Dipeptidyl peptidase-4 (or DPP-4) is an enzyme that breaks down the protein (GLP-1) that stimulates insulin release in your body.
Inhibitors of DPP-4 are used in the treatment of Type 2 diabetes, because they help increase insulin levels in the body.
Recently some Swedish researchers noticed something curious about DPP-4 inhibitors: They appear to reduce the risk of developing Parkinson’s disease.
In today’s post, we will review what DPP-4 inhibitors do and look at how this could be reducing the risk of Parkinson’s disease.
Sitagliptin. Source: Diabetesmedicine
Last year an interesting research report about a class of medications that could possibly reduce the risk of developing Parkinson’s disease was published in the journal Movement disorders:
Title: Reduced incidence of Parkinson’s disease after dipeptidyl peptidase-4 inhibitors-A nationwide case-control study.
Authors: Svenningsson P, Wirdefeldt K, Yin L, Fang F, Markaki I, Efendic S, Ludvigsson JF.
Journal: Movement Disorders 2016 Jul 19.
In this study, the investigators used the Swedish Patient Register, to find the medical records of 980 people who were diagnosed with Parkinson’s disease but also had type 2 diabetes. Importantly, all of the subjects had been treated with Type 2 diabetes medication for at least 6 months prior to the date of Parkinson’s being diagnosed.
For comparative sake, they selected 5 controls (non-Parkinsonian) with Type 2 diabetes (n = 4,900) for each of their Parkinsonian+diabetes subjects. They next looked at whether GLP-1R agonists (such as Exenatide), Dipeptidyl peptidase-4 (or DPP-4) inhibitors, or any other oral Type 2 diabetic medication can influence the incidence of Parkinson’s disease.
Now, if all things are considered equal, then when looking at each diabetes medication there should be 1 person in the Parkinson’s disease + Type 2 diabetes for every 5 people in the Type 2 diabetes control group taking each medication right? That is because there are almost 1000 people in the first group and 5000 in the second group.
But this is not what the researchers found.
In my previous post, we briefly reviewed the results of the phase II double-blind, randomised clinical trial of Exenatide in Parkinson’s disease. The study indicates a statistically significant effect on motor symptom scores after being treated with the drug.
Over the last few days, there have been many discussions about the results, what they mean for the Parkinson’s community, and where things go from here, which have led to further questions.
In this post I would like to address several matters that have arisen which I did not discuss in the previous post, but that I believe are important.
I found out about the Exenatide announcement – via whispers online – on the afternoon of the release. And it was in a mad rush when I got home that night that I wrote up the post explaining what Exenatide is. I published the post the following evening however because I could not access the research report from home (seriously guys, biggest finding in a long time and it’s not OPEN ACCESS?!?!?) and I had to wait until I got to work the next day to actually view the publication.
I was not really happy with the rushed effort though and decided to follow up that post. In addition, there has been A LOT of discussion about the results over the weekend and I thought it might be good to bring aspects of those different discussion together here. The individual topics are listed below, in no particular order of importance:
1. Size of the effect
There are two considerations here.
Firstly, there have been many comments about the actual size of the effect in the results of the study itself. When people have taken a deeper look at the findings, they have come back with questions regarding those findings.
And second, there have also been some comments about the size of the effect that this result has already had on the Parkinson’s community, which has been considerable (and possibly disproportionate to the actual result).
The size of the effect in the results
The results of the study suggested that Exenatide had a positive effect on the motor-related symptoms of Parkinson’s over the course of the 60 week trial. This is what the published report says, it is also what all of the media headlines have said, and it sounds really great right?
The main point folks keep raising, however, is that the actual size of the positive effect is limited to just the motor features of Parkinson’s disease. If one ignores the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and focuses on the secondary measures, there isn’t much to talk about. In fact, there were no statistically significant differences in any of the secondary outcome measures. These included:
The title of today’s post is written in jest – my job as a researcher scientist is to find a cure for Parkinson’s disease…which will ultimately make my job redundant! But all joking aside, today was a REALLY good day for the Parkinson’s community.
Last night (3rd August) at 23:30, a research report outlining the results of the Exenatide Phase II clinical trial for Parkinson’s disease was published on the Lancet website.
And the results of the study are good:while the motor symptoms of Parkinson’s disease subject taking the placebo drug proceeded to get worse over the study, the Exenatide treated individuals did not.
The study represents an important step forward for Parkinson’s disease research. In today’s post we will discuss what Exenatide is, what the results of the trial actually say, and where things go from here.
Last night, the results of the Phase II clinical trial of Exenatide in Parkinson’s disease were published on the Lancet website. In the study, 62 people with Parkinson’s disease (average time since diagnosis was approximately 6 years) were randomly assigned to one of two groups, Exenatide or placebo (32 and 30 people, respectively). The participants were given their treatment once per week for 48 weeks (in addition to their usual medication) and then followed for another 12-weeks without Exenatide (or placebo) in what is called a ‘washout period’. Neither the participants nor the researchers knew who was receiving which treatment.
At the trial was completed (60 weeks post baseline), the off-medication motor scores (as measured by MDS-UPDRS) had improved by 1·0 points in the Exenatide group and worsened by 2·1 points in the placebo group, providing a statistically significant result (p=0·0318). As you can see in the graph below, placebo group increased their UPDRS motor score over time (indicating a worsening of motor symptoms), while Exenatide group (the blue bar) demonstrated improvements (or a lowering of motor score).
Reduction in motor scores in Exenatide group. Source: Lancet
This is a tremendous result for Prof Thomas Foltynie and his team at University College London Institute of Neurology, and for the Michael J Fox Foundation for Parkinson’s Research who funded the trial. Not only do the results lay down the foundations for a novel range of future treatments for Parkinson’s disease, but they also validate the repurposing of clinically available drug for this condition.
In this post we will review what we know thus far. And to do that, let’s start at the very beginning with the obvious question:
So what is Exenatide?
If I were to tell you that there exists a miraculous elixir derived from the saliva of a monster and it may aid us in the treatment of Parkinson’s disease, would you think me mad?
In 1974, a small study was published in the Journal of Chronic Diseases that presented a rather startling set of results:
In the study, Lipman and colleagues conducted some routine glucose tolerance tests on a group of 56 people with Parkinson’s Disease (7 additional subjects with Parkinson’s were excluded because they had been previously diagnosed with diabetes).
After being asked to fast overnight, the subjects were then given 100g of glucose and blood samples were collected from them every hour for 3 hours. When the glucose levels in the blood were measured and compared with the results of 5 previous studies conducted on normal healthy adults of the same age (one of those studies involved 7000 participants), it was found that the people with Parkinson’s disease in the Lipman study had a much higher average level of glucose in their blood than all of the other 5 studies looking at healthy individuals.
Shockingly, almost half (46.4%) of the participants in the Lipman study actually fulfilled the criteria for a diagnosis of diabetes.
More recent survey data has revealed that diabetes is established in between 8–30% of people with Parkinson’s disease (click here for more on this) – obviously this is in excess of the approximately 6% prevalence rate in the general public (Source: DiabetesUK).
What is diabetes?
‘Diabetes mellitus’ is what we commonly refer to as diabetes. It is basically a group of metabolic diseases that share a common feature: high blood sugar (glucose) levels for a prolonged period.
There are three types of diabetes:
- Type 1, which involves the pancreas being unable to generate enough insulin. This is usually an early onset condition (during childhood) and is controlled with daily injections of insulin.
- Type 2, which begins with cells failing to respond to insulin. This is a late/adult onset version of diabetes that is caused by excess weight and lack of exercise.
- Type 3, occurs during 2-10% of all pregnancies, and is transient except in 5-10% of cases.
What is this stuff called insulin?
Insulin is a hormone – that our body makes – which allows us to use sugar (glucose) from the food that you eat. Glucose is a great source of energy. After eating, our body is releases insulin which then attaches to cells and signals to those cells to absorb the sugar from our bloodstream. Without insulin, our cells have a hard time absorbing glucose. Think of insulin as a “key” which unlocks cells to allow sugar to enter the cell.
Ok, so how is it all connected to Parkinson’s disease?
The short answer is ‘we currently don’t know’.
There have, however, been numerous studies now that suggest an association between diabetes and Parkinson’s disease. The first of these studies was:
Title: Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease.
Authors: Driver JA, Smith A, Buring JE, Gaziano JM, Kurth T, Logroscino G.
Journal: Diabetes Care. 2008 Oct;31(10):2003-5.
In this study, 21,841 male doctors (participants in the Physicians’ Health Study) were followed over 23 years. The researchers found that people with diabetes had an increased risk of developing Parkinson’s disease risk. Interestingly they reported that the highest Parkinson’s disease risk was seen in individuals with short-duration, older-onset diabetes.
In another study:
Title: Diabetes and risk of Parkinson’s disease.
Authors: Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, Chen H.
Journal: Diabetes Care. 2011 Apr;34(4):910-5. doi: 10.2337/dc10-1922. Epub 2011 Mar 4.
This study came from another long term study, which was following 288,662 participants of the National Institutes of Health-AARP Diet and Health Study. The researchers found that the risk of Parkinson’s disease was approximately 40% higher among diabetic patients than among participants without diabetes. In this study, however, the analysis showed that the risk was largely limited to individuals who had diabetes for more than 10 years.
A third study:
Title: Diabetes and the risk of developing Parkinson’s disease in Denmark.
Authors: Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B.
Title: Diabetes Care. 2011 May;34(5):1102-8.
Using data from the nationwide Danish Hospital Register hospital records, the researchers found that having diabetes was associated with a 36% increased risk of developing Parkinson’s disease. Interestingly, they reported that the risk was stronger in women and patients with early-onset Parkinson’s disease (eg. diagnosed before the age of 60 years).
EDITORIAL NOTE HERE: It is important to understand that these studies do not suggest that having diabetes will naturally lead to Parkinson’s disease. They are simply pointing out that diabetics have an increased risk of developing the condition. We present this data here for informative purposes and to make people aware.
It is of interest to note that there is also an association between diabetes and Alzheimer’s disease (click here and here for more on this). Thus Parkinson’s disease is not the only neurodegenerative condition associated with diabetes.
Is the association between Parkinson’s disease and diabetes genetic?
At present, the answer is no.
The connection between diabetes and Parkinson’s disease does not appear to be genetic, as genome wide sequencing studies have found no common mutations or associations between the two conditions (click here for more on this).
So what are we doing with this knowledge?
This is the Gila monster (Source: Californiaherps).
Named after the Gila River Basin of New Mexico and Arizona, where these lizards are found found, the saliva of the Gila monster was found to have some rather amazing properties with regards to the management of type 2 diabetes. This was due largely to a protein extracted from the saliva, called exendin-4. Scientists have made a synthetic version of exendin-4 which they have called Exenatide.
When tested in a three year clinical trial, Exenatide was found to return people with type 2 diabetes to healthy sustained glucose levels and progressive weight loss.
Exenatide is a glucagon-like peptide-1 (GLP-1) agonist. These types of drugs work by mimicking the functions of the natural hormones in your body that help to lower blood sugar levels after meals. They do this by aiding the release of insulin from the pancreas, blocking a hormone that causes the liver to release its stored sugar into the bloodstream, and slowing glucose absorption into the bloodstream.
Great, but what has this got to do with Parkinson’s disease?!?
Exenatide has also been found to have impressive results in both animal models of Parkinson’s disease and in an open-label clinical trial.
The first study to report a positive effect of Exenatide in a Parkinson’s disease model was:
Title: Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease.
Authors: Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Rönnholm H, Wikström L.
Journal: J Neurosci Res. 2008 Feb 1;86(2):326-38.
In this study, the scientists found that exendin-4 (aka Exenatide) improved both behavioural motor ability and protected dopamine neurons in a rodent model of Parkinson’s disease (and the drug was given 5 weeks after the animals developed the motor features). How these results were achieved – the biology behind the results – is unclear, but the effect was interesting enough to encourage other groups to also test Exenatide and they found similar results:
Title: Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease.
Authors: Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS.
Journal: J Neuroinflammation. 2008 May 21;5:19. doi: 10.1186/1742-2094-5-19.
PMID: 18492290 (This study is OPEN ACCESS if you would like to read it)
The scientists in this study tested exendin-4 (aka Exenatide) on two different rodent models of Parkinson’s disease and they found similar results to the previous study. The drug was given 1 week after the animals developed the motor features, but still positive effects were observed.
These (and other) initial results led to the initiation of a clinical trial. Given that Exenatide is already approved for use with diabetes, testing the drug in Parkinson’s disease was a relatively straightforward process (funded by the Cure Parkinson’s Trust).
Title: Exenatide and the treatment of patients with Parkinson’s disease.
Authors: Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T.
Journal: J Clin Invest. 2013 Jun;123(6):2730-6.
PMID: 23728174 (This study is OPEN ACCESS if you would like to read it)
The researchers running the clinical study gave Exenatide to a group of 21 patients with moderate Parkinson’s disease and evaluated their progress over a 14 month period (comparing them to 24 control subjects with Parkinson’s disease). Exenatide was well tolerated by the participants, although there was some weight loss reported amongst many of the subjects (one subject could not complete the study due to weight loss). Importantly, Exenatide-treated patients demonstrated improvements in their clinician assessed PD ratings, while the control patients continued to decline.
Importantly, in a two year follow up study – this was 12 months after the patients stopped receiving Exenatide – the researchers found that patients previously exposed to Exenatide demonstrated a significant improvement (based on a blind assessment) in their motor features when compared to the control subjects involved in the study.
The results of this initial clinical study are intriguing and exciting, but it is important to remember that the study was open-label: the subjects knew that they were receiving the drug. This means that we can not discount the placebo effect causing some of the beneficial effects reported.
We look forward to reading the results of that trial.
And Exenatide is not the only diabetes drug being tested
Pioglitazone is another licensed diabetes drug that is now being tested in Parkinson’s disease. It reduces insulin resistance by increasing the sensitivity of cells to insulin. Pioglitazone has been shown to offer protection in animal models of Parkinson’s disease (click here and here for more on this). And the drug is currently being tested in a clinical trial.
We look forward to reading these results as well.
As with melanoma and red hair, there appears to be a curious connection between diabetes and Parkinson’s disease. Large longitudinal studies point to people with diabetes as having a higher risk of Parkinson’s disease than non-diabetic individuals. Why this is remains unclear, but some of the drugs used for treating diabetes may provide novel therapeutic options in the treatment of Parkinson’s disease. We will continue to follow this research and report results as they come to hand.
And you didn’t believe me about the monster saliva!