Recent in vitro and animal experiments suggest that peroxisome proliferation-activated receptor gamma (PPARɣ) agonist medications, such as antidiabetic glitazone (GTZ) drugs, are neuroprotective in models of Parkinson’s disease (PD). These findings have not been tested in humans. We hypothesized that individuals prescribed GTZ drugs would have a lower incidence of PD compared to individuals prescribed other treatments for diabetes.
Methods and Findings
Using primary care data from the United Kingdom Clinical Practice Research Datalink (CPRD), we conducted a retrospective cohort study in which individuals with diabetes who were newly prescribed GTZ (GTZ-exposed group) were matched by age, sex, practice, and diabetes treatment stage with up to five individuals prescribed other diabetes treatments (other antidiabetic drug-exposed group). Patients were followed up from 1999 until the first recording of a PD diagnosis, end of observation in the database, or end of the study (1 August 2013). An incidence rate ratio (IRR) was calculated using conditional Poisson regression, adjusted for possible confounders. 44,597 GTZ exposed individuals were matched to 120,373 other antidiabetic users. 175 GTZ-exposed individuals were diagnosed with PD compared to 517 individuals in the other antidiabetic drug-exposed group. The incidence rate (IR) of PD in the GTZ-exposed group was 6.4 per 10,000 patient years compared with 8.8 per 10,000 patient years in those prescribed other antidiabetic treatments (IRR 0.72, 95% confidence interval [CI] 0.60–0.87). Adjustments for potential confounding variables, including smoking, other medications, head injury, and disease severity, had no material impact (fully adjusted IRR 0.75, 0.59–0.94). The risk was reduced in those with current GTZ prescriptions (current GTZ-exposed IRR 0.59, 0.46–0.77) but not reduced among those with past prescriptions (past GTZ-exposed IRR 0.85, 0.65–1.10). Our study only included patients with diabetes who did not have a PD diagnosis when they were first prescribed GTZ, and thus, it cannot establish whether GTZ use prevents or slows the progression of PD.
In patients with diabetes, a current prescription for GTZ is associated with a reduction in incidence of PD. This suggests PPAR gamma pathways may be a fruitful drug target in PD.
In a retrospective cohort study, Ruth Brauer and colleagues examine the association between treatment with glitazone and incidence of Parkinson's disease.
Parkinson’s disease (PD) is a common, progressive neurological disease. The condition is caused by the gradual loss of nerve cells that normally produce dopamine, a neurotransmitter that regulates the body’s movements. PD does not usually begin to develop until people are around 60 years old, although it can sometimes affect younger people. Its symptoms, which develop slowly, include tremor (trembling of the hands, legs, arm, jaw, and face), slow movement, and rigidity (muscle stiffness). As these symptoms worsen, affected individuals may have trouble walking, speaking, swallowing, and sleeping, and they may become depressed. No one has found a way to halt the loss of dopamine-producing nerve cells yet, but medications that replace or mimic the lost dopamine can reduce the severity of these symptoms. PD does not directly kill people, but it puts a great strain on the body that can make affected individuals vulnerable to life-threatening infections. Nevertheless, these days, many people with PD have a normal or near-normal life expectancy.
Why Was This Study Done?
Recent experiments suggest that drugs that bind to the peroxisome proliferation-activated receptor gamma (PPARγ agonist medications) may be neuroprotective (prevent nerve cell loss) in animal models of PD. PPARγ regulates how the body uses fats and sugars, and PPARγ agonist medications such as rosiglitazone and pioglitazone (glitazone [GTZ] drugs) are used to treat people with diabetes, a condition characterized by high levels of sugar in the blood. It is not known, however, whether GTZ drugs provide protection against PD in people. In this retrospective cohort study, the researchers investigate whether individuals with diabetes exposed to GTZ drugs have a lower incidence of PD than individuals using other antidiabetic drugs. A retrospective cohort study uses data already collected on a group (cohort) of people to look for associations between specific characteristics such as use of a drug and outcomes.
What Did the Researchers Do and Find?
The researchers identified 44,597 patients with diabetes who were newly exposed to GTZ drugs in the UK Clinical Practice Research Datalink, a database that contains primary care data on more than 13 million individuals. They matched each patient with up to five users of other antidiabetic drugs (120,373 controls) who were similar in terms of age, sex, attendance at the same primary care practice, and diabetes treatment stage; people with diabetes usually initially take a single drug but often switch to a different drug or to a combination of drugs as their disease progresses. Finally, the researchers followed up the entire cohort from January 1999 (when glitazones were introduced to treat diabetes) until diagnosis of PD, the end of inclusion in the database, or the end of the study (August 2013). During follow up, 175 glitazone users and 517 non-glitazone users were diagnosed with PD. The incidence rates of PD among glitazone-using individuals and among users of other antidiabetic treatments were 6.4 per 10,000 patient years and 8.8 per 10,000 patient years, respectively (an incidence rate ratio [IRR] of 0.72; an IRR compares the rate of occurrence of new cases of a disease in two groups of people). Adjustment for potential confounding variables (characteristics that might affect an individual’s likelihood of developing PD) such as smoking and head injury did not alter the IRR. Notably, the risk of PD was reduced among current users of GTZ drugs but not among past users.
What Do These Findings Mean?
These findings indicate that, among people with diabetes, current (but not past) GTZ use is associated with a 28% lower rate of clinical presentation of PD compared to the use of other antidiabetic drugs. Because the study only included patients with diabetes who did not have a PD diagnosis when they started GTZ treatment, these findings cannot establish whether GTZ use is associated with prevention of PD or with slower progression of the disease. Moreover, the accuracy of these findings may be affected by misdiagnosis of PD and misclassification of exposure periods to various antidiabetic drugs in the database and by residual confounding. Finally, these findings may not be applicable to people without diabetes. Importantly, the researchers do not recommend that GTZ drugs (which have been associated with some serious side effects) be used as a treatment for PD. Rather, they suggest that the pathways in which PPARγ is involved might contain potential drug targets for PD and should be investigated in future research.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001854.
The United States National Institute of Neurological Disorders and Stroke provides detailed information about PD (in English and Spanish), including links to US organizations that help people with PD
The UK National Health Service Choices website provides information on all aspects of PD (including personal stories)
The UK not-for-profit organization Parkinson'sUK and the US not-for-profit organization National Parkinson Foundation also provide detailed information about PD and personal stories
The UK not-for-profit organization Healthtalk.Org provides stories about all aspects of living with PD
MedlinePlus has links to further resources about PD and information about rosiglitazone and pioglitazone (in English and Spanish)