I toured the Lilly pharmaceutical museum in Indianapolis last week.  It was fascinating.   I was in town to attend the American Association of Diabetes Educators annual meeting.  Lilly & Co. produced the first commercial insulin in the united states starting in 1922.

Prior to the 1920’s virtually everyone who developed type 1 diabetes died with a year.  The only known treatment was to stop ALL sugar and other carbohydrates.  This could prolong life for another year, but was absolutely miserable.  Many died of starvation.

In 1922 at the University of Toronto, Dr. Frederick Banting discovered that the secretions from a a dog pancreas, (later called insulin) when injected in diabetes patients could quickly restore their strength and vitality.  In 1923 Dr. Banting was awarded the Noble prize for medicine.

With Dr. Banting’s techniques to gather insulin, it was possible to treat only a handful of patients.  They partnered with the pharmaceutical company Eli Lilly.  By the end of 1923, the company was producing enough insulin to supply all of North America.  When it came, insulin was like a miracle.  People with severe diabetes and only days or hours to live were saved.  As long as they kept getting their insulin, they could live an almost normal life.

As I toured the Lilly  museum, one thing in particular touched me.  It was a placard from 2004.  The placard listed over 100 names of people who had now lived over 75 years while taking insulin.  Without the discovery  of insulin, all of these people would have died in the 1920’s.  Please see the attached photo.   If you are interested in a more in depth review, I read an excellent book last year covering this subject: Diabetes, the Biography. 

I am here in Indianapolis with 3000 other Certified Diabetes Educators. It has been amazing.  I am energized to bring back the best of what I have seen to Saipan and the rest of the CNMI.  In the following paragraphs, I will go through some of the highlights.

Continuous Glucose Monitoring

We are proud to be bringing continuous glucose monitoring (CGM) to Saipan.  CGM has been widely used throughout the US for years to help in the care of type 1 diabetes, and in difficult to control cases of type 2.  Unfortunately, it has never been available in the CNMI.  With CGM a sensor is placed on the arm and is worn for up to two weeks.  I had a sensor placed on my arm, it was about the size of three quarters and completely painless.

After the sensor is worn, it will be removed in our office and connected to our computer.  We will than have a complete 24 hour reading of the blood sugar variations over the last two weeks.  Our current tests only give brief snapshots.  See here a review of the Abbott Libre sensor we will be using.

The American Academy of Endocrinology calls for continue glucose monitoring for the following:

1.        Any diabetes patient on intensive insulin therapy
   2.   Patients at high risk of hypoglycemia (low blood sugar)
   3.   Patients on insulin or insulin secretagogues (Glyburide, Glynase, Amaryl) who manifest
   hypoglycemia unawareness.
   4.  In severe diabetic kidney disease

Continuous glucose monitoring has been called the EKG of diabetes. It brings a great deal of additional information so that both doctors and people with diabetes can make better treatment decisions.

Helping our patients afford their diabetes medications

So many of my patients on Saipan, have great difficulty affording their medications. Even when they have insurance, they often have large deductibles.  This has especially been a problem for those who require insulin, or other very expensive diabetes medications like Victoza.  Every major medication manufacturer has so called “patient assistance programs”.  In the past, the companies have not provided this assistance to people in the CNMI.  I have been working on this for the last few years.  In Indianapolis, I met with high level executives from several companies producing diabetes medications. One has committed to establishing this program for the CNMI.  We will see, but I am optimistic.   This potentially could be a big deal for improving our overall health and avoiding the worst complications like blindness.

Preventing Diabetes

There is a lot of work being done on the national and local level to prevent diabetes from starting.  The leaders from the Centers for Disease Control (CDC) were very active at this conference.  The CDC is the federal agency tasked which conducting and supporting health promotion and prevention in the United States.  They just updated their 2017 diabetes statistics showing that 30.3 million Americans have diabetes, and that 84 million have prediabetes (studies show that most people with prediabetes will go onto full diabetes within 5-7 years).

 

The best evidence for how to prevent diabetes came from the Diabetes Prevention Program (DPP).  It was a large study which demonstrated that lifestyle changes were much more effective than medication in preventing the progression to diabetes.  I will be writing much more fully on this in a future post. There is currently a strong effort to scale up the DPP and bring it out on a national level to help more people.  We are planning to implement the DPP in our office on Saipan as well as in Rota next year, and hopefully soon after in Tinian.

Metformin updates

Metformin has for many years been the most commonly prescribed medication for diabetes.  The American Diabetes Association has called for nearly every type 2 diabetes patient to be on Metformin for life.  It has until recently, been the only major medication to significantly lower the rate of cardiovascular (heart) disease in diabetes.  Also, late last year the FDA changed their guidelines, and now call for most patients with diabetic kidney disease to remain on Metformin.  At this conference, some new studies were presented.  It has now been established that people with diabetes who take Metformin, get less cancer than those taking other diabetes medication.  It also seems to have an anti-inflammatory effect, as well as having positive effects on our microbiome.  I will write more explaining these findings in a future post.

Reframing our thought processes for better diabetes control

Dr. Alison Ledgerwood, a behavioral scientist from UC Davis, presented a series of studies, some her own, showing how the human mind tends to focus on the negative.  There are specific studies showing people with diabetes often get caught up in a negative cycle of thoughts which make sticking to lifestyle changes much more difficult.  She presented a plethora of evidence based strategies.  I will be using these in my own personal life (like so many of you, I also struggle with maintaining a healthy weight).  I will also be sharing these with my patients as well.  I plan to write on this topic in more detail in the future.

Nutrition Update

My favorite nutrition writer, Dr. David Katz, gave a thought provoking presentation.  I have read all of his books, and most of his columns, so I was aware of most of what he said from my previous reading. Hearing it in person still made quite an impression on me.  He talks about feet, forks, and fingers.  How using these things correctly can benefit our health.  In other words, using our feet to walk, our forks to eat healthy food, our fingers, not to smoke.  He presented a series of studies demonstrating that over 80% of all chronic disease, of course including diabetes, could be prevented.  This prevention is in all of our control, again, by using our feet, forks and fingers correctly.   I encourage you to see his much more articulate writing here.

Dr. Katz also spoke about Blue Zones.  These are areas of the world, such as Okinawa, where people live long healthy lives.  The blue zones project is attempting to bring what works in these blue zones to other areas.  My friend Lisa Hacskaylo from Northern Mariana College has been working diligently to have the blue zone project started here.  Dr. Katz spoke passionately on how this could help.

Cardiovascular disease and diabetes

I discussed earlier how Metformin has been proven to lower the risk of cardiovascular disease (heart attacks and strokes).  Treating diabetes with other medication has for many years been proven effective for preventing complications like blindness from diabetic retinopathy, amputation, and kidney failure. Only over the last two years several new medications have come out which are also proven to lower the risk for cardiovascular disease.  There was a great deal of talk about these new findings.

The first study called EMPA-REG was released less than two years ago.  It showed that in patients at high risk, taking the medication Jardiance for about three years, lowered a persons risk of dying from cardiovascular disease by 38%.  Now similar findings have been shown for other medications, like Invokana in the CANVAS trial, and Victoza in the LEADER trial.  These findings have shaken up the diabetes treatment world.  The above medications are now often used as second line therapy after Metformin.  I will be writing about these studies further in a future post.

Insulin Pumps

In the United States over one third of patients with type 1 diabetes (childhood onset) wear an insulin pump. Even though we have hundreds of people with type 1, there has never been an insulin pump prescribed in the CNMI.  We are trying to change this, and hope to bring insulin pumps to Saipan by next year.  There have been some amazing advances in the technology.

Insulin pumps deliver a small amount of insulin constantly throughout the day, with larger quantities after each meal.  Medical studies show fewer complications, and much less severe hypoglycemia than is seen with insulin injections.  There is some new technology’s in pumps that I will write about further in the future.  My two favorite pumps at this time are from Medtronic and Omnipod.

Miscellaneous

-New Blood glucose meters.  There are several new blood glucose meters out this year.  I am most intrigued with the Accu-Chek Guide.  We have long used the earlier Accu-chek Aviva, as it is highly accurate and very easy to use.   Several studies were presented showing the new meter is even more accurate.  It also has blue-tooth technology to connect automatically to apps on smart phones.

-New inhaled insulin, called Afrezza.  It lowers blood sugar more quickly than other insulin.  In addition it gives us another option for people who are afraid of needles.

Fenofibrate dramatically reduces diabetic retinopathy progression

Diabetes is by far the number one cause of blindness here in Saipan.  Diabetes can damage any part of the eye, but the most common way it leads to blindness is through the complication of diabetic retinopathy.  In the US mainland the National Institutes of Health (NIH) estimates that 28% of people with diabetes have retinopathy.  The problem in Saipan is much worse, over the last five years in our practice we have consistently seen that between 70-72% of our patients with diabetes have retinopathy.

While treatments like laser photocoagulation and intravitreal injections such as avastin can prevent much of the most serious vision loss, they are only beneficial with more severe retinopathy.  Until recently there has been no available medication to prevent the worsening of retinopathy to the severe stages.  Recent evidence has shown overwhelmingly that fenofibrate effectively reduces the worsening of mild to moderate retinopathy.

 

 

Fenofibrate first became available in the 1990’s and has been used to treat elevated cholesterol and triglyceride levels.  Studies indicate that the beneficial effects seen for retinopathy are independent of any changes in the cholesterol levels.  The particular mechanism is not fully understood, but fenofibrate seems to protect against the breakdown of the blood-retinal barrier.  Numerous studies show that significant side effects are rare.

Evidence

The FIELD Trial

The first major study identifying a possible oral treatment for retinopathy was the Fenofibrate Intervention and Event Lowering in Diabetes   the FIELD trial in 2009.   9795 diabetes patients were randomized to fenofibrate or placebo for five years.   The results were dramatic, the fenofibrate group was 79% less likely to have worsening retinopathy, and 31% less likely to need retinal laser surgery.  Both findings were highly significant.

The ACCORD Lipid trial

The Action to Control Cardiovascular Risk in Diabetes, ACCORD Lipid trial which studied 5518 diabetes patients considered at high risk for cardiovascular disease, was released in 2010.  Patients were randomized to statin plus fenofibrate, or statin plus placebo.  Simvastatin was used, the majority were at the maximal usual dose of 40 mg.  Again, dramatic results were seen.  The fenofibrate group showed  36% less retinopathy progression, and was also 31% less likely to need laser surgery.

There are other results from these trials that have special interest in the CNMI.  In the FIELD trial, the fenofibrate group had a significant 36% reduction in foot amputation.  Both FIELD and ACCORD Lipid showed decreased risk of both micro and macroalbuminuria in the fenofibrate group.  Albuminuria is a test for protein in the urine.  Protein excretion in the urine is an early sign of kidney disease.  Decreasing this find

ing would likely decrease new cases of dialysis from diabetes.  There was also a non-significant trend towards less diabetic related dialysis in both trials for the fenofibrate group.

Following these studies there has been increasing talk of using fenofibrate to treat retinopathy.  In 2013 Australia approved fenofibrate for retinopathy treatment.  In December 2014 an editorial in the journal Ophthalmology discussed this in great detail, see also this discussion in the American Journal of Ophthalmology   This summer I attended the Scientific Sessions of the American Diabetes Association.  While there I listened as Emily Chew, the lead Ophthalmologist at the NIH presented as yet unpublished new findings showing the effectiveness of fenofibrate for retinopathy.

Potential concerns

Kidney function is monitored when prescribing, as studies indicate fenofibrate should be stopped if GFR (a marker of kidney disease) goes below 30.  We also monitor liver enzymes, as this has been an issue in rare cases.  Fenofibrate is contraindicated in those with gallbladder disease, and has not been tested in pregnancy, so should be avoided in women of childbearing years.  It is relatively inexpensive, with an average US retail price under $30.00 per month, and is covered by every insurance in the CNMI.    An older, related medication gemfibrozil did have some significant side effects.  When combined with Statin medications it lead to an increased risk of a serious muscle condition called rhabdomyolysis.  The vast majority of studies have not shown this to be a concern with fenofibrate.  However, one study did show a possible link.  In that study there were 12.37 cases of rhabdomyolysis per 100,000 patient years of treatment, in other words it was rare.  Even though most studies do not show this link, caution is still warranted.  Patients taking fenofibrate should report muscle pain to their physicians right away.

In our clinic we take potential side effects very seriously.  We take careful precautions to avoid them whenever possible.  Also whenever concerns arise, we check with the best experts on medications, a Pharmacist.   We are blessed in Saipan to have two very good pharmacies.  If you have any questions about diabetes or fenofibrate, please call me at 235-2030.  Further information is also available on our websight at hardteyeclinic.com   I have been corresponding with one of our pharmacists about Fenofibrate.  I will share some of this correspondence below.  It goes into greater scientific detail than I usually will write in my blog, but I include it for those who might be interested.

 

My Correspondence with one of our local Pharmacists.

Thank you so much for calling me the other day about fenofibrate, and the concerns it could lead to rhabdomyolysis when combined with statins, especially with higher statin dosage.  We have been studying the use of fenofibrate to treat diabetic retinopathy carefully for about five years.  I have attached to this email my “diabetes update” I sent this out to the CNMI’s physicians early last year, which briefly discussed this issue.   As you know diabetic retinopathy is by far the leading cause of blindness here in the CNMI. 

Systemic drugs like fenofibrate, indicated primarily for cardiovascular disease and hyperlipidemia, have been considered the province of internal medicine practitioners.  For this reason we have moved very slowly and cautiously before prescribing fenofibrate ourselves.  We have had growing conviction, however, that many patients would benefit greatly from this therapy, so we have started prescribing.  Each time we do, we send detailed reports to the primary care physician or nurse practitioner.

Like you stated in our phone call, there have been concerns about possible adverse events, especially when combining with statins.  First regarding rhabdomyolysis.  I discussed above that there was no indication of this combination increasing the risk in the major trials listed above (FIELD & ACCORD Lipid) in diabetes patients.  A more general study was released in 2011.http://journals.sagepub.com/doi/pdf/10.1345/aph.1Q110  This study was a records review of over 1 million patient files who were on statin and/or fibrate therapy.  Of those 5,296 were taking a statin and a fibrate (either gemfibrozil or fenofibrate).  In this study the relative risk of rhabdomyolysis was higher with a fenofibrate/statin combination, than with a statin alone.  The IRR (incidence relative risk) for the fenofibrate/statin combination was 3.26.  The IR per 100,000 treatment years was 12.37.  The risks were much higher for gemfibrozil than fenofibrate.  There was no reporting in this study of the statin dosages used.  Another study in 2013 https://www.ncbi.nlm.nih.gov/pubmed/23324122?dopt=Abstract (this link is for the abstract, I do have a copy of the whole article if you would like to see it)  was a meta analysis of 13 studies looking at adverse events following statin-fenofibrate therapy versus statin alone.  There were no significant difference in rhabdomyolysis occurrence between the two groups.  They also specifically looked at the combination of fenofibrate with different dosages of statins.  There was no significant difference in rhabdomyolysis rates regardless of the dosage used.

 

The next study was a meta-analysis of 12 studies published in 2016, again looking for increased risks when statins are combined w/ fenofibrate. http://www.ijcem.com/files/ijcem0019029.pdf   There was no increased risk of rhabdomyolysis when comparing the two groups, this was true with both low and higher dosages of statins.

 

I read with interest the warnings on drugs.com  https://www.drugs.com/drug-interactions/simvastatin-with-tricor-2067-0-1071-611.html?professional=1  They recommend avoiding the combination of fenofibrate with statins, and further state NOT to use fenofibrate with the higher doses of statins.  There are 42 references listed, I carefully looked through each one.  I could find nothing in those references to support their cautions regarding dosages of statins.  In my careful literature review I could find no evidence of increased risks from higher doses of statins when combining with fenofibrate.  There is very extensive evidence of this with gemfibrozil.  If you find any evidence from the literature that contraindicates my findings, I would greatly appreciate it if you would share it with me.

 

While any indication of an increased risk of a condition as serious as rhabdomyolysis should be taken seriously, of course we must balance the risks with the potential rewards.  If we ignore the benefits for albuminuria & limb amputation, the benefits in retinopathy progression in our opinion far outweigh the potential risks.  We feel this is the case even if we only look at the one major study showing increased risk.  Even in this study there were about 12 events per 100,000 patient years.  We would have to balance this with the known prevention of worsening retinopathy in thousands of patients per case of rhabdomyolysis.  The evidence is mixed, and in our opinion, overall points away from an increased risk for rhabdomyolysis in our treatment population.  The studies specifically looking at diabetes patients showed no link.  The meta-analysis of all available RCT’s from 2013 and 2016, found no link.  Again we could find no evidence from the literature of an increased risk of rhabdomyolysis and higher dosages of statin.  See this discussion of the safety of combining fenofibrate with statins.  https://www.ncbi.nlm.nih.gov/pubmed/26134595#

 

While you specifically mention rhabdomyolysis in your call, I would also like to address another concern that has been raised.  Citing the lack of evidence  of cardiovascular benefit in combining fenofibrate with statins, the FDA withdrew the approval of this combination for cardiovascular disease in April 2016.  http://www.medscape.com/viewarticle/862022   Again we are not prescribing fenofibrate for the cardiovascular benefit, but to treat diabetic retinopathy.  Studies indicate that the retinal benefits are unrelated to improved cholesterol or triglyceride parameters.  The FDA also cited a possible concern of increased cardiovascular events in women.  In the ACCORD Lipid trial there was a slight decrease in cardiovascular events in men, an increase in women.  Neither change was statistically significant on its own.  The difference between the sexes also was not noted in the FIELD trial.  

 

Based on all of the above, we feel that in diabetes patients with mild to moderate diabetic retinopathy without contraindications (GFR below 30, elevated liver enzymes, gallbladder disease, and women of childbearing years), that fenofibrate will benefit our patients.  This will be true whether or not they are also taking statin medication.  Of course we are anxious to hear any and all evidence that would lead in a different direction as we all try to serve our mutual patients.

 

Thank you again for your help, and your service to our community.