18 ms·

Rare genital defects seen in sons of men taking major diabetes drug

209 points by jimmy2020 5y ago

Gatsky 5y ago
> In the United States, prescriptions to 18- to 49-year-olds with type 2 diabetes grew from fewer than 2200 in 2000 to 768,000 in 2015. What the hell… that has to be a mistake? What is going on? Can poor lifestyle really cause this massive increase in young people with diabetes??
- TylerE 5y ago
  Despite being used in Europe since the '50s, Metformin wasn't introduced in the US until 1995.
  - Gatsky 5y ago
    Ah right, that is surprisingly late, and would likely explain the numbers.
- deleted 5y ago
  [deleted]
- lmkg 5y ago
  It's an increase in a particular treatment for a disease, which is only a contingent proxy for the disease itself. A change on that scale could plausibly be explained by a change in the standard approach to treatment or diagnostic criteria. Wouldn't be surprised if insurance played a role somehow.
- steanne 5y ago
  that doesn't say that diagnoses increased that much, just that this particular drug has become a much more popular way to treat it.
- refurb 5y ago
  Treatment guidelines change all the time. Last time I checked metformin is now the the 1st drug therapy for type II diabetes and even "pre-diabetes". It's basically "oh, your blood sugar might be an issue, let's start with metformin" where in the past it was "lets try a bunch of others things and just watch your levels for a bit"
  - alistairSH 5y ago
    This. I have a few family members who struggle with blood sugar levels. Their doctors are quick to turn to pills instead of lifestyle/diet and monitoring. Likely because lifestyle/diet changes are hard and not very successful. Most of them have managed to adapt and deal without the pills, but it does take regular monitoring and they're all still borderline (pre-diabetic, I think is the term).
ars 5y ago
"The researchers analyzed records from more than 1.1 million babies born in Denmark between 1997 and 2016, using the country’s comprehensive medical registries to connect data on births, paternal metformin prescriptions, and birth defects." Did they look for any defect correlated with any drug? Because if they did, random chance alone would find something. Anyone read the actual study?
- bencollier49 5y ago
  Hopefully if they didn't apply Bonferroni correction, the study wouldn't pass peer review.
- ImaCake 5y ago
  I sought it out after seeing this link and found it to be very unimpressive. Science would do well to delete this article spruiking pretty trash science. P-values seem to be carefully hidden (not in the tables) and as far I could tell were not passing FDR. A lot of models were displayed in various tables and very few of them even had OR CIs that didn't overlap 1.
golem14 5y ago
I don't get why this is called rare in the article. It's not called that in the actual study, so the article seems to do some editorializing: https://www.acpjournals.org/doi/10.7326/M21-4389 https://www.acpjournals.org/doi/10.7326/M21-4389 Looks like of the kids taken from dads taking metformin, .9% had a genital defect, which seems pretty high to me (defect in control is 0.24%). Granted, not as high as Thalidomide, but still, 9 in 1000 are not great odds.
- pxeger1 5y ago
  I think it means the genital defect is normally rare, but is much more common in these kids?
  - golem14 5y ago
    Even .24% isn't that rare. From NIH.gov: "In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the US."
    - ianai 5y ago
      That works out to 6.0341E-06%
      - eMSF 5y ago
        A condition which would affect 6e-6%, or 0.000006% of the US population (330M) would affect 20 persons. 200000/330M = 0.0006 = 0.06%.
        ccalloway 5y ago
        The deformity in the general population affects 0.24% of male babies, so 0.12% of the population.
        InitialLastName 5y ago
bayesian_horse 5y ago
This doesn't change that Metformin is an extremely useful drug. Even people without the official indication take it because it reduces propensity for weight gain and cancer. Maybe don't take it before trying to get pregnant. Also maybe this needs to get confirmed in larger studies and in other countries.
based69 5y ago
Obese women’s offspring have double the risk of hypospadius, and women having babies after 40 have 4x the risk of hypospadius. Metformin is a drug that men are probably 100x more likely to be on at 45 vs 25. Therefore men on metformin are far more likely to be reproducing with older (and likely obese) women. I’m not saying this explains all the correlation, I’m just saying if the study doesn’t really make a good effort at addressing these confounders, its not worth reading.
- lippel82 5y ago
  From the artcile: "The numbers were small — 13 metformin-exposed boys were born with genital defects. But after the researchers adjusted for factors including parental ages and maternal smoking status, they found a 3.39-fold rise in the odds of a genital defect. “The rate per se was surprisingly high,” Wensink says."
  - ovi256 5y ago
    > after the researchers adjusted for factors including parental ages and maternal smoking status The exact adjustments made can change the solidity of the finding into anything from "rock solid" to "complete trash". Seemingly solid studies are routinely trashed by third party method reviewers that the initial peer reviewers missed. So we'll know better when they get around to it.
  - carlmr 5y ago
    >But after the researchers adjusted for factors including parental ages and maternal smoking status, they found a 3.39-fold rise in the odds of a genital defect If they didn't adjust for obesity, then it's really pointless to attribute this to the drug. Age and smoking status is not enough.
    - rat9988 5y ago
      Why would you assume they didn't? They most likely did.
bsder 5y ago
Wait ... 86 million scrips for Metformin? Roughly 1 IN 3 people in the US? That can't possibly be right. What am I missing?
- RachelF 5y ago
  Patients will normally get multiple scripts per year. A typical script might only provide one month's worth of medication, perhaps with 3 to 6 "repeats" before needing a new script.
- sacred_numbers 5y ago
  A single patient may receive multiple prescriptions per year, so the number of patients will be lower than the number of prescriptions. According to this source the number of patients taking metformin is 17 million. https://clincalc.com/DrugStats/Drugs/Metformin https://clincalc.com/DrugStats/Drugs/Metformin
- SpodGaju 5y ago
DeWilde 5y ago
Metformin is also pretty bad when comes to impact to testosterone levels, at least in most men. The exact mechanism that this happens is that it saps the cholesterol from your blood. This cholesterol would otherwise be used for T production by the testes.
ImaCake 5y ago
Whatever your opinion on metformin this study is not really providing strong enough evidence to take seriously. No one should give it any attention, except the researchers who will try and do a better one next time and hopefully can prove/disprove this important hypothesis. The authors have done a lot of tests here. If you do enough tests, even on null data, you eventually get false positive results. Nevermind the effects of confounding which are difficult to control for effectively in a non-random study. The smallest p-value I could find was P = 0.012. Which is for "elevated birth defect fre- quencies among metformin-exposed offspring". This comes from a table with 6 rows of models with different OR values. Presumably they did have p-values testing if those ORs were statistically different from OR == 1. Which means one should adjust p-values by dividing the significance threshold by 6. So, 0.05/6 = 0.0083 which is smaller than 0.012. So I would be very hesitant to say that the evidence points to metformin really causing this. At least based on this study.
- rscho 5y ago
  The bonferoni correction is known to be overly restrictive, though. But yes, probably many more models were fit and results are questionable. The author will at least be able to claim a Science paper... Also, adjustment of the p-value doesn't do anything to solve the flaws of hypothesis testing. But that's another debate entirely.
  - dhmallon 5y ago
    I believe it was published in Annals of Internal Medicine (impact factor of ~4). The link is to a news article in Science discussing the paper.
    - rscho 5y ago
      Ah, then I understand better. Was wondering why such a paper would be in Science.
- arijun 5y ago
  Relevant xkcd: https://xkcd.com/882/ https://xkcd.com/882/
nisegami 5y ago
I'm 26 and have been on Metformin for almost a decade at this point and will probably be on it until I die. Thankfully though, children are not in my future.
- SpodGaju 5y ago
  Please get your serum zinc levels tested. I am saying this from experience and knowledge.
  - nisegami 5y ago
    I'm obese and of south asian ancestry, so there's no real question as to why my insulin sensitivity is shot, but I'll add zinc to the list next time I do bloodwork.
eric4smith 5y ago
It’s so interesting that type 2 diabetes is curable with diet. Type 1 is incurable. My point is that the psychology of eating is so strong that people would rather take a drug that pass on birth defects to the future than change eating habits. And I’m a person coming from struggling with just those habits. I think if someone could come up with a treatment to adjust mindsets - it would change healthcare forever and end the need for drugs like Metaform.
- macilacilove 5y ago
  Type 2 diabetes is not curable with diet. Some (but not all) cases of type 2 can be _prevented_ by proper diet (i.e. avoiding obesity). There is no known diet that cures any type of existing diabetes.
  - eric4smith 5y ago
    The thing is, Type 2 is not even a disease. Its just an imbalance of glucose. So there is really nothing to cure, its just about bringing back your blood glucose levels in balance so that the liver and pancreas can begin to function correctly again. Of course there could be irreversible damage to those organs and that would be really bad (Several relatives who died of this). But you are partly right. There can be remission and back to normal with lifestyle changes and Type 2. Substantial studies and clinical evidence shows this.
    - nradov 5y ago
      Type-2 diabetes is characterized more by insulin resistance than by an imbalance of glucose. And glucose isn't really something you "balance" in relation to another substance anyway. In order to be metabolically healthy you have to keep glucose levels in the appropriate range, and that will generally prevent the onset of insulin resistance.
  - nradov 5y ago
    Type-2 diabetes can't be cured, but it can be put into permanent remission with diet for many patients. Virta Health has peer-reviewed research supporting this approach. https://www.virtahealth.com/resource-type/research https://www.virtahealth.com/resource-type/research
Kalanos 5y ago
The anti-aging community is also studying metformin
SpodGaju 5y ago
My hypothesis is that a functional zinc deficiency is the cause of most cases of diabetes, and by taking metformin, it will at least, not correct a zinc deficiency, and probably make it worse. To begin I would like to share that I was born with an undecended testicle (cryptorchidism) that had to be removed surgically when I was 3. My brother was born with hypospadia. I have been studying the genetics and environmental issues around these for the last 15 years. I carry several high risk genes for diabetes but probably the most relevant is that I carry the homozygous risk alleles for rs2466293 in SLC30A8 which is a zinc transporters gene. So I absorb zinc more slowly than most people. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428214/ "Conclusion ZnT8A detection increases T1D diagnosis rate even in mixed populations. SLC30A8 rs2466293 was associated with T1D predisposition in non-European descents." I had my serum zinc tested and it was low. So now I need to take 240mg of Zinc Sulphate and eat a lot of oysters to keep my zinc levels up. I was diagnosed with Lupus and now I no longer present constant symptoms. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544280/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544280/ "Ikaros family zinc finger 1(IKZF1) encodes a lymphoid-restricted zinc finger transcription factor named Ikaros that regulates lymphocyte differentiation and proliferation as well as self-tolerance. Increasing evidence indicates that IKZF1 could contribute to the pathogenesis of autoimmune diseases." So also understand that my mother had diabetes, an immune disorder, and a mood disorder, all of them linked to zinc deficiency. So, in studies zinc deficiency has been linked to diabetes: https://www.mdpi.com/260782 https://www.mdpi.com/260782 "Zinc deficiency is a risk factor for obesity and diabetes." And genital abnormalities: (This is just one study, but there are hundreds like it.) https://www.karger.com/Article/Fulltext/441988 https://www.karger.com/Article/Fulltext/441988 "WT1 is a transcriptional regulator with various functions including signalling in both the embryonic kidneys and gonads. Mutations in this zinc finger transcription factor are associated with Denys-Drash or Frasier syndromes, which result in a broad range of malformations including hypospadias." So I do not think the problem is metformin. I think the problem is doctors not providing patients with diabetes a full nutritional workup and ignoring the role of nutrition in human health.
hirundo 5y ago
Metformin is the first resort in diabetes treatment. If it proves to truly increase birth defects by 40% that may have to change. It was my doctor's first resort for me, but the side effects were too severe and I stopped it. He vaguely mentioned that it would help if I lost weight, but made no mention of what actually resolved my diabetes, a low carb diet. I hope that becomes the first resort. Apparently around here it's not even in the standard toolkit.
- somenameforme 5y ago
  IMO relative percents should really not be used when trying to consider the impact of things because it gives you no clue about it. If the rate of something is 1 in 1 million then a 40% increase means your odds of having an issue go from negligible to negligible, but a 40% increase makes it sound much scarier. I think the reason for that is that a 40% increase subconsciously tickles our "40% of" intuition, even when we consciously understand that's not what it means. That said in this case the 40% is genuinely scary, because it's a jump from 3.3% with birth defects to 5.2%, or in other words nearly 1 in 50 babies (1.9% of births) standing to be affected by this issue. Although just quickly skimming their numbers, the sample size is unclear to me. That jump was driven by only 13 birth defects among those taking the drug, based on what the article says is a sample of 1.1 million births.
- bladley 5y ago
  The Diabetes Code is a great book about reversing diabetes through dietary intervention. The author discusses exactly what you're saying here: surprisingly few doctors know how effective a low-carb diet is at treating and curing type 2 diabetes.
  - hirundo 5y ago
    Agree. If you have diabetes I highly recommend making Jason Fung your doctor by reading his books, watching his videos, and taking his advice.
- Zircom 5y ago
  Unfortunately the vast vast majority of people won't commit to a big lifestyle change like that in the first place, and a big majority of the people that due end up not following through. So most doctors won't bother suggesting it as a legitimate option because for most people it kind of isn't.
chiefalchemist 5y ago
> "...because tens of millions of people worldwide take metformin, chiefly for type 2 diabetes." In nearly all cases, T2 is preventable. That is, unlike T1, there are things an individual can do to not reach T2.
- pdpi 5y ago
  Your point being…?
- woodruffw 5y ago
  On a micro level, most cases of T2 are preventable. On the macro level, many aren't: food deserts have higher rates of diabetes and heart disease, and the people who live in those areas are frequently "stuck" there for socioeconomic and racial reasons. There are also subgroup susceptibilities in play: Asians and people with Hispanic backgrounds are disproportionately represented among American T2 diabetics[1]. Recent studies suggest these groups are actually underdiagnosed still, since the dominant T2 tests are less reliable on them[2]. [1]: https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes-race-ethnicity.html https://www.cdc.gov/diabetes/library/socialmedia/infographic... [2]: https://jamanetwork.com/journals/jama/fullarticle/2757817?guestAccessKey=357114c9-93bb-459d-b78c-01867571ad41 https://jamanetwork.com/journals/jama/fullarticle/2757817?gu...
  - chiefalchemist 5y ago
    Yes. But again...food deserts - in the country that put a man on the moon - certainly solvable. And certainly such efforts are more ethical than rolling genetic defect dice. But we're led to believe it's Big Pharma or nothing? That's an injustice to Truth. https://www.ted.com/talks/ron_finley_a_guerrilla_gardener_in_south_central_la/transcript https://www.ted.com/talks/ron_finley_a_guerrilla_gardener_in...
  - idorosen 5y ago
    Thank you for the references.
- BurningFrog 5y ago
hombre_fatal 5y ago
I only knew Metformin by name from HNers using it as an anti-aging wonder drug over the years: https://hn.algolia.com/?dateRange=all&page=0&prefix=false&query=Metformin&sort=byPopularity&type=comment https://hn.algolia.com/?dateRange=all&page=0&prefix=false&qu...
- robbiep 5y ago
  It is also beginning to be prescribed by many of the subscription medication/doctor businesses that are springing up, powered by VC cash and looking to build strong forward flowing subscription businesses. Their model is: - find areas that aren’t medically serious (speaking relatively, and in relation to life threatening - erectile dysfunction and male pattern baldness) - run people through online questionnaires - get an online subscription runner stamped by a doc on their payroll - send out generic medications that they get cheap, package them nicely, and make bank on markup - catch them on the next condition they roll along to The last year I’ve seen a lot of them shifting into metformin (after finasteride and viagra/cialis) for weight loss
  - nradov 5y ago
    I expect those guys will start pushing SGLT2 inhibitors (gliflozins) next.
    - robbiep 5y ago
      I just discovered that apparently that is exactly what they’re doing, not metformin presently. And there a planned shift to GLP1s - but the injectables present some interesting administration aspects
  - freedomben 5y ago
    Do you see this as a bad thing? As someone who doesn't have any insurance, I'm extremely grateful for these. I don't want to have to go through the current medical racket where unless you pay a doc $300 you won't be allowed to purchase the medication you want. And then of course there's the follow up appointments, a "med check" where they can bill you $150 every 90 to 180 days just to hear you say, "yep, things are fine."
KMag 5y ago
Metformin is also sometimes used to induce ovulation in non-obese women of childbearing age with polycystic ovarian syndrome.[0] Luckily, this study seems to only show an effect if taken within the 90 day window before conception, so it seems to be doing something to the sperm, and not causing genetic changes. Also, of course, we'd want to see corroborating studies. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200666/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200666/
- cperciva 5y ago
  I think "sometimes" is a bit weak here. My second-hand understanding (from multiple women who have gone through this) is that it's routinely the very first treatment tried for women with PCOS who are having trouble conceiving.
- jessriedel 5y ago
  > it seems to be doing something to the sperm, and not causing genetic changes. To be clear, spermatogenesis takes roughly 75-120 days, so this is consistent with metformin causing genetic changes to the sperm when or after they are formed, with those genetic changes being propagated through the germ line to children conceived by the sperm. But it's true that the (very preliminary) data does not suggest that this is causing permanent genetic changes in the father.
mensetmanusman 5y ago
It’s sad seeing the crazy downstream multigenerational damage that massive sugar consumption is causing as obesity rates reach 50%. Good luck future humanity.
- akomtu 5y ago
  I believe this is intentional. If the ruling class wanted workers to live long, they'd force them to switch to oatmeals, fruits and water, while sugar would be a substance competing in price with cocaine.
  - ako 5y ago
    So the ruling class is forcing you to eat sugar, and you don't have the option to choose for healthier food?
    - alwillis 5y ago
      From a big picture, socio-economic point of view, yes, the ruling class (Fortune 500 CEOs and elected officials they donate to and lobby) are essentially forcing the poor, the unaware, the average Joe to eat a diet full of high-fructose corn syrup and other carbohydrates, which happens to be produced by giant agricultural companies. Corn is a subsidized crop by the US Department of Agriculture—we pay farmers to grow it. See the documentary "King Corn" about two guys who didn't know the first thing about growing corn but still made a profit on 1 acre of corn [1]. It's often said your zip code is a huge indicator of many demographic stats and what food you have access to is one of them. I've lived in food deserts and I can tell you getting healthy food can be quite an arduous task, especially if you rely on public transportation. Recent data shows that 80%(!) of black women in the United States are obese [2]. This isn't an organic phenomenon; this level of obesity is the result of a system—some intentional and some not—at work. [1]: https://www.kingcorn.net https://www.kingcorn.net [2]: https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=25 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=2...
      - inglor_cz 5y ago
willcipriano 5y ago
Any clues on the mechanism? Wouldn't this require altering the DNA of the sperm?
- bencollier49 5y ago
  It's possible that the mechanism is epigenetic, albeit unlikely. The sad truth is that this is probably now present in lots of genomes, and in the absence of eugenics or genome modification to correct the fault, will add to the slow and burgeoning medicalisation of the whole population, as the end of natural selection for baseline health multiplies disorders over time.

209 points by jimmy2020 5y ago

> In the United States, prescriptions to 18- to 49-year-olds with type 2 diabetes grew from fewer than 2200 in 2000 to 768,000 in 2015. What the hell… that has to be a mistake? What is going on? Can poor lifestyle really cause this massive increase in young people with diabetes??

TylerE 5y ago
Despite being used in Europe since the '50s, Metformin wasn't introduced in the US until 1995.
- Gatsky 5y ago
  Ah right, that is surprisingly late, and would likely explain the numbers.
deleted 5y ago
[deleted]
lmkg 5y ago
It's an increase in a particular treatment for a disease, which is only a contingent proxy for the disease itself. A change on that scale could plausibly be explained by a change in the standard approach to treatment or diagnostic criteria. Wouldn't be surprised if insurance played a role somehow.
steanne 5y ago
that doesn't say that diagnoses increased that much, just that this particular drug has become a much more popular way to treat it.
refurb 5y ago
Treatment guidelines change all the time. Last time I checked metformin is now the the 1st drug therapy for type II diabetes and even "pre-diabetes". It's basically "oh, your blood sugar might be an issue, let's start with metformin" where in the past it was "lets try a bunch of others things and just watch your levels for a bit"
- alistairSH 5y ago
  This. I have a few family members who struggle with blood sugar levels. Their doctors are quick to turn to pills instead of lifestyle/diet and monitoring. Likely because lifestyle/diet changes are hard and not very successful. Most of them have managed to adapt and deal without the pills, but it does take regular monitoring and they're all still borderline (pre-diabetic, I think is the term).

ars 5y ago

"The researchers analyzed records from more than 1.1 million babies born in Denmark between 1997 and 2016, using the country’s comprehensive medical registries to connect data on births, paternal metformin prescriptions, and birth defects." Did they look for any defect correlated with any drug? Because if they did, random chance alone would find something. Anyone read the actual study?

bencollier49 5y ago
Hopefully if they didn't apply Bonferroni correction, the study wouldn't pass peer review.
ImaCake 5y ago
I sought it out after seeing this link and found it to be very unimpressive. Science would do well to delete this article spruiking pretty trash science. P-values seem to be carefully hidden (not in the tables) and as far I could tell were not passing FDR. A lot of models were displayed in various tables and very few of them even had OR CIs that didn't overlap 1.

golem14 5y ago

I don't get why this is called rare in the article. It's not called that in the actual study, so the article seems to do some editorializing: https://www.acpjournals.org/doi/10.7326/M21-4389 https://www.acpjournals.org/doi/10.7326/M21-4389 Looks like of the kids taken from dads taking metformin, .9% had a genital defect, which seems pretty high to me (defect in control is 0.24%). Granted, not as high as Thalidomide, but still, 9 in 1000 are not great odds.

pxeger1 5y ago
I think it means the genital defect is normally rare, but is much more common in these kids?
- golem14 5y ago
  Even .24% isn't that rare. From NIH.gov: "In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the US."
  - ianai 5y ago
    That works out to 6.0341E-06%
    - eMSF 5y ago
      A condition which would affect 6e-6%, or 0.000006% of the US population (330M) would affect 20 persons. 200000/330M = 0.0006 = 0.06%.
      - ccalloway 5y ago
        The deformity in the general population affects 0.24% of male babies, so 0.12% of the population.
        InitialLastName 5y ago

bayesian_horse 5y ago

This doesn't change that Metformin is an extremely useful drug. Even people without the official indication take it because it reduces propensity for weight gain and cancer. Maybe don't take it before trying to get pregnant. Also maybe this needs to get confirmed in larger studies and in other countries.

based69 5y ago

Obese women’s offspring have double the risk of hypospadius, and women having babies after 40 have 4x the risk of hypospadius. Metformin is a drug that men are probably 100x more likely to be on at 45 vs 25. Therefore men on metformin are far more likely to be reproducing with older (and likely obese) women. I’m not saying this explains all the correlation, I’m just saying if the study doesn’t really make a good effort at addressing these confounders, its not worth reading.

lippel82 5y ago
From the artcile: "The numbers were small — 13 metformin-exposed boys were born with genital defects. But after the researchers adjusted for factors including parental ages and maternal smoking status, they found a 3.39-fold rise in the odds of a genital defect. “The rate per se was surprisingly high,” Wensink says."
- ovi256 5y ago
  > after the researchers adjusted for factors including parental ages and maternal smoking status The exact adjustments made can change the solidity of the finding into anything from "rock solid" to "complete trash". Seemingly solid studies are routinely trashed by third party method reviewers that the initial peer reviewers missed. So we'll know better when they get around to it.
- carlmr 5y ago
  >But after the researchers adjusted for factors including parental ages and maternal smoking status, they found a 3.39-fold rise in the odds of a genital defect If they didn't adjust for obesity, then it's really pointless to attribute this to the drug. Age and smoking status is not enough.
  - rat9988 5y ago
    Why would you assume they didn't? They most likely did.

bsder 5y ago

Wait ... 86 million scrips for Metformin? Roughly 1 IN 3 people in the US? That can't possibly be right. What am I missing?

RachelF 5y ago
Patients will normally get multiple scripts per year. A typical script might only provide one month's worth of medication, perhaps with 3 to 6 "repeats" before needing a new script.
sacred_numbers 5y ago
A single patient may receive multiple prescriptions per year, so the number of patients will be lower than the number of prescriptions. According to this source the number of patients taking metformin is 17 million. https://clincalc.com/DrugStats/Drugs/Metformin https://clincalc.com/DrugStats/Drugs/Metformin
SpodGaju 5y ago

DeWilde 5y ago

Metformin is also pretty bad when comes to impact to testosterone levels, at least in most men. The exact mechanism that this happens is that it saps the cholesterol from your blood. This cholesterol would otherwise be used for T production by the testes.

ImaCake 5y ago

Whatever your opinion on metformin this study is not really providing strong enough evidence to take seriously. No one should give it any attention, except the researchers who will try and do a better one next time and hopefully can prove/disprove this important hypothesis. The authors have done a lot of tests here. If you do enough tests, even on null data, you eventually get false positive results. Nevermind the effects of confounding which are difficult to control for effectively in a non-random study. The smallest p-value I could find was P = 0.012. Which is for "elevated birth defect fre- quencies among metformin-exposed offspring". This comes from a table with 6 rows of models with different OR values. Presumably they did have p-values testing if those ORs were statistically different from OR == 1. Which means one should adjust p-values by dividing the significance threshold by 6. So, 0.05/6 = 0.0083 which is smaller than 0.012. So I would be very hesitant to say that the evidence points to metformin really causing this. At least based on this study.

rscho 5y ago
The bonferoni correction is known to be overly restrictive, though. But yes, probably many more models were fit and results are questionable. The author will at least be able to claim a Science paper... Also, adjustment of the p-value doesn't do anything to solve the flaws of hypothesis testing. But that's another debate entirely.
- dhmallon 5y ago
  I believe it was published in Annals of Internal Medicine (impact factor of ~4). The link is to a news article in Science discussing the paper.
  - rscho 5y ago
    Ah, then I understand better. Was wondering why such a paper would be in Science.
arijun 5y ago
Relevant xkcd: https://xkcd.com/882/ https://xkcd.com/882/

nisegami 5y ago

I'm 26 and have been on Metformin for almost a decade at this point and will probably be on it until I die. Thankfully though, children are not in my future.

SpodGaju 5y ago
Please get your serum zinc levels tested. I am saying this from experience and knowledge.
- nisegami 5y ago
  I'm obese and of south asian ancestry, so there's no real question as to why my insulin sensitivity is shot, but I'll add zinc to the list next time I do bloodwork.

eric4smith 5y ago

It’s so interesting that type 2 diabetes is curable with diet. Type 1 is incurable. My point is that the psychology of eating is so strong that people would rather take a drug that pass on birth defects to the future than change eating habits. And I’m a person coming from struggling with just those habits. I think if someone could come up with a treatment to adjust mindsets - it would change healthcare forever and end the need for drugs like Metaform.

macilacilove 5y ago
Type 2 diabetes is not curable with diet. Some (but not all) cases of type 2 can be _prevented_ by proper diet (i.e. avoiding obesity). There is no known diet that cures any type of existing diabetes.
- eric4smith 5y ago
  The thing is, Type 2 is not even a disease. Its just an imbalance of glucose. So there is really nothing to cure, its just about bringing back your blood glucose levels in balance so that the liver and pancreas can begin to function correctly again. Of course there could be irreversible damage to those organs and that would be really bad (Several relatives who died of this). But you are partly right. There can be remission and back to normal with lifestyle changes and Type 2. Substantial studies and clinical evidence shows this.
  - nradov 5y ago
    Type-2 diabetes is characterized more by insulin resistance than by an imbalance of glucose. And glucose isn't really something you "balance" in relation to another substance anyway. In order to be metabolically healthy you have to keep glucose levels in the appropriate range, and that will generally prevent the onset of insulin resistance.
- nradov 5y ago
  Type-2 diabetes can't be cured, but it can be put into permanent remission with diet for many patients. Virta Health has peer-reviewed research supporting this approach. https://www.virtahealth.com/resource-type/research https://www.virtahealth.com/resource-type/research

Kalanos 5y ago

The anti-aging community is also studying metformin

SpodGaju 5y ago

My hypothesis is that a functional zinc deficiency is the cause of most cases of diabetes, and by taking metformin, it will at least, not correct a zinc deficiency, and probably make it worse. To begin I would like to share that I was born with an undecended testicle (cryptorchidism) that had to be removed surgically when I was 3. My brother was born with hypospadia. I have been studying the genetics and environmental issues around these for the last 15 years. I carry several high risk genes for diabetes but probably the most relevant is that I carry the homozygous risk alleles for rs2466293 in SLC30A8 which is a zinc transporters gene. So I absorb zinc more slowly than most people. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428214/ "Conclusion ZnT8A detection increases T1D diagnosis rate even in mixed populations. SLC30A8 rs2466293 was associated with T1D predisposition in non-European descents." I had my serum zinc tested and it was low. So now I need to take 240mg of Zinc Sulphate and eat a lot of oysters to keep my zinc levels up. I was diagnosed with Lupus and now I no longer present constant symptoms. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544280/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544280/ "Ikaros family zinc finger 1(IKZF1) encodes a lymphoid-restricted zinc finger transcription factor named Ikaros that regulates lymphocyte differentiation and proliferation as well as self-tolerance. Increasing evidence indicates that IKZF1 could contribute to the pathogenesis of autoimmune diseases." So also understand that my mother had diabetes, an immune disorder, and a mood disorder, all of them linked to zinc deficiency. So, in studies zinc deficiency has been linked to diabetes: https://www.mdpi.com/260782 https://www.mdpi.com/260782 "Zinc deficiency is a risk factor for obesity and diabetes." And genital abnormalities: (This is just one study, but there are hundreds like it.) https://www.karger.com/Article/Fulltext/441988 https://www.karger.com/Article/Fulltext/441988 "WT1 is a transcriptional regulator with various functions including signalling in both the embryonic kidneys and gonads. Mutations in this zinc finger transcription factor are associated with Denys-Drash or Frasier syndromes, which result in a broad range of malformations including hypospadias." So I do not think the problem is metformin. I think the problem is doctors not providing patients with diabetes a full nutritional workup and ignoring the role of nutrition in human health.

hirundo 5y ago

Metformin is the first resort in diabetes treatment. If it proves to truly increase birth defects by 40% that may have to change. It was my doctor's first resort for me, but the side effects were too severe and I stopped it. He vaguely mentioned that it would help if I lost weight, but made no mention of what actually resolved my diabetes, a low carb diet. I hope that becomes the first resort. Apparently around here it's not even in the standard toolkit.

somenameforme 5y ago
IMO relative percents should really not be used when trying to consider the impact of things because it gives you no clue about it. If the rate of something is 1 in 1 million then a 40% increase means your odds of having an issue go from negligible to negligible, but a 40% increase makes it sound much scarier. I think the reason for that is that a 40% increase subconsciously tickles our "40% of" intuition, even when we consciously understand that's not what it means. That said in this case the 40% is genuinely scary, because it's a jump from 3.3% with birth defects to 5.2%, or in other words nearly 1 in 50 babies (1.9% of births) standing to be affected by this issue. Although just quickly skimming their numbers, the sample size is unclear to me. That jump was driven by only 13 birth defects among those taking the drug, based on what the article says is a sample of 1.1 million births.
bladley 5y ago
The Diabetes Code is a great book about reversing diabetes through dietary intervention. The author discusses exactly what you're saying here: surprisingly few doctors know how effective a low-carb diet is at treating and curing type 2 diabetes.
- hirundo 5y ago
  Agree. If you have diabetes I highly recommend making Jason Fung your doctor by reading his books, watching his videos, and taking his advice.
Zircom 5y ago
Unfortunately the vast vast majority of people won't commit to a big lifestyle change like that in the first place, and a big majority of the people that due end up not following through. So most doctors won't bother suggesting it as a legitimate option because for most people it kind of isn't.

chiefalchemist 5y ago

> "...because tens of millions of people worldwide take metformin, chiefly for type 2 diabetes." In nearly all cases, T2 is preventable. That is, unlike T1, there are things an individual can do to not reach T2.

pdpi 5y ago
Your point being…?
woodruffw 5y ago
On a micro level, most cases of T2 are preventable. On the macro level, many aren't: food deserts have higher rates of diabetes and heart disease, and the people who live in those areas are frequently "stuck" there for socioeconomic and racial reasons. There are also subgroup susceptibilities in play: Asians and people with Hispanic backgrounds are disproportionately represented among American T2 diabetics[1]. Recent studies suggest these groups are actually underdiagnosed still, since the dominant T2 tests are less reliable on them[2]. [1]: https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes-race-ethnicity.html https://www.cdc.gov/diabetes/library/socialmedia/infographic... [2]: https://jamanetwork.com/journals/jama/fullarticle/2757817?guestAccessKey=357114c9-93bb-459d-b78c-01867571ad41 https://jamanetwork.com/journals/jama/fullarticle/2757817?gu...
- chiefalchemist 5y ago
  Yes. But again...food deserts - in the country that put a man on the moon - certainly solvable. And certainly such efforts are more ethical than rolling genetic defect dice. But we're led to believe it's Big Pharma or nothing? That's an injustice to Truth. https://www.ted.com/talks/ron_finley_a_guerrilla_gardener_in_south_central_la/transcript https://www.ted.com/talks/ron_finley_a_guerrilla_gardener_in...
- idorosen 5y ago
  Thank you for the references.
BurningFrog 5y ago

hombre_fatal 5y ago

I only knew Metformin by name from HNers using it as an anti-aging wonder drug over the years: https://hn.algolia.com/?dateRange=all&page=0&prefix=false&query=Metformin&sort=byPopularity&type=comment https://hn.algolia.com/?dateRange=all&page=0&prefix=false&qu...

robbiep 5y ago
It is also beginning to be prescribed by many of the subscription medication/doctor businesses that are springing up, powered by VC cash and looking to build strong forward flowing subscription businesses. Their model is: - find areas that aren’t medically serious (speaking relatively, and in relation to life threatening - erectile dysfunction and male pattern baldness) - run people through online questionnaires - get an online subscription runner stamped by a doc on their payroll - send out generic medications that they get cheap, package them nicely, and make bank on markup - catch them on the next condition they roll along to The last year I’ve seen a lot of them shifting into metformin (after finasteride and viagra/cialis) for weight loss
- nradov 5y ago
  I expect those guys will start pushing SGLT2 inhibitors (gliflozins) next.
  - robbiep 5y ago
    I just discovered that apparently that is exactly what they’re doing, not metformin presently. And there a planned shift to GLP1s - but the injectables present some interesting administration aspects
- freedomben 5y ago
  Do you see this as a bad thing? As someone who doesn't have any insurance, I'm extremely grateful for these. I don't want to have to go through the current medical racket where unless you pay a doc $300 you won't be allowed to purchase the medication you want. And then of course there's the follow up appointments, a "med check" where they can bill you $150 every 90 to 180 days just to hear you say, "yep, things are fine."

KMag 5y ago

Metformin is also sometimes used to induce ovulation in non-obese women of childbearing age with polycystic ovarian syndrome.[0] Luckily, this study seems to only show an effect if taken within the 90 day window before conception, so it seems to be doing something to the sperm, and not causing genetic changes. Also, of course, we'd want to see corroborating studies. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200666/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200666/

cperciva 5y ago
I think "sometimes" is a bit weak here. My second-hand understanding (from multiple women who have gone through this) is that it's routinely the very first treatment tried for women with PCOS who are having trouble conceiving.
jessriedel 5y ago
> it seems to be doing something to the sperm, and not causing genetic changes. To be clear, spermatogenesis takes roughly 75-120 days, so this is consistent with metformin causing genetic changes to the sperm when or after they are formed, with those genetic changes being propagated through the germ line to children conceived by the sperm. But it's true that the (very preliminary) data does not suggest that this is causing permanent genetic changes in the father.

mensetmanusman 5y ago

It’s sad seeing the crazy downstream multigenerational damage that massive sugar consumption is causing as obesity rates reach 50%. Good luck future humanity.

akomtu 5y ago
I believe this is intentional. If the ruling class wanted workers to live long, they'd force them to switch to oatmeals, fruits and water, while sugar would be a substance competing in price with cocaine.
- ako 5y ago
  So the ruling class is forcing you to eat sugar, and you don't have the option to choose for healthier food?
  - alwillis 5y ago
    From a big picture, socio-economic point of view, yes, the ruling class (Fortune 500 CEOs and elected officials they donate to and lobby) are essentially forcing the poor, the unaware, the average Joe to eat a diet full of high-fructose corn syrup and other carbohydrates, which happens to be produced by giant agricultural companies. Corn is a subsidized crop by the US Department of Agriculture—we pay farmers to grow it. See the documentary "King Corn" about two guys who didn't know the first thing about growing corn but still made a profit on 1 acre of corn [1]. It's often said your zip code is a huge indicator of many demographic stats and what food you have access to is one of them. I've lived in food deserts and I can tell you getting healthy food can be quite an arduous task, especially if you rely on public transportation. Recent data shows that 80%(!) of black women in the United States are obese [2]. This isn't an organic phenomenon; this level of obesity is the result of a system—some intentional and some not—at work. [1]: https://www.kingcorn.net https://www.kingcorn.net [2]: https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=25 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=2...
    - inglor_cz 5y ago

willcipriano 5y ago

Any clues on the mechanism? Wouldn't this require altering the DNA of the sperm?

bencollier49 5y ago
It's possible that the mechanism is epigenetic, albeit unlikely. The sad truth is that this is probably now present in lots of genomes, and in the absence of eugenics or genome modification to correct the fault, will add to the slow and burgeoning medicalisation of the whole population, as the end of natural selection for baseline health multiplies disorders over time.