The POWERED Study: Prophylaxis with metformin to prevent PTDM
Research type
Research Study
Full title
A single site, placebo controlled, double blind randomised clinical trial evaluating the effectiveness of metformin to prevent post-transplant diabetes in a cohort of patients undergoing renal transplantation.
IRAS ID
203080
Contact name
McCafferty Kieran
Contact email
Sponsor organisation
Barts Health NHS Trust
Eudract number
2017-004880-11
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
Research Summary
Kidney transplantation is widely held to be the optimal form of renal replacement therapy for patients with end-stage renal disease, leading to a longer survival and improved quality of life compared to those that remain on dialysis. However renal transplantation brings with it a new set of challenges for the clinician. One of the most important of these is Post Transplant Diabetes Mellitus (PTDM). The prevalence of PTDM has increased over time and may occur in up to a third of all patients post transplant making it a critical challenge for transplant physicians. PTDM represents a significant risk factor to both patient and transplant survival, with some studies suggesting an increase of 60% for transplant failure and an almost 90% increase in mortality. PTDM tends to occur early post transplant due to high doses of immunosuppression needed. Thus the early post transplant period represents a crucial window to intervene to reduce the incidence of PTDM.
Recent evidence suggests that insulin may help reduce the rates of PTDM. However insulin requires patients to inject themselves, may lead to weight gain and risks triggering low blood sugar levels, which can lead to loss of consciousness and even death.
Metformin is the first line treatment for type 2 diabetes, with the main advantage that it does not lead to weight gain and importantly does not lead to low blood sugar levels.
This novel study seeks to investigate the beneficial effects of Metformin to prevent PTDM in patients without the significant risks of weight gain and hypoglycaemia seen with insulin treatment.Summary of Results
"This study started in January 2019 and ended in May 2022. The study was run in the Royal London Hospital, Barts Health NHS Trust.
This Phase 2 study was done to see if taking metformin for 3 months prevents the development of diabetes after transplant in new kidney transplant recipients.
Having a kidney transplant can be the best form of treatment for kidney patients. However, as many as 1 in 3 patients will go on to develop diabetes after getting a new kidney, usually within the first year after transplant. People who develop diabetes after transplant have an increased risk of heart attacks and strokes. The kidney may also not work as well or last as long. The standard practice is to monitor people who have had a transplant for signs of diabetes. If they develop diabetes, then they are started on diabetes medicines to control their blood sugar.
We wanted to find out whether giving a diabetes medicine for the first 3 months after transplant could prevent patients from developing diabetes. There was a study carried out in 2012 that suggested giving insulin to patients without diabetes for the first 3 months after kidney transplant could decrease their risk of having diabetes at 1 year after transplant.
However, insulin is a medicine which needs to be injected and can cause weight gain and dangerously low sugar levels if not used carefully. We wanted to see if metformin could have a similar protective effect.
Metformin is a drug commonly used in people who have Type 2 diabetes mellitus (when diabetes starts in adulthood). It is a tablet taken by mouth. Metformin helps to control blood sugars without lowering sugar levels dangerously low. It has been used for over 50 years and has very few side effects. Some people who take metformin complain of stomach side effects like stomach pain and bloating. Metformin is avoided in patients with very low kidney function to avoid the drug building up in the body or causing acid to build up in the body. It has therefore not been used immediately after transplant for people with kidney transplants before.
This study was affected by the COVID-19 pandemic: the clinical team at the Royal London stopped doing kidney transplants and the study team were reassigned to assist the pandemic response. Many patients who were already taking part in the study did not attend their follow-up visits during this period.
Who was included in this study?
Male or female patients aged 18-75 years, who did not have diabetes and were having a kidney transplant at the Royal London Hospital were eligible for this study.
We had a screening period of 10 days after transplant in order to make sure that:
a) It was safe to start metformin: if a patient’s new kidney was not working at a safe level (30ml/min or above) within 10 days post-transplant, we did not start them on the study tablet, and they did not take further part in the trial.
b) Patients did not already have diabetes without knowing it: we checked their blood sugar levels before giving them a sugar drink and then again 2 hours afterwards. This is called an oral glucose tolerance test (OGTT). If the second sugar level after the drink was too high, then we did not start them on the study tablet and they did not have any further active role in the trial. We asked their permission to see how they were doing with normal kidney care at 1 year after their transplant.190 patients were invited to be part of the study. Of these, 39 did not want to take part, the transplant did not take place for 9 people, and 6 were not eligible for other reasons. 49 patients did not have high enough kidney function, 24 had a second blood sugar that was too high, and 2 had both.
60 patients went on to participate in the drug phase of the trial. They were split into 2 groups of 30 people by chance (randomised) to reduce differences between the groups. Putting people into groups by chance helps to make the 2 groups equal. Reducing differences between the groups in this way makes the comparison between the groups fairer.
30 people received metformin at a dose of 500mg once daily for 3 months. The other 30 people received a placebo tablet. Placebos are identical looking tablets but with no medicine in them. Placebos are used to make sure that any effects seen during the study are due to the active medicine (metformin) and not just because people were taking part in the study.The trial was “double-blindedâ€. This means that neither participants nor doctors knew who was given which treatment: metformin or placebo. This was done to make sure that the trial results were not influenced in any way.
Participants had routine kidney care from their clinical team after their transplant. They had 3 extra study visits at 3 months, 6 months and 12 months after their transplant. At these visits, the study team took their vital signs, recorded what medicines they were taking, and performed some additional blood tests including checking blood sugar levels before and after a sugar drink (the OGTT test). The study medicine (either metformin or placebo) was stopped after the study visit at 3 months. The study team performed virtual reviews at month 1 and month 2 whilst the participants were taking the study drug.
If participants developed diabetes during the study, they could be started on a diabetes drug as per routine clinical care.
Of those who participated in the study, there were no major differences between the people who were given placebo and those given metformin. In both groups, about 40% were women and it was the first kidney transplant for 83%. The average age was 47 years in the placebo group and 42 years in the metformin group. In the placebo group, 13.3% were Asian, 40% were Black, 43.3% were White and 3.3% were Other. In the metformin group, 33.3% were Asian, 16.6% were Black, and 41% were White. Both groups had similar weights, cause of kidney disease, and type of dialysis (kidney replacement treatment). They received the same transplant medication regime and there was no difference in the type of kidney transplant they received. There was no difference between the two groups in kidney function or sugar test values (OGTT 2 hours after the sugar drink) at the beginning of the trial when they started taking the different treatments.
What were the side effects?
Common and serious medical issues that happened during the study are listed here. All problems reported by patients during the trial were recorded as “adverse events†regardless of whether the team thought that they might be related to the study drug or not. 372 adverse events were recorded in the placebo group and 376 adverse events in the metformin group. There were 15 serious adverse events in the placebo group and 10 serious adverse events in the metformin group. Serious adverse events are events that are life threatening or require the individual to have to go to hospital.
There was only one type of adverse event which appeared more frequently in patients taking metformin: the “General disorders and administration site conditions†class. Types of adverse event in this class include tiredness, fever, foot swelling and nonspecific pain. 26 events (67%) were reported in the metformin group compared to 11 events (31%) in the placebo group.
There was no increase in the “Gastrointestinal disorders†class of adverse events in the metformin group. Types of adverse event in this class include stomach pain, feeling sick, diarrhoea and acid reflux. 14 events (47%) were reported in the metformin group compared to 22 events (73%) in the placebo group.
In two cases, the study drug was stopped by a clinical team looking after a participant without discussion with the study team. In the first case, the drug was stopped 19 days early (metformin); in the second case, the drug was stopped after about 1 month of treatment (placebo).
No patients died or lost their kidney transplant. There was no significant difference in kidney function between the groups at 1 year after transplant: this means any difference between the groups is likely to be by chance rather than a difference caused by the treatment.
Rejection occurs when the immune system of the person receiving a transplant organ attacks the organ. There were 5 episodes of kidney rejection during the course of the study. 3 of these took place in the placebo group and 2 in the metformin group. There was no significant difference between the groups. One of these events was reported as a serious adverse event because it took place during the COVID-19 pandemic, which meant that the patient had to stay in hospital longer to receive anti-rejection treatment.
What were the overall results of the study?
The purpose of the study was to see whether fewer patients in the metformin group had a high blood sugar after having a sugar drink (OGTT) in the 1 year after transplant compared to the patients taking metformin.
At 1 year after transplant, 3 patients (12%) in the metformin group had a positive sugar test, compared with 1 patient (4%) in the placebo group. There was no statistically significant difference between the groups: this means that any difference between the groups is likely to be by chance rather than a difference caused by the treatment.
At 3 months after transplant, 6 patients (21%) in the metformin group had a positive sugar test, compared with 5 patients (17%) in the placebo group. At 6 months, 2 patients (11%) in the metformin group had a positive sugar test, compared with 1 patient (4%) in the placebo group. There was no statistically significant difference between the groups at any time point.
Due to COVID-19, there were a number of missing sugar tests at the three follow-up visits.
Whilst there was no difference in other tests of sugar metabolism between the groups, it was found that sugar metabolism did change significantly over the course of the 12 months after transplant in both groups. In the same way that the number of positive OGTT tests fell over the course of the year, the number of impaired sugar tests peaked at 3 months and then reduced. This was also the case in a test which measured how resistant the body is to insulin, the hormone which reduces sugar levels.
This study found that:
• Metformin 500mg once daily given for the first 3 months after kidney transplant did not appear to have an effect on the development of diabetes in the first 12 months after transplant
• Metformin 500mg once daily appears to be safe to give immediately after transplant to people whose kidney function is 30ml/min or greater
• There is a disruption to sugar metabolism in the first 12 months after transplant which appears to peak at 3 months and then improveHow has this study helped patients and researchers?
These results are for new kidney transplant recipients aged between 16-75 who had a kidney transplant function of 30ml/min or above and a negative sugar test (OGTT) within the first 10 days after transplantation. Results are limited to the particular people studied and cannot be assumed to be true for everybody. Not all participants had the same results.
The most important limitations of this study are the small size, the missing data caused by the COVID-19 pandemic, and the relatively low dose of metformin that we used in the study. In diabetes, patients can be given up to 2000mg (2g) per day: we used 500mg per day. We used a smaller dose because we wanted to make sure that the drug was safe for patients with kidney transplants who were not diabetic and we wanted to avoid any side effects.
This research helps future patients and families by helping us understand more about metformin, its use in patients who have had kidney transplants and about how sugar metabolism changes in patients who have had kidney transplants.
Findings from this study will be used to:
-Suggest that metformin can be safely used in the immediate period after transplantation
-Seek approval for future trials with bigger doses of metformin and comparing different diabetes drugs
-Seek approval for future trials to see whether the routine use of sugar tests (OGTTs) in the early period after transplantation helps doctors to identify people most at risk of developing diabetes"REC name
London - Brighton & Sussex Research Ethics Committee
REC reference
18/LO/0958
Date of REC Opinion
25 Jul 2018
REC opinion
Further Information Favourable Opinion