Pharmaceuticals

Summary

Links Between Pharmaceuticals and Diabetes/Obesity

The Details

Studies on Pharmaceuticals and:
References


Summary

Links Between Pharmaceuticals and Diabetes/Obesity

Certain pharmaceutical drugs appear to be able to cause diabetes. Cancer immunotherapy drugs are linked to type 1 diabetes, for example. It is also very clear that drugs can cause weight gain -- insulin is one well-known example.

One drug has been found to delay the onset of type 1 diabetes in people at high risk of getting the disease.


The Details

Type 1 Diabetes

Immunotherapy

Cancer immunotherapy drugs activate the immune system to attack cancer cells. One problem is that they can also activate the immune system to attack other cells, like the insulin-producing beta cells in the pancreas (these drugs can also cause other autoimmune diseases as well (Ferrari et al. 2019King et al. 2018; Young et al. 2018)). A number of studies have documented cases of type 1 diabetes following or in conjunction with immunotherapy treatment, although the overall incidence is rare (less than 1% of those who take the drugs) (Gauci et al. 2018; Godwin et al. 2017; Venetsanaki et al. 2019). A review identified 283 cases of diabetes following treatment with these drugs between 2014-2018 (Wright et al. 2018). At the Mayo Clinic, over a 6 year period, of 1163 patients who received PD-1 treatment, 12 people developed type 1 diabetes, and 9 experienced a worsening of type 2 diabetes (that's 1.8% total). Diabetes occurred most frequently with pembrolizumab (2.2%) compared with nivolumab (1%) and ipilimumab (0%). The progression to type 1 appears to be quite rapid, and 62% of patients developed additional immune-related problems, especially thyroid disease (Kotwal et al. 2019).

Some authors, however, have proposed that these patients are developing a distinct form of diabetes, characterized by sudden permanent beta cell failure, but not often associated with autoimmunity or genetic risk of type 1. They are calling it "Checkpoint inhibitor associated autoimmune diabetes mellitus (CIADM)" (Tsang et al. 2019). This discussion will be something to watch.

Immunotherapy

The New York Times article, The Immune System, Unleashed by Cancer Therapies, Can Attack Organs, discusses how at least 17 people (this was only the beginning of when the issue was recognized) developed acute-onset type 1 diabetes following immunotherapy treatment for cancer.
Doctors are wondering if they can predict in advance who might be at risk of developing diabetes after immunotherapy. One lab did a genetic analysis on a patient who took ipilimumab and nivolumab and developed rapid-onset type 1 diabetes (ketoacidosis, positive autoantibodies, no detectable beta cell function). This patient did not have a genetic risk of type 1 diabetes, so genetic testing may not be useful (although larger studies would be helpful here) (Lowe et al. 2016). Further studies are also analyzing if genetic differences may play a role in the response to these drugs (e.g., Matsumura et al. 2018), and if the treatment can be altered to help deal with this problem (Del Rivero et al. 2019).

These and other case studies have led to the recognition that autoimmunity is one side-effect of immunotherapy, and efforts are underway to limit it (June et al. 2017). Other autoimmune diseases have also been linked to immunotherapy drugs as well (Zitouni et al. 2019). Interestingly, one patient who developed type 1 after immunotherapy tested negative for autoantibodies, but did have immune cell infiltration in his pancreatic islets (Yoneda et al. 2019).

Chemotherapy and Other Cancer Treatments

Case studies describe people who developed type 1 diabetes while taking uracil-tegafur with leucovorin chemotherapy for colon/rectal cancer (Adachi et al. 2015; Iwata et al. 2019).

Interferon-α (INF-α) appears to have caused type 1 diabetes in one cancer patient (Sossau et al. 2017).

Acetaminophen

Acetaminophen and other analgesic antipyretics, including Non-Steroidal Anti-inflammatory Drugs (NSAIDs), taken in the first 2.5 years of life, have been found to not increase the risk of islet autoimmunity by age 6. However, acetaminophen use in children who had a fever was weakly associated with the development of islet autoimmunity by age 3. Acetaminophen use was much more common in the U.S. than in most European countries (Lundgren et al. 2017). A large, population-based study from Norway found that acetaminophen in the prenatal period or early childhood was not associated with the development of childhood T1D (Tapia et al. 2018). This is something to watch.

Phototherapy

A few studies have investigated whether light therapy, i.e., phototherapy, increases the risk of type 1 diabetes. Neonatal phototherapy is used to treat jaundice in newborns. A meta-analysis of 12 published studies found that newborns with jaundice had a slightly increased risk of later developing type 1 diabetes, especially if the jaundice required phototherapy (McNamee et al. 2012). However, a large study from California found no increased risk of type 1 diabetes from neonatal phototherapy (Newman et al. 2016).

Antipsychotics

A Danish study has found that numerous second-generation (atypical) antipsychotic medications were associated with diabetic ketoacidosis (DKA) and the development of type 1 diabetes (Polcwiartek et al. 2016), as well as DKA and type 2 diabetes (Polcwiartek et al. 2017). One case study describes a 52 year old woman who developed type 1 after taking risperidone for many years. Her blood sugar was 1687 mg/dL when diagnosed! (Hörber et al. 2018).

One of these antipsychotic medications is olanzapine; a case study from Japan describes a 32 year old man who developed acute-onset, autoantibody-positive type 1 diabetes four months after beginning this drug, which was then followed by an extended honeymoon period (Iwaku et al. 2017). This drug is also known for its link to obesity and type 2 diabetes. Exposure to olanzapine in the womb even had metabolic effects on first- and second-generation mice, including glucose intolerance and higher body weight (Courty et al. 2018). 

Anti-Viral Medications

According to a review, interferon therapy to treat hepatitis C increases the risk of developing rapid-onset type 1 diabetes 10-18 fold (Zornitzki et al. 2015). 

A case study also showed a Japanese man developed type 1 while taking highly active antiretroviral therapy (HAART) for HIV. This appears to be partly due to a gene that is present in Japanese people but not Caucasians (Kamei et al. 2015).

Steroids

It is well known among people with diabetes that taking steroids will generally increase your blood sugar. In fact, there are even articles on "steroid induced diabetes" (Hwang and Weiss, 2014).

A Danish study found that if pregnant women took steroids, their offspring had a higher risk of developing type 1 diabetes (Greene et al. 2013). Prenatal steroids also affect diabetes development in non-obese diabetic mice, a mouse model of type 1 diabetes (Perna-Barrull et al. 2019).

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Drug-Induced Hypersensitivity Syndrome (DIHS)

A case study and review finds that while rare, this adverse drug reaction can cause type 1 diabetes (Zhu et al. 2019).

Antibiotics and Other Drugs

A case study describes a woman diagnosed with fulminant (fast-acting) type 1 diabetes following drug-induced hypersensitivity syndrome (DIHS). She also had a virus that has been linked to type 1 diabetes (Takeno et al. 2018).

There are a number of studies on antibiotics and type 1 diabetes, discussed on the Diet and the Gut page.

Drugs to Prevent Type 1 Diabetes

Teplizumab, an anti-CD3 antibody, delayed progression to type 1 diabetes in people at high risk of developing the disease, in a randomized, placebo-controlled, double-blind trial (Herold et al. 2019). The participants were relatives of people with type 1 diabetes (in the TrialNet study) who had tested positive for at least two of the autoantibodies associated with type 1, and had irregular glucose tolerance. This is the first successful prevention trial that I know of for type 1 diabetes in humans! For an editorial commenting on the study, see Traveling down the Long Road to Type 1 Diabetes Mellitus Prevention (Rosen and Ingelfinger 2019). While 43% of the people taking the drug still developed type 1 diabetes, 72% of those who received the placebo developed type 1, and the time to diagnosis was 4 years in the teplizumab group and 2 years in the placebo group. Now the discussion becomes, who should take this drug, when, and how (Dayan et al. 2019).

Additional drugs are also in trials to prevent type 1 diabetes, including oral insulin (Winkler et al. 2019). 

Type 2 Diabetes, Insulin Resistance, and Body Weight

I do not have the time nor inclination to review all the drugs that can cause weight gain, insulin resistance, or even type 2 diabetes here. There are a few lessons we can learn from some of them, however.

Diethylstilbestrol

Diethylstilbestrol (DES), was a drug given to pregnant women decades ago to prevent miscarriage (it didn't work, but instead led to various health problems in these women's offspring, and now their grandchildren as well). As an estrogen, DES is thought to act similarly to endocrine disrupting chemicals. Fetuses are most vulnerable to its effects, and outcomes may not appear until adulthood. DES is strongly linked to vaginal cancer and adverse reproductive outcomes in offspring. Prenatal exposure to DES may also be linked to other health outcomes, including diabetes, cardiovascular disease, high blood pressure, and high cholesterol (the association with diabetes was not statistically significant, but the risk was higher) (Troisi et al. 2013). Prenatal DES exposure is also linked to slightly increased weight gain in adulthood (Hatch et al. 2015). Prenatal DES exposure is also linked to coronary artery disease and heart attacks, but not strokes (Troisi et al. 2018).

There is some limited evidence linking autoimmunity and DES in humans: women exposed to DES in utero seem to have a higher incidence of autoimmune disease, but only when various autoimmune diseases are grouped together (Ahmed et al. 1999). Yet a more recent study that followed these women over 25 years found that there was not an overall increase in autoimmune diseases in DES exposed daughters, although type 1 diabetes was not included in this study (only four autoimmune diseases were included). However, there was an increased risk of the autoimmune disease rheumatoid arthritis in women under 45, and a lower risk in those over 45 (Strohsnitter et al. 2010).

In animals, when female mice were exposed to a low dose of DES in the first five days of life, they gained more weight by six months of age than mice who were not exposed (Newbold et al. 2009). DES promotes the formation of fat cells in laboratory studies, and increases body weight in mice (Hao et al. 2012). DES also enhances autoantibody production in mice (Yurino et al. 2004).

Rosiglitazone

Rosiglitazone, also known as Avandia, is a drug used to treat type 2 diabetes. It works by binding to PPAR receptors in fat cells and making the cells less insulin resistant. It also causes weight gain (and possibly heart attacks, and thus has been taken off the market in many countries). Activating PPAR receptors causes weight gain because these receptors play an important role in the development of fat cells and fat storage. 

The interesting part is that some "obesogenic" environmental chemicals also bind to PPAR receptors, and therefore may also cause weight gain. Tributyltin, for example, binds the PPARγ receptor, and promotes fat cell development (Heindel et al. 2017). Phthalates also activate PPARγ receptors, and are linked to type 2 diabetes and insulin resistance (e.g., Lind et al. 2012; see more studies on the phthalates page).

Contraceptives

There is animal evidence that the continuous use of birth control pills (i.e., not taking the "dummy" pills to avoid getting your period) can lead to insulin resistance, in mice anyway (Roso de Oliveira et al. 2019).

Statins

Statins-- drugs used for many people with diabetes to reduce the risk of cardiovascular disease-- may have side effects that affect the pancreas and the risk of diabetes. Numerous studies have found that statins are associated with an increased risk of type 2 diabetes (Chen et al. 2013Dormuth et al. 2014Jones et al. 2017; Park et al. 2014; Preiss et al. 2011; Rajpathak et al. 2009; Sattar et al. 2010; Zigmont et al. 2019). Animal studies suggest that statins can decrease insulin secretion. One laboratory study, for example, has found that atorvastatin affected the mitochondria of rat pancreas cells (Sadighara et al. 2017).

Metformin and Pharmaceuticals in Wastewater

The diabetes medication metformin is a common pollutant released from wastewater treatment plants, and can act as an endocrine disruptor to fish and other organisms living in the water (Briones et al. 2016; Crago et al. 2016; Cummings et al. 2018Lee et al. 2018Niemuth et al. 2015; Niemuth and Klaper 2018; Niemuth and Klaper 2015), and can affect the behavior of fish (MacLaren et al. 2018) and other species (Godoy et al. 2018). Pharmaceuticals released from wastewater treatment plants are becoming more and more of a problem. Wastewater discharged from water treatment plants contains numerous endocrine disrupting compounds, and mice who drank this water gained more fat (Biasiotto et al. 2016).

In China, metformin in wastewater is used as a method of tracking diabetes prevalence trends, and it tracks the trends quite well, as compared to more traditional methods (Xiao et al. 2019).

In people, however, metformin is not only an effective diabetes medication, it can also protect the beta cells and liver cells from the toxic effects of both arsenic and the food fatty acid butyric acid (Ahangarpour et al. 2017). It can protect against arsenic-induced cardiovascular problems in rats (Wang et al. 2019). Metformin may also be protective against the effects of air pollution in people with diabetes (Sade et al. 2015).

Yet metformin taken during pregnancy is associated with an increased risk of offspring having a lower birthweight, and then later on a higher weight or being overweight in childhood (Hanem et al. 2019Hanem et al. 2018; Rowan et al. 2018; reviewed by Tarry-Adkins et al. 2019Xu et al. 2019).

Sterilizing wastewater with sodium hypochlorite can react with pharmaceuticals to generate disinfection by-products and can cause the final effluent to be even more harmful to aquatic organisms. One study, for example, found that the metabolism of Daphnia magna is sensitive to changes in the final effluent that are caused by sterilization. With the addition of the persistent contaminant PFOS, the metabolic profile is further altered (Wagner et al. 2019).

Acetaminophen

Children who had obesity by age 3-5 years were more likely to have elevated levels of acetaminophen metabolites at birth (Sorrow et al 2018). In Denmark, prenatal exposure to acetaminophen was associated with overweight in girls at age 11 if exposure occurred in all 3 trimesters, and not with weight in boys (Liew et al. 2019).

Topical Steroids

The use of topical steroids, skin creams used to treat inflammatory skin conditions such as eczema and psoriasis, are associated with an increased risk of type 2 diabetes, according to a very large study from Denmark and the UK (Andersen et al. 2019).

Prostate Cancer Drugs

In Taiwan and the UK, men with prostate cancer who took dutasteride or finasteride had an increased risk of developing type 2 diabetes compared to men who took tamsulosin (Wei et al. 2019).

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Phosphoinositide_3-kinase_inhibitors are also cancer drugs, used to treat cancer such as lymphoma. Many are in trials now. One (small) study found that over half of the people taking them for cancer developed diabetes-- and almost a third of those people had remission of diabetes after stopping the drugs (Kim et al. 2019). For more on these drugs also see Hopkins et al. 2018 with commentaries from Greenhill 2018 and Harjes 2018.

Immunosuppressants

Up to 50% of people who get an organ transplant and take immunosuppressants develop "Post Transplant Diabetes Mellitus." Metformin may help counteract this (Bhat et al. 2019).

Antibiotics, Surgery, Radiation, and Other Medical Procedures

Studies on antibiotics and diabetes/obesity are discussed on the Diet and the Gut page, as are studies on bariatric surgery. Studies on radiation for cancer are discussed on the Radiation page. Other drugs linked to type 2 diabetes include steroids like prednisone (e.g., after kidney transplantation (Zbiti et al. 2012), which also raise blood glucose levels in people with type 1 diabetes (Bevier et al. 2008). Growth hormones also can increase the risk of diabetes, although the good news is that children given growth hormones for short stature did not have an increased risk of diabetes at age 30 (Poidvin et al. 2017).

And totally unrelated but I think it is interesting, did you know that insulin-producing tumors are a thing? And that they can cause low blood sugar? Even in people with type 1 diabetes! (Gjelberg et al. 2017).

Transgenerational Effects

Like environmental chemicals, exposure to pharmaceuticals during development may contribute to diabetes or obesity-related effects in multiple subsequent generations. For example, the antibotic sulfomethoxazole is obesogenic in roundworms, and induces changes in gene expression linked to metabolism in multiple generations, even after exposure ends (Li et al. 2019).

Gestational Diabetes

Pregnant women taking certain anti-psychotic medications have an increased risk of gestational diabetes (Galbally et al. 2019; Kucukgoncu et al. 2019). While some studies have found that anti-depressants are associated with an increased risk of gestational diabetes (e.g., Dandjinou et al. 2019), not all have (e.g., Wartko et al. 2019).

References

For these and other studies on pharmaceuticals and diabetes/obesity, see the PubMed collection, Pharmaceuticals and diabetes/obesity.