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Metformin ‘could slow development of heart disease’ in type 1 diabetes? Release vastly overstates what small study can tell us.

Scientists at Newcastle University believe a drug commonly prescribed for Type 2 diabetes could be routinely taken by Type 1 diabetic patients to slow the development or delay heart disease.

Metformin is an inexpensive treatment that is often used for Type 2 diabetes to lower blood sugar levels by reducing glucose production in the liver.

The drug is not regularly given to patients with Type 1 diabetes. However, for the first time, a clinical trial has revealed metformin can promote a patient’s ability to repair their own damaged blood vessels by increasing vascular stem cells.

Heart disease is the leading cause of illness in diabetic patients, accounting for more than half of all fatalities. Metformin may be used to lower Type 1 diabetic patients’ risk of developing this complication.

Findings of the clinical trial are published today in the journal, Cardiovascular Diabetology. This follows previous laboratory work at Newcastle University which explored the mechanism behind metformin.

Dr Jolanta Weaver, Senior Lecturer in Diabetes Medicine at Newcastle University and Honorary Consultant Diabetologist at Queen Elizabeth Hospital, Gateshead, led both studies.

She believes this new research is a major development in understanding the best ways to further improve treatment in Type 1 diabetes.

Dr Weaver said: “As the outcomes of heart disease is worse in diabetic versus non-diabetic patients, there is a need to identify additional treatment options.

“Metformin could routinely be used by patients with Type 1 diabetes to help lower their chances of developing heart disease, by increasing a repair mechanism created by vascular stem cells released from the bone marrow.

“Our research is an exciting step forward as it may have positive clinical implications for patients with increased risk of cardiovascular disease by improving their treatment options.

“For the first time, this study has shown metformin has additional benefit beyond improving diabetes control when given to patients with relatively well controlled Type 1 diabetes.

“We have established the drug increases patients own vascular stem cells, which will help delay or slowdown heart disease.

“Our findings also show that the cells associated with damaged blood vessels were reduced, confirming that the repair of blood vessels was taking place in our patients.”

Researchers studied a treatment group of 23 people aged 19-64 who had Type 1 diabetes for up to 23 years and had no evidence of heart disease.

Patients were given metformin at a dose they could tolerate, between one to three tablets a day, for eight weeks. Participants were advised to adjust their insulin to keep blood glucose levels safe.

Scientists measured patients’ stem cells directly in the blood and also grew stem cells in a test tube, observing how they behaved. Another cell type was also counted to assess damaged blood vessels.

The participants were matched with nine patients within the same age bracket who took standard insulin treatment and 23 healthy non-diabetic people aged 20-64.

Experts found that the stem cells of patients who took metformin were able to promote the repair of the blood vessels and there was an improvement in how vascular stem cells worked.

Type 1 diabetes is a lifelong autoimmune condition that develops when the pancreas does not produce any insulin, causing a person’s blood sugar level to become too high. It is estimated around 400,000 people in the UK have the condition.

Dr Weaver said: “We have shown that all our patients in the study had their insulin doses reduced after taking metformin and have not suffered any serious adverse effect.

“Patients with Type 1 diabetes may wish to consider discussing with their GP the possibility of adding metformin, even at a very low dose, to the insulin that they are taking. However, care needs to be taken to adjust insulin dose to prevent too low glucose levels.”

A pilot study was funded by Diabetes Research and Wellness Foundation and the extended study was financially supported by the Diabetes Research Fund in Gateshead.

Dr Eleanor Kennedy, Research Manager at Diabetes Research and Wellness Foundation, said: “The Diabetes Research and Wellness Foundation is delighted to have funded the initial pilot study that led Dr Weaver and her colleagues to conduct this small clinical trial.

“The results, which indicate that metformin, a drug commonly used in the treatment of Type 2 diabetes, could also have a powerful effect in people with Type 1 diabetes is unexpected.

“We hope that these results can lead to a much larger clinical trial.”

Case study

Quantity surveyor Alex Laws was part of the Newcastle University clinical trial and is delighted with the results of the study.

The 31-year-old, of Gateshead, was diagnosed with Type 1 diabetes at the age of just seven and has good control of her condition. She was enrolled on the clinical trial in the summer of 2013.

Alex said: “I was keen to be part of the clinical trial as I know how important research is into helping people with the condition – I previously worked in the medical research field.

“People with Type 1 diabetes can suffer from a number of complications, especially in the long-term, so it’s important as much as possible is done to limit serious problems.

“Heart disease is a concern for people with Type 1 diabetes so any treatment that can help with this and give an advantage to the patient is a good thing.”

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Reference

Metformin improves circulating endothelial cells and endothelial progenitor cells in Type 1 diabetes: MERIT Study

Fahad W Ahmed, Rachel Rider, Michael Glanville, Kilimangalam Narayanan, Salman Razvi and Jolanta U Weaver.

Cardiovascular Diabetology. DOI: 10.1186/s12933-016-0413-6

Experts say inexpensive drug could slow heart disease for type 1 diabetic patients

Our Review Summary

metforminThis news release from Newcastle University reports on a small pilot study testing whether type 1 diabetes patients who add the drug metformin to their daily regimen reduce their risk of cardiovascular disease. Based on a reduction in markers indicating blood vessel damage, and an increase in markers indicating blood vessel repair, the researchers conclude the risk is lowered, but the study wasn’t designed in a way that would show an actual risk reduction. Thus, claims such as this one by the study researchers — “this study has shown metformin has additional benefit beyond improving diabetes control when given to patients with relatively well controlled Type 1 diabetes” — represent an overreach, because the study wasn’t capable of showing a benefit on any outcome that would actually matter to a patient. Additionally, the release offers no numerical data on changes in levels of the measured markers — only general statements. Nor does it mention the cost of the drug, which is nominal, but which could garner a large sales market. Lastly, it offers a patient testimonial by way of anecdotal information which may or may not be representative of the experiences of others.

 

Why This Matters

Type I diabetes is a serious lifelong disease that places patients in a constant state of risk, depending on their blood sugar levels. People with the disease are more prone to cardiovascular disease so any treatment that might lower that risk, slowing that degradation, should benefit the 400,000 people in the United Kingdom who have this disease, as well as similar patient populations around the world.  Because of that, people deserve quantitative information about how treatments affect patient outcomes improvements in treating the disease, and this release, sadly, offers little. Because the study reports on disease oriented outcome but doesn’t measure any patient oriented outcomes, it should be followed by a large randomized clinical trial conducted over a very long period of time.

Criteria

Does the news release adequately discuss the costs of the intervention?

Not Satisfactory

The release makes no mention of costs at all, although the unit cost of the drug is both quite low and readily available.  Diabetic patients already spend a substantive amount for their medications over their lives and knowing that the addition of this other drug would not be an undue financial burden would be a welcome piece of information. Since the study was done in the UK, one might have expected some comment on the effect of the use of this drug in a large number of type I diabetics on the health care system.

Does the news release adequately quantify the benefits of the treatment/test/product/procedure?

Not Satisfactory

The release makes clear that cardiovascular disease is a major risk for patients with diabetes and the study was intended to show whether the additional drug, metformin, could lower that risk. The release states that the study showed a decrease in markers indicating damaged blood vessels and an increase in markers showing blood vessel repair, among other findings. But the release falls short by not providing any numerical data suggesting the degree of improvement in these markers, and therefore denies readers the ability to make their own determination as to the importance of this research.

Does the news release adequately explain/quantify the harms of the intervention?

Not Satisfactory

The release makes no mention of any side effects or harms to participants from the use of metformin, although a host of minor-to-moderate side effects may be routinely seen with this drug. The research paper itself limits discussion of side effects to “any major or severe episodes of hypoglycemia,” which it defines as instances of low blood sugar “requiring intervention of another person to resolve the event,” or any episode of hypoglycemia “resulting in a loss of consciousness.” Although none were reported, both instances seem substantively more serious than minor side effects. Gastrointestinal side effects, for example, are commonly reported by patients taking metformin. And there are some relatively commonly found metabolic adverse effects of metformin (metabolic acidosis) that could have been looked for to determine if there is an increased incidence in this ‘vulnerable’ group.

Does the news release seem to grasp the quality of the evidence?

Not Satisfactory

While the research paper goes into substantial detail in providing numerical data on the levels of markers measured in this study, the news release offers none of that.  It does state that this was a pilot study comparing a small number of patients split between the standard treatment for type 1 diabetes and those receiving additional doses of metformin. It also states that findings from these patients were compared to those from a group of healthy volunteers. But again, the findings reported in the release are general statements that offer readers no way to gauge change.

Perhaps more importantly, the release never directly cautions that the outcomes studied are surrogate markers of risk, and that the study wasn’t capable of showing an actual reduction in the number of cardiovascular events — something which may or may not be demonstrated in additional studies.

Lastly, there is a feature of the study that raised some questions. There was a “run-in” period (often used by drug sponsors to select or exclude patients based on their potential response to the drug) that was not clearly or comprehensively described. There is no description of what was measured here and what the criteria were for “passing” the run-in period.

Does the news release commit disease-mongering?

Satisfactory

The release does not appear to commit disease mongering.

Does the news release identify funding sources & disclose conflicts of interest?

Satisfactory

The release mentions that the study was funded by the Diabetes Research and Wellness Foundation and the Diabetes Research Fund in Gateshead. Neither the news release or published study address potential conflicts of interest. The funding foundation lists only its board of directors and no background information on the group is readily available.

Does the news release compare the new approach with existing alternatives?

Not Satisfactory

There are no mentions in the release of possible alternatives to metformin as a means to reduce the risk of cardiovascular disease in type 1 diabetes patients. It would be of interest to patients to know if intensive dietary and exercise counseling had been studied and what the results were.

Does the news release establish the availability of the treatment/test/product/procedure?

Satisfactory

Since metformin is readily available and currently used in treating type 2 diabetes, the release gets a satisfactory rating in this category.

Does the news release establish the true novelty of the approach?

Satisfactory

Since cardiovascular disease is a major risk for diabetic patients, research indicating that an existing (presumably inexpensive) drug may lower that risk clearly qualifies as significant enough to warrant a release, in spite of the fact that this was only a small, limited pilot study.

Does the news release include unjustifiable, sensational language, including in the quotes of researchers?

Not Satisfactory

This release does not appear to offer any unjustifiable language per se. However, the release seems to point only towards this being totally beneficial without any statement about the likelihood that this “basic science” study would translate to clinically important patient centered outcomes.

And there are statements that are clearly overreaching. For example, “We have established the drug increases patients own vascular stem cells, which will help delay or slowdown heart disease.” It’s not at all clear that increasing vascular stem cells will delay or slow down heart disease. We’d need another much larger larger study to show that.

Finally, use of anecdotal statements from a trial participant offers little of value for readers. We don’t know if his was the best experience among all the participants, or the worst, or somewhere in between.

Total Score: 4 of 10 Satisfactory

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