Last year I wrote a diabetes newsletter to the Physicians and other medical providers on Saipan, Rota & Tinian. It detailed new treatments for diabetic retinopathy with Fenofibrate. Also updates on diabetes medications Metformin and Jardiance. I will be writing more on these topics soon. Till then here is last years update:
Diabetes information for health care professionals
-Metformin safe to a GFR of 30, see FDA announcement.
-Jardiance lowers death and heart disease from diabetes
-Fenofibrate proven effective to treat worsening retinopathy
Metformin Safe for most patients with renal disease
On April 8, the FDA announced changes in its guidelines for Metformin. They no longer recommend using creatinine readings to restrict its usage. The American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists(AACE) have long called for this change. When metformin was approved in 1995, it was not initially approved for patients with kidney disease. This restriction was based on experience with phenformin, which was removed from the market in 1976 after it induced severe lactic acidosis in many patients with kidney disease. Metformin, in numerous studies over the years, has not been associated with this problem. In fact, most studies have shown a lower rate of lactic acidosis with metformin, compared to patients taking other diabetes medications.
The new guidelines from the FDA call for the use of Metformin down to a glomerular filtration rate (GFR) of 30. The ADA is slightly more conservative. Their standards, call for the use of Metformin in nearly every patient for the entire course of their diabetes, first as monotherapy, then in combination with other oral medications and/or insulin. The ADA recommends using maximal dose Metformin until stage 3b kidney disease, when the GFR goes to 44 or lower. If the GFR falls between 30 and 44, limiting the dosage to 1000 mg/day is recommended. If the GFR drops below 30, then Metformin should be discontinued. These are similar to the clinical guidelines being used in most developed nations.
This decision from the FDA has been widely praised by diabetes experts, here is one example: Silvio Inzucchi, MD, of Yale Diabetes Center, New Haven, Connecticut,” I am very pleased that the FDA has made their decision to expand the potential use of metformin to more patients. Evidence has emerged over the past 2 decades that the prior guidelines as related to renal function were overly restrictive and, essentially, prevented the use of this important, effective, and inexpensive generic medicine to hundreds of thousands of patients in the US.”
Jardiance (Empagliflozin) and Cardiac Death
Dramatic decreases in heart failure and cardiovascular death surprised researchers studying diabetes patients taking Jardiance (empagliflozin). The study: EMPA-REG or Empagliflozin, Cardiovascular Outcomes & Mortality in Type 2 diabetes, was released in the New England Journal of Medicine in Sept. 2015. It was a randomized, double blind, placebo controlled study of just over 6,000 patients followed for a period of 3.1 years. Patients had an entering A1C of 7.0 to 9.0, the majority had pre-existing cardiac disease.
In the study Jardiance showed a 38% reduction in cardiovascular mortality, and a 32% reduction in all-cause mortality. This was a surprise to researchers as studies of other medicines have shown limited to no improvements in cardiovascular disease deaths. Metformin is the only other diabetes medication that has been proven to lower cardiovascular mortality.
These results have shifted the treatment strategies for many physicians. Please see this discussion from Anne Peters M.D., an endocrinologist and director of the USC Westside Center for Diabetes. Many leading diabetes specialists are now placing Jardiance as second line therapy to add when Metformin fails to achieve glycemic targets, especially in patients at higher risk for heart disease.
Jardiance is a Sodium Glucose Transport (SGLT- 2) inhibitor, first approved by the FDA in 2013. Other medications in the same class include Invokana and Farxiga. SGLT-2 inhibitors work by decreasing renal glucose re-absorption in the proximal tubule, thus increasing urinary glucose excretion. This extra excretion of glucose averages about 100 g of sugar in the urine per day, leading to weight loss. In most studies including EMPA-REG, the weight loss averaged about 8 pounds over the first 26 weeks. In EMPA-REG the weight loss was maintained throughout the three-year study period.
Studies have shown a low rate of side effects. The most common has been termed a “nuisance” as opposed to serious side effect. Between 5-10% of women experienced genital mycosis infection, a smaller percentage occurred in uncircumcised males. These infections usually occurred just once, early in the treatment course, with very few recurrences. More serious side effects have proven rare. The largest studies showed a similar rate of ketoacidosis in Jardiance and placebo treated patients. Other, smaller studies have raised a concern about rare, but increased rates of ketoacidosis with Jardiance treatment, ongoing trials are in place.
Jardiance is on the Formulary for every major insurance in the CNMI including Calvos, Staywell,
Netcare/Moylan’s and Aetna. It is covered by Medicaid, but would require a prior authorization form to be filled out. Jardiance is an expensive medication, the average retail price in the U.S. is $371.00 per month, slightly lower than the cost of Januvia. In most studies it lowers the A1C an additional 0.7-1.0 when added to Metformin. It is available in dosages of 10 and 25 mg, with the 25 mg dose having slightly higher efficacy, but also a slighter higher risk of side effects.
Fenofibrate dramatically reduces diabetic retinopathy progression
Several large placebo controlled, double blind studies have demonstrated dramatic reductions in diabetic retinopathy with fenofibrate. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was centered in Australia. 10,000 patients were randomized to Fenofibrate or placebo. Over a five-year period, those in the Fenofibrate group were 79% less likely to have worsening retinopathy, and 31% less likely to require laser surgery. The ACCORD Eye Study randomized 5518 diabetes patients to either statin & placebo, or statin with fenofibrate. Both groups were followed for four years. The fenofibrate group had a 36% decrease in retinopathy progression and was also 31% less likely to need laser surgery, See this link for expert discussion of these study findings.
There have been growing calls for wider use of fenofibrate to treat retinopathy. In 2013 it was approved for treatment of retinopathy in Australia. See this editorial printed in Ophthalmology last year, Ophthalmology is the official journal of the American Academy of Ophthalmology.
The editorial calls for the use of fenofibrate in those with worsening retinopathy. Studies indicate that the beneficial effects seen for retinopathy are independent of any changes in cholesterol levels. The particular mechanism is not fully understood, but fenofibrate seems to protect against the breakdown of the blood-retinal barrier. In these large studies significant side effects were rare.
Kidney function is monitored when prescribing, as studies indicate fenofibrate should be stopped if GFR goes below 30. We will 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.
Don Hardt is a Board Certified Optometrist and Certified Diabetes Educator, (C.D.E.). He and his partner, his brother David, are two of only ten eye doctors in the United States who have become C.D.E.’s. Their clinic has the first, and the only Diabetes Education program to be officially recognized by the American Diabetes Association in any of the US Pacific territories.