.362. Epub 2014 Jul 18. The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. Dinicola S1, Chiu TT, Unfer V, Carlomagno G, Bizzarri M. PMID: 25042908

...Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.

Eur Rev Med Pharmacol Sci. 2013 Feb;17(4):537-40. The Combined therapy myo-inositol plus D-Chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. Minozzi M1, Nordio M, Pajalich R. PMID: 23467955

BACKGROUND: ...The aim of the present study was to evaluate whether the combined therapy myo-inositol plus D-chiro-inositol (in a in a physiological ratio of 40:1) improve the metabolic profile, therefore, reducing cardiovascular risk in PCOS patients. PATIENTS AND METHODS: Twenty obese PCOS patients [BMI 33.7 ± 6 kg/m2 (mean ± SD)] were recruited. The lipid profile was assessed by measuring total cholesterol, LDL, HDL and triglycerides before and after 6 months treatment with the combined therapy. Secondary end points included changes in BMI, waist-hip ratio, percentage of body fat, HOMA-IR and blood pressure. RESULTS: The combined therapy myo-inositol and D-chiro-inositol improved LDL levels (3.50 ± 0.8 mmol/L versus, 3 ± 1.2 mmol/L p < 0.05), HDL (1.1 mmol/L ± 0.3 versus 1.6 mmol/L ± 0.4 p < 0.05) and triglycerides (2.3 ± 1.5 mmol/L versus 1.75 ± 1.9 mmol/L p < 0.05). Furthermore, significant improvements in HOMA-IR were also observed. CONCLUSIONS: The combined therapy myo-inositol plus D-chiro-inositol is able to improve the metabolic profile of PCOS women, therefore, reducing the cardiovascular risk.

Monotherapy vs. Combined Therapy

Eur Rev Med Pharmacol Sci. 2012 May;16(5):575-81. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Nordio M1, Proietti E. PMID: 22774396

...In this study, we aim to verify whether the two molecules have a synergistic action by acting on their specific cellular pathways. The effectiveness in reducing the risk of metabolic syndrome as well as in enhancing the ovarian functions of a combined therapy with MI and DCI was compared to a mono therapy in a randomized controlled trial. METHODS: Fifty overweight women with PCOS were enrolled and divided in two groups to receive MI and DCL (MI+DCI group) or MI alone (MI group) for a period of six months. Baseline measurements were repeated at three months (T1) and at the end of the treatment (T2). RESULTS: At the end of the treatment, both MI and MI+DCI groups showed an improvement of the metabolic parameters and no significant differences were found. As expected, the combined supplementation with MI and DCI resulted to be more effective, compared to the MI group, after three months of treatment. CONCLUSIONS: The combined administration of MI and DCI in physiological plasma ratio (40:1) should be considered as the first line approach in PCOS overweight patients, being able to reduce the metabolic and clinical alteration of PCOS and, therefore, reduce the risk of metabolic syndrome.

Arch Gynecol Obstet. 2013 Dec;288(6):1405-11. doi: 10.1007/s00404-013-2855-3. Epub 2013 May 25. The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial. Colazingari S1, Treglia M, Najjar R, Bevilacqua A. PMID: 23708322

PURPOSE: The present study aims to investigate the effects of the combined therapy myo-inositol (MI) plus D-chiro-inositol (DCI) or D-chiro-inositol treatment in oocyte quality. METHODS: Polycystic ovary syndrome (PCOS) women undergoing IVF-ET were treated with myo-inositol combined with D-chiro-inositol in the physiological ratio (1.1 g myo-inositol plus 27.6 mg of D-chiro-inositol; INOFOLIC combi Lo.Li.pharma) or D-chiro-inositol alone (500 mg; Interquim, s.a., Barcelona, Spain) to evaluate the umber of morphological mature oocytes, total International Units (IU) of recombinant FSH administered and the number of grade 1 embryos. RESULTS: The data clearly showed that only the combined therapy was able to improve oocyte and embryo quality, as well as pregnancy rates, in PCOS women undergoing IVF-ET. CONCLUSION: The present paper further supports the hypothesis that MI plays a crucial role in the ovary in PCOS women. In particular, due to the physiological role played by MI and DCI, the combined therapy should represent a better choice.

PCOS and Diabetes: Glucose-Lowering Medication Options

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. Today, let's discuss the use of glucose-lowering medication options for those who have developed diabetes.

So far we've talked about PCOS's definition and symptoms, how it presents, its testing and diagnosis, and its possible causes. Now we are discussing common treatment protocols for PCOS, and the pros and cons of each.

We've already discussed insulin-sensitizing medications like metformin, the TZDs, and inositol.

Now let's chat about medication options for lowering blood sugar for those women with PCOS who have already developed diabetes. These drugs are not to treat PCOS per se, but to treat diabetes, which many women with PCOS develop at some point as they age.

Disclaimer: I am not a medical health-care professional. While the following information is based on my best understanding of the research, always do your own research. This information is not a complete explanation of all the risks and benefits of a particular medication, nor is it medical advice about a health condition or treatment. Consult your healthcare provider before making any decisions about your care plan.

Trigger Warning: Passing mention of the possible weight effects of several medications, and a mention of the emphasis on weight loss in typical diabetes treatment.

Introduction

How different blood sugar medications affect the body

It is an unfortunate truth that many women with PCOS will probably develop full-blown diabetes at some point in their lives. As a result, women with PCOS often need to inform themselves about diabetes medication choices. This post is designed to help with that process.

For a long time, doctors had few choices for medicines to treat Type 2 diabetes. In the past 20 years, however, their choices have greatly expanded. Now there are so many choices, it's hard to know which is the best choice for any one person. Negotiating this maze can be confusing for care providers, let alone consumers.

But basically, diabetes medications attempt to address the two main problems of type 2 diabetes:

1. Insulin Resistance, which makes it hard for the body to utilize its own insulin optimally
2. Pancreatic Beta Cell Defects, which makes it hard for the body to produce enough insulin for its needs

Most diabetes medications reduce blood sugar by either reducing insulin resistance, stimulating the body's own insulin secretion, or by delaying carbohydrate absorption.

Remember, diabetes is usually a progressive condition. What works at first to control blood sugar will gradually become less effective. Treatment must change over time to reflect the needs of the patient.

Lifestyle changes can be helpful for some at first, but eventually most diabetics need medication. This post will discuss diabetes drug options, including some of the newer medications. However, it is not meant to be a complete discussion of these options; rather, it is an introduction to some of the more common options out there.

The most common medications used to control high blood sugar include:

• Insulin Sensitizers - medications to lessen insulin resistance 
• Secretagogues - medications to force the pancreas to secrete more insulin 
• Alpha-Glucosidase Inhibitors - medications to delay carbohydrate digestion
• Incretin Mimetics - synthetic gut hormones to increase insulin production, but only in response to high blood sugar (technically also a secretagogue, but by a different means)

There are other drugs that control blood sugar in other ways, but they are less common and will not be covered in this post.

Because each person has unique needs, conditions, and reactions to medications, it's very important to consult closely with your care provider when developing your care plan.

If you find your care provider is not listening to you or treats you poorly because of your size or PCOS status, then vote with your feet and find a new care provider. The last thing you should do is go without care or put up with suboptimal care.

Managing diabetes is not an easy task, but it is critical to your long-term health. Therefore it's important that you have a care provider you can trust, who truly has your best interests at heart, and who listens to your input. Keep searching till you find one of these.

Insulin Sensitizers

Over time, many people become resistant to their own insulin, causing the body to try to crank out more and more insulin to compensate. Eventually, the pancreas can no longer produce enough of its own insulin to keep blood sugar normal. Blood sugar rises and complications start to develop.

Rather than keep on adding more insulin to the mix, one of the most logical diabetes treatments is to encourage the body to use its own insulin more efficiently.

Exercise is one of the best ways to improve insulin sensitivity, so regular exercise (both aerobic and weight training) is one of the rock-solid pillars of diabetes treatment. Research shows that exercise alone can lower blood sugar significantly, sometimes by 0.5 - 1% of the HbA1c reading. This is as good as some diabetes medications.

However, as diabetes progresses, exercise alone may not be enough. Insulin-sensitizing medications can help. It used to be that these were only prescribed once a trial of diet and exercise had failed to keep blood sugar normal. Now, however, the standard of care is to start an insulin-sensitizing medication along with diet and exercise as soon as diabetes is diagnosed. Outcomes seem to be better by starting multiple modes of care at once.

[Note ─ "diet" in this context does not have to mean a low-calorie or reducing diet, but rather a way of managing food intake that keeps the blood sugar as normal and as stable as possible. This has more to do with timing, choice, and combination of foods than anything else.]

Of course, Insulin Resistance (IR) is not just a problem of diabetes; it is also one of the primary problems in PCOS. Most women with PCOS have hyperinsulinemia (too much insulin), probably caused by problems with insulin signaling pathways or insulin receptor defects. The theory is that by encouraging the body to use its own insulin better, some of the hormonal imbalances of PCOS may be lessened.

As a result, insulin-sensitizing drugs are a cornerstone of therapy for both women with PCOS and Type 2 Diabetics.

As we've mentioned before, there are two main drug classes used to improve insulin sensitivity, the biguanides and the thiazolidinediones (also known as glitazones or TZDs).

The primary insulin-sensitivity drugs on the market today are the biguanide Glucophage (metformin) and two TZDs, Avandia (rosiglitazone) and Actos (pioglitazone). Because these drug classes have been extensively discussed in previous posts, they will only be briefly summarized here.

Metformin is the first-line treatment of choice in diabetes. It works primarily by decreasing glucose output by the liver, but also improves insulin sensitivity elsewhere in the body.

Its long record of safety and efficacy makes metformin an excellent choice for most diabetics, despite the G.I. side effects that some people experience. It is inexpensive and extremely effective, lowering A1c blood sugar on by about 1-2% on average. It has been shown to improve not only clinical risk factors, but also long-term outcomes (endpoints like cardiovascular events and death). This is a huge advantage that no other diabetes drug can claim at this time.

Because of its effectiveness against insulin resistance, many care providers also prescribe metformin for women with PCOS. Although not every care provider agrees, many care providers see metformin as the drug of choice for PCOS, regardless of glucose status. Certainly, in pre-diabetic and diabetic women with PCOS, it is the first drug that should be tried.

Another effective insulin-sensitizer is the family of TZDs (glitzaones). TZDs also are extremely effective at reducing blood sugar, also around 1-2% A1c on average, and improve symptoms of PCOS. They often work in people who are resistant to metformin.

TZDs improve glucose uptake and insulin sensitivity in muscle and fat tissue in the body. They work by stimulating peroxisome proliferator-activated receptors (PPARs); most of the current generation of TZDs stimulate the PPAR-gamma receptor. Future generations of TZDs may stimulate other PPAR receptors (or multiple receptors).

Unfortunately, the current generation of TZDs have been associated with increased cardiovascular risk or liver toxicity; Rezulin (troglitazone) was pulled from the market, and Avandia (rosiglitazone) has been restricted in some countries. On the other hand, Actos (pioglitazone) so far seems to have fewer side effects and is still in regular use.

In addition to metformin and the TZDs, an emerging class of insulin-sensitizers are the inositols (myo-inositol, d-chiro inositol). Inositols work by improving insulin signaling, which helps the body use its own insulin more effectively. They seem particularly effective for women with PCOS. They received a lot of buzz at first and are now experiencing a resurgence of interest, but research is still emerging on their safety and efficacy.

Metformin, TZDs, and inositols are all used in women with PCOS, although their use in those who still have normal blood sugar is controversial. Some care providers feel they should be reserved only for those who have developed diabetes, while others feel that they should be utilized long before diabetes develops in order to help prevent or delay it, as well as to minimize symptoms of PCOS.

Regardless, insulin sensitizers are one of the most important medications for both PCOS and diabetes, because they help the body use its own insulin more efficiently. This is the first and most important goal for clinicians to address.

Insulin Secretagogues: Increasing Insulin Production

There are several classes of drugs commonly used to lower blood sugar in diabetics. One of the oldest is the secretagogues, including sulfonylureas and meglitinides. These work in a different way than the insulin-sensitizing drugs.

Remember, in Type 2 diabetes, the problem is usually both insulin resistance and a relative shortfall of insulin relative to the body's needs. It's not just the body's resistance to its own insulin, but also that the pancreas cannot produce enough to compensate, either because of an inborn beta cell defect or because the pancreas has exhausted itself.

The secretagogues work on this problem by forcing the pancreas to produce more insulin, which in turn, helps to lower blood sugar. If there is enough pancreatic beta cell reserve, these drugs can work quite well. If there is not enough pancreatic beta cell reserve, however, these medicines don't work very well.

Use of secretagogues is controversial in women with PCOS. These drugs do not reduce the hyperinsulinemia of PCOS and may actually worsen outcomes because they force the pancreas to produce more insulin. However, because high blood sugar causes so much damage in the body, they are often still used with diabetics (PCOS or not) if normal blood sugar cannot be achieved on metformin or a TZD alone.

Sulfonylureas are the most common secretagogue and were the first widely-used oral anti-diabetes medication. Modern versions include drugs like glimepiride, gliclazide, glibenclamide (glyburide), and glipizide. An older version that is still sometimes used is tolbutamide.

The advantages of sulfonylureas are that they are extremely effective at lowering blood sugar and are available in generic forms so they are very affordable. They work quickly, are taken orally, and are easy to dose.

The side effects of sulfonylureas nearly always include some weight gain and periodic episodes of low blood sugar (hypoglycemia) as a result of the increased insulin. Hypoglycemic episodes can be dangerous, so this is a serious side effect that must be watched for carefully. A regular meal schedule is important, and meals should not be delayed or skipped.

Sulfonylureas are often quite effective at lowering blood sugar at first but lose their efficacy over time as the pancreas exhausts itself from producing more and more insulin. They may also increase the risk of poor long-term outcomes like cardiovascular disease and cancer-related mortality compared to treatment with metformin. This is a serious disadvantage, but the risk may vary strongly by which sulfonylurea is used.

Meglitinides are another medication that make the pancreas produce more insulin. These drugs include repaglinide (Prandin) and nateglinide (Starlix). They are similar to sulfonylureas but work on a different binding site in the pancreatic beta cells. They also differ in how they are excreted and how long their effects last.

Meglitinides have side effects similar to the sulfonylureas, including weight gain and low blood sugar episodes. However, the side effects are usually less severe than with the sulfonylureas. They are taken shortly before meals, have a quick effect on insulin production, and are particularly helpful in lowering postprandial blood sugar (the rise in blood sugar after eating). This can be a key advantage for people who have normal fastings but significantly raised postprandial readings.

Repaglinide has been shown to be effective in lowering blood sugar, even in elderly patients and in those with kidney disease. It is usually used in combination with metformin and has been shown to be more effective than metformin alone. However, its disadvantage is that it is expensive and can result in low blood sugar episodes.

Obviously, medications that increase insulin production are not ideal for most women with PCOS, since they already produce far too much insulin. These medications can temporarily improve blood sugar but may worsen PCOS symptoms. This is why the first-choice drugs for diabetic women with PCOS are usually insulin-sensitizers.

However, sulfonylureas and meglitinides are very effective at lowering blood sugar long-term, and are usually fairly well tolerated. Thus, they are often part of diabetes treatment, even in women with PCOS, because as diabetes progresses, keeping blood sugars as normal as possible will hopefully help prevent the most serious complications of diabetes, like heart disease, stroke, neuropathy, or eye damage. This may be worth the trade-off of possibly worsening PCOS symptoms.

Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors are another medication option for diabetics.

This group includes acarbose (Precose) and miglitol (Glyset). These are oral medications and should be taken with the first bite of each meal. They inhibit the production of alpha-glucosidase enzymes, which are intestinal enzymes needed to digest carbohydrates.

These medications act by delaying carbohydrate absorption, which can help lower blood sugar. They also lower insulin levels somewhat. They primarily affect post-meal blood sugar levels because they inhibit the enzymes close to the stomach and delay carbohydrate digestion to lower in the intestines. Blood sugar will still go up, but much more slowly and evenly, which will also help blunt the insulin surge the body produces in response to a quick rise in blood sugar.

However, these medications don't lower blood sugar all that much. Some sources state that they lower the HbA1c only by 0.5 - 0.8%. They have little effect on lipids or bodyweight. The effect, if any, on mortality or cardiovascular events is unclear.

The good news is that this medication does not increase insulin secretion in the pancreas, so it should not add to hyperinsulinemia problems in women with PCOS. Because it doesn't increase insulin production, it doesn't usually cause low blood sugar episodes or weight gain unless combined with a sulfonylurea or meglitinide. Another advantage is that acarbose has been on the market since 1995 and an affordable generic form is available.

The bad news is that because it delays carbohydrate absorption, it has lots of G.I. side effects, including diarrhea and gas/bloating. In one study, as many as 50% of people who took these medications experienced significant G.I. symptoms, although this number decreased to 14% over time.

More is not better; high doses result in more G.I. side effects without an increase in efficacy. If you are prescribed acarbose, slowly increasing the medication dosage over time and reducing the amount of carbohydrate in a meal may help reduce G.I. side effects.

Because of the G.I. side effects, it should not be prescribed to people with Inflammatory Bowel Disease or Crohn's Disease. Hepatitis may also occur, so liver enzymes must be monitored while on this drug.

Because it offers only mild advantages in exchange for significant side effects, this medication is not used as much as other diabetes medications, but it can be used in combination with them to improve blood sugar via multiple pathways.

It seems most useful for those who are recently diagnosed with diabetes and those who have normal fasting blood sugars and only mildly-elevated post-meal readings.

Incretin Mimetics

Image from Gallwitz 2010

A fairly new but much-heralded class of anti-diabetes drugs includes the incretin mimetics.

Incretins are G.I. hormones like glucagon-like peptide (GLP-1) that are produced by your own body. They help your body respond to glucose production from food. They are responsible for much of your insulin response to food intake.

Incretin mimetics are a man-made version of these G.I. hormones, synthesized from other substances. They are designed to work like your body's own incretins, but to have a longer-lasting effect.

Technically, incretin mimetics are also a secretagogue because they help the body produce more insulin, but are generally discussed separately from sulfonylureas and meglitinides because they act only in response to raised blood sugar. 

Once your blood sugar is normal, the action of incretin mimetics shuts off, making low blood sugar episodes less likely. Sulfonylureas, on the other hand, cause your pancreas to keep churning out insulin no matter what your blood sugar is doing, making low blood sugar episodes more likely. This is a very important distinction.

Your own gut incretins work by causing your pancreatic beta cells to release more insulin, by inhibiting glucagon release from pancreatic alpha cells (thereby keeping your liver from dumping its stored glucose into your body), and by slowing absorption of nutrients into the blood stream by reducing gastric emptying.

Incretins also increase pancreatic beta cell proliferation, lessen beta cell death, and improve first-phase insulin release. 

In other words, they help the pancreas work more quickly and efficiently, and they help preserve pancreatic function longer. This is a huge benefit. They are the only medication that is thought to help keep or even improve beta cell function, which may delay or keep diabetes from progressing so quickly.

The problem with your own body's incretins is that their effect doesn't last long; they work for just a few minutes and then they are blocked by DPP-4 enzymes. So for a long time, incretins really weren't that useful for helping to control blood sugar in diabetics; you'd have to receive a continuous infusion for them to help.

But now there are incretin mimetics, synthesized from other sources, that are similar to your own incretins but changed just enough to be effective. They are called "mimetics" because they mimic the action of your own G.I. incretin hormones, but are not quite the same because they make the effect last longer. Incretin mimetics include:

• GLP-1 receptor agonists
• GLP-1 analogs
• DPP-4 inhibitors

GLP-1 Receptor Agonists are the most common form of incretin mimetics. They are a protein, so if they were taken orally, they would be digested. Therefore, they must be injected in order to be effective.

Byetta (exenatide) is a synthetic version of a substance found in the saliva of Gila monster lizards. It is a GLP-1 receptor agonist that is just different enough from your own body's GLP-1 that it is absorbed more slowly. It can lower A1c numbers by up to 1.5%, which is quite significant.

Byetta must be injected twice a day, preferably an hour before breakfast and dinner. It slows down the progression of food or medicines through the intestinal tract, so any oral medications should be taken an hour before Byetta is injected.

Like insulin, it should be kept out of hot temperatures and direct sunlight. The manufacturer recommends refrigerating it until it is first opened, then storing it in a cool area for up to 30 days.

Byetta's G.I. side effects include nausea, vomiting, and diarrhea. Many people report a feeling of fullness, stomach discomfort, and nausea when first starting the drug. These effects are reduced after a few weeks, but may recur periodically.

Byetta is excreted via the kidneys and so should not be used in people with severe kidney disease. It can sometimes cause headaches, sweating, acid reflux, or thyroid issues. It has been under close scrutiny for a possible increase in pancreatitis, and should not be prescribed to anyone with a history of pancreatic issues, alcohol abuse, or a family history of thyroid cancer.

Doctors like Byetta because it often results in a small weight loss (about 2-10 lbs.), and can be used in conjunction with metformin, TZDs, or sulfonylureas. The main disadvantage to Byetta is that it must be injected, and multiple times per day at that.

The drug companies have responded to this concern by creating a long-acting version (Bydureon); patients only have to inject it once a week instead of twice a day. So far, the long-acting version seems to improve blood sugar better and reduce some G.I. issues, but longer trials are needed.

Victoza (liraglutide) is a GLP-1 analog. It is structurally very close to the GLP-1 hormone that naturally occurs in the human body.

Its main advantages are that it only has to be injected once per day, without regard to time of day or mealtimes, and it has a low rate of low blood sugar episodes. It also improves triglyceride levels better than Byetta, although whether this has any long-term effect on cardiovascular events is unknown.

Its main side effect is mild nausea. Some studies suggest it may lower blood sugar even more than Byetta. It has also been shown to lower blood pressure and sometimes result in a small amount of weight loss. However, it is a newer drug (FDA-approved in 2010) and only time will tell how safe it is.

So far, the GLP-1 drugs do not seem to increase cardiovascular risk in the short term (and may help decrease blood pressure and cholesterol), but more research is needed to confirm this and to investigate its long-term effects.

Like Byetta, Victoza should not be prescribed to people with a history of pancreatitis or thyroid cancer. Caution should also be taken in people with a history of gallstones.

DPP-4 inhibitors act by inhibiting the enzyme that inactivates the body's own GLP-1, thus increasing your own GLP-1's length of effect in the body.

Januvia (sitagliptin) is the most famous of the DPP-4 inhibitors, although there are others as well (saxagliptin/Onglyza, vildagliptin/Galvus, and linagliptin/Tradjenta). Januvia was approved by the FDA in 2006.

The main advantage of DPP-4 inhibitors is that they can be taken orally, as opposed to the GLP-1 drugs which must be injected. DPP-4 inhibitors also result in less nausea and so are better tolerated by many patients.

However, they do not decrease blood sugar as well as GLP-1 drugs, and they are usually weight neutral (no gain but also no loss, which of course most doctors see as a disadvantage). Other side effects include an increased reporting of respiratory infections and cold-like symptoms with nearly all the DPP-4 inhibitors. Headaches may also be increased.

On the other hand, when combined with metformin, DPP-4 inhibitors improved post-meal blood sugars far better than metformin alone, which also improves long-term blood sugars (A1c) more efficiently.

One of the most exciting potential effects of DPP-4 inhibitors is that they are thought to preserve or even improve pancreatic function, thus maintaining the patient's own insulin function over time. Since the progression of diabetes involves declining pancreatic function, DPP-4 inhibitors are sometimes prescribed early on in the treatment of diabetes, either as a stand-alone therapy or in combination with metformin or TZDs, in order to delay the progression of diabetes and give the patient more time before drugs with more serious side effects are needed.

A recent drug trial found that DPP-4 inhibitors did not increase the risks of heart attack, pancreatic inflammation or cancer, but may modestly increase the risk for heart failure. They should not be prescribed in conjunction with sulfonylureas but, as noted, may be prescribed with metformin or the TZDs.

All in all, the incretin mimetics seem to be a major advance in treating diabetes, especially when other treatment options (like metformin) aren't enough. They effectively lower blood sugar, and have modest beneficial effects on blood pressure, insulin sensitivity, cardiovascular risks, and other clinical goals. Many clinical guidelines now promote early use of incretin mimetics, rather than waiting until the diabetes has progressed.

However, they are a relatively young drug class, so more research is needed. They may raise the risk for thyroid cancer, for example. Since each drug presents its own unique profile of benefits and risks, careful clinical judgment is needed to individualize their usage appropriately.

The other major disadvantage of the incretin mimetics is that they are very expensive (several hundred dollars a month, usually), and many insurance plans do not cover them.

Combination Drugs

Image from Medscape (link in references)

Diabetes treatment these days often combines two or more drugs together. Rather than using an ever-increasing dose of one drug, care providers often prescribe two drugs instead to work on blood sugar in different ways and therefore lower blood sugar more effectively.

This combination therapy offers a distinct advantage in that it targets not only insulin resistance, but also pancreatic beta cell function and hepatic (liver) glucose production.

Combination therapy often has better results than monotherapy. Research shows that more patients reach blood sugar target ranges when two drugs are used than when one drug is used at a higher dose.

Combining two medications into one pill also makes it simpler and more convenient for the consumer, making them more willing to take the drugs as needed. Furthermore, the drug company is able to hold onto exclusive patent use longer for the drugs, thus prolonging their profit margins.

Time will tell if these combination therapies truly improve long-term outcomes better than monotherapy, but so far results seem promising. Here are some common combination drugs:

• Metaglip is a combination of metformin and the sulfonylurea glipizide (a generic form is available)
• Glucovance is a combination of metformin and the sulfonylurea glyburide (a generic form is available)
• Janumet is a combination of metformin and the DPP-4 inhibitor sitagliptin/Januvia

The Importance of Reducing Stigma

The bottom line is that women with PCOS are profoundly vulnerable to developing Type 2 diabetes at some point in their lives and thus need good information about the latest diabetes drug choices.

It should be pointed out that this tendency towards diabetes does not reflect a lack of willpower or a poor lifestyle, but rather the underlying metabolic issues of PCOS. This cannot be emphasized enough.

In our society, there is far too much shaming and blaming around the development of Type 2 Diabetes. This leads many people to put off or avoid medical treatment until their blood sugar is very high or they have developed significant complications.

It also blames people for developing something that may have far more to do with an inborn metabolic defect than with their habits. Although poor habits can impact health and personal responsibility is important, there are many people with very poor habits who never develop diabetes, and some people with very reasonable habits who do develop diabetes. It's rarely related to only lifestyle, but more to a combination of factors, some of which are modifiable and some of which are not.

In the case of PCOS, there is almost certainly some sort of underlying metabolic defect that predisposes these patients to diabetes. Combine that with low pancreatic beta cell reserve, and you get early-onset diabetes that has nothing to do with habits or personal responsibility.

Careful attention to nutrition and exercise and use of some medications may help prevent or delay some cases but many women with PCOS will develop diabetes despite their best efforts. Therefore it's important to reduce the stigma of this diagnosis so it can be diagnosed quickly and treated effectively.

Finding diabetes early on can help delay the progression of diabetes, and may even prevent some of the more serious complications. It's important that women with PCOS feel comfortable in getting yearly blood sugar tests to make sure any problems are caught quickly, and that those who do develop diabetes get treatment that does not shame them or inhibit their willingness to pursue treatment. Yet far too many receive scoldings and blame and reluctance to prescribe any help except dieting.

The scoldings, shaming, and emphasis on weight loss at any cost causes many fat people to avoid or delay seeing a doctor. It should be pointed out that although weight loss is sometimes helpful to blood sugar in the short term, it often leads to regain and a higher weight than the patient began with. In addition, recent research suggests that it does not decrease cardiovascular events.

Care providers need to take a more nuanced view of weight loss as the foundation of diabetes prevention and treatment. While some patients will want to pursue weight loss, others will not because they do not want to risk rebound weight cycling or because they are concerned about developing disordered eating patterns. Opting out of weight loss treatment can be a legitimate choice and should be respected by care providers.

It's important for patients to know that lifestyle tweaks (like increasing exercise or lowering carbohydrate intake) can often improve blood sugar and other risk factors significantly, independent of weight loss. Lifestyle tweaks do not have to involve weight loss to be effective. Care providers need to incorporate more Health At Every Size models that emphasize healthy habits and improving lab numbers instead of focusing only on the scale.

The current stigma around the diagnosis and treatment of Type 2 diabetes just adds to the disease burden felt by people with diabetes and PCOS, and may well backfire in trying to improve outcomes in this group.*

Summary of Diabetes Medication Options

Image from Medscape and Joslin Diabetes Center

The good news is that people with diabetes are living longer and with a better quality of life now, thanks to easier self-monitoring and better medication options.

However, it is very difficult to find the "perfect" diabetes drug because there are so many competing priorities. You need a drug that:

• reduces insulin resistance
• improves pancreatic beta cell function
• reduces blood sugar, both fasting and after meals
• reduces the average blood sugar over time (A1c)
• does not cause low blood sugar episodes
• does not have side effects (or only mild side effects)
• does not cause weight gain
• delays the progression of diabetes
• is safe for people with kidney or liver impairment
• does not have many drug interactions, especially with blood pressure or lipid drugs
• is easy to take (preferably once daily)
• is not too expensive
• is covered by most insurance

Unfortunately, there is no drug that meets all of these criteria. All involve a trade-off of some sort. This is the challenge of treating diabetes, to find the "sweet spot" of treatment that involves the most benefits for the fewest risks.

What's most important is that blood sugar is lowered. That is the most important goal of diabetes treatment, and patients may have to accept some side effects or disadvantages in order to achieve this most basic goal. What side effects or trade-offs are acceptable, however, will differ from person to person.

Because of decreasing pancreatic function leads to diabetes progression, sooner or later nearly everyone with diabetes is going to need some sort of medication. 

Which drug is used will depend on how high your blood sugar is, what additional complications you may have developed, what other medications you may be on, the side effects you experience, and how you respond to the various options. An individualized treatment plan is important and will change over time in response to your condition.

The medication uniformly recommended as the first-line choice of therapy in diabetes is metformin. It is comparatively safe and well-tolerated, and is quite effective at lowering A1c levels. In addition, it works to increase insulin sensitivity, which in turn seems to improve long-term outcomes, including cardiovascular disease and death.

TZDs are another insulin-sensitizing medication which can be used in patients who do not tolerate metformin or who are metformin-resistant. Many people with severe diabetes are able to normalize their blood sugar with a combination of metformin and a TZD. However, TZDs come with significant risks, including edema, liver issues, and heart failure. They should only be used with caution.

The inositols are another option for lessening blood sugar and improving insulin sensitivity. D-chiro-inositol seems to be more effective for this than myo-inositol, and may be particularly effective for women with PCOS. However, studies so far are small and of uneven quality. It is also not clear how inositols may interact with other medications. Research is ongoing.

Secretagogues such as sulfonylureas and meglitinides can be used in addition to metformin or a TZD. They work by forcing the body to continually produce more insulin. They are extremely effective in lowering blood sugar in those people with significant pancreatic reserves. However, these drugs have substantial side effects, and they may increase the risk for cancer and cardiovascular issues. Because they increase insulin production and most women with PCOS already have too much insulin, their use in PCOS is more questionable but cannot be ruled out.

Alpha-glucosidase inhibitors like acarbose slow down digestion of carbohydrates enough to blunt post-meal blood sugars significantly. Although they do not lower blood sugar as much as some other medications, they can still be useful for some patients, especially early in the course of diabetes.

Incretin mimetics are a fairly new class of drugs and we are still learning about their risks and benefits. Thus far, they are a very promising addition to diabetes treatments but longer-term research is needed.

DPP-4 inhibitors are often prescribed to newly diagnosed diabetics nowadays because they are thought to preserve pancreatic function fairly effectively. However, they are not as effective at lowering blood sugar, so they are usually prescribed in conjunction with metformin or a TZD.

GLP-1 agonists and analogs are injectable medications that mimic your own body's GLP-1 proteins but their effect lasts longer. Like sulfonylureas, they increase insulin secretion, but unlike sulfonylureas, they shut off when normal blood sugar is reached, decreasing the risk for low blood sugar episodes. They are often utilized when other medications start being less effective.

These are the main types of glucose-lowering medications on the market today. There are other types of glucose-lowering drugs (for example, SGLT-2 inhibitors, dual PPAR agonists, amylin agonist analogs), but those are much less commonly used or are very new to the market. In most cases, the drugs discussed earlier are the main diabetes medications you will encounter right now.

However, there are sure to be new drugs in the future, so it's important to keep on top of the latest research. When considering a new drug, remember that medications are always a work in progress. Serious side effects may not become apparent until population-wide use, like with some of the TZDs. So while many of these newer medications have great advantages, long-term use may turn up problems currently unknown to us.

And of course, even the best medications always have pros and cons, risks and benefits. The complete profile must be considered when deciding on a treatment plan. Sometimes a known risk is worth taking if the advantages of the medication are strong enough, but this trade-off can only be judged on an individual basis.

Another important point is that people respond differently to drugs. One woman may do extremely well on metformin with minimal side effects, while another cannot tolerate the G.I. side effects. Another may need metformin plus additional drugs in order to achieve normal blood sugar and reduce long-term complications. Still others may be able to achieve good results with only lifestyle, herbs, or alternative medicine options.

There is no one standardized treatment that is right for everyone. That's why it's so important to discuss the benefits and risks of all your treatment options with a trusted care provider. Do your research so you can become a partner in your own care.

Remember, a big limitation on our discussion here is that we do not have much information on the use of these drugs for women with PCOS. Most of the information we have on these drugs has been done on the type 2 diabetes population only, so their effect on diabetic women with PCOS is often speculative.

The bottom line is that data on the long-term efficacy and safety of these drugs in PCOS populations is urgently needed. 



References

*See the links in the post for many further references. Be aware that many of these references are very mainstream and so strongly promote weight loss as "the" treatment of choice.

Overview of Various Diabetes Medications

Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Mar. Report No.: 11-EHC038-EF.
AHRQ Comparative Effectiveness Reviews.  PMID: 21735563

...The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. RESULTS: The review included 140 randomized controlled trials and 26 observational studies..Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users...Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.

Links with Information on Various Diabetes Medications

• http://en.wikipedia.org/wiki/Anti-diabetic_medication - summary from Wikipedia about various anti-diabetic medications available
• http://en.wikipedia.org/wiki/Meglitinide - information from Wikipedia on meglitinides
• http://en.wikipedia.org/wiki/Sulfonylurea - information from Wikipedia on sulfonylureas
• http://www.health.com/health/condition-article/0,,20189203,00.html - information about incretin mimetics and how they work on blood sugar
• http://jcem.endojournals.org/content/92/4/0.1.full - information on incretin mimetics
• http://www.diabetesnet.com/about-diabetes/diabetes-medications/incretins - information on incretin mimetic medications
• http://www.medscape.org/viewarticle/558473 - lecture with powerpoint slides on the pros and cons of various diabetes medications

Alpha-Glucosidase Inhibitors

Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003639. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. PMID: 15846673

BACKGROUND: Alpha-glucosidase inhibitors such as acarbose or miglitol, have the potential to improve glycemic control in type 2 diabetes mellitus. The true value of these agents, especially in relation to diabetes related mortality and morbidity, has never been investigated in a systematic literature review and meta-analysis...MAIN RESULTS: We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life...AUTHORS' CONCLUSIONS: It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated hemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.

Incretin Mimetics

Rev Diabet Stud. 2008 Summer;5(2):73-94. doi: 10.1900/RDS.2008.5.73. Epub 2008 Aug 10.
Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors. Pratley RE, Gilbert M. PMID: 18795210

...Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.

Am J Manag Care. 2010 Aug;16(7 Suppl):S187-94. Incretin-based therapies in the management of type 2 diabetes: rationale and reality in a managed care setting. Garber AJ. PMID: 20809667

...The recently introduced incretin-based therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving beta-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin. Earlier and more frequent use of these incretin-based therapies is recommended in the treatment of type 2 diabetes, based on their overall safety and ability to achieve the glycosylated hemoglobin level goal. As such, both the American Diabetes Association and the American Association of Clinical Endocrinologists/ American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naive and previously treated patients. The AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy.

Further studies/information on Incretin Mimetics:

• http://www.ncbi.nlm.nih.gov/pubmed/22436069
• http://www.ncbi.nlm.nih.gov/pubmed/23263796
• http://www.ncbi.nlm.nih.gov/pubmed/22471248
• http://www.ncbi.nlm.nih.gov/pubmed/22804841
• http://www.ncbi.nlm.nih.gov/pubmed/23550180
• http://www.ncbi.nlm.nih.gov/pubmed/20646668
• http://forecast.diabetes.org/medications-jun2012
• http://www.diabetesnet.com/about-diabetes/diabetes-medications/incretins/glp-1-agonist

*To the trolls: No, I do not have diabetes at this time. I write about this topic because I know that with PCOS, I am very likely to develop diabetes at some point. I also write about it because I have seen good friends treated so poorly by care providers that their diabetes went undiagnosed or under-treated for too long. I write about this because women need better and less-judgmental information in order to optimize their outcomes and quality of life.