In May 2013, I wrote a blog about INVOKANA [canagliflozin] – the first sodium glucose co-transporter 2 (SGLT-2) inhibitor. It was the first Food and Drug Administration (FDA)-approved agent in this new therapeutic class for the management of type 2 diabetes. This new class was developed to target another defect for hyperglycemia (i.e., kidneys). In development, it had desired characteristics for an anti-hyperglycemic agent, such as minimal to no risk of hypoglycemia and weight loss with an effective, proven A1c reduction.
Another SGLT-2 inhibitor was approved in January 2014 for the management of type 2 diabetes – dapagliflozin or FARXIGA. In healthy individuals, approximately 90 percent of the filtered glucose is reabsorbed by SGLT2 in the proximal renal tubule. The kidney desires to excrete excessive, filtered glucose in order to restore normal levels of glucose in the blood. In a patient with type 2 diabetes, the kidney is dysfunctional and responds to hyperglycemia through glucose reabsorption. (Defronzo RA, Diabetes 2009)
Dapagliflozin works similarly to canagliflozin to decrease plasma glucose due to increased glucosuria. Theoretically, this primary action would lead to: (1) increased insulin sensitivity; (2) increased insulin secretion; and (3) decreased glucose production by the liver. Based on the evidence, dapagliflozin has similar A1c reduction and weight reduction as canagliflozin.
While there may be benefits to this new class, there are still some concerns. For example, there is a risk of urinary tract or genital mycotic infections from its activity of glucosuria with canagliflozin and dapaglifozin. On a serious note, bladder and breast cancer was found in a small number of patients who received dapagliflozin; this adverse event was the reason for its first drug application to be denied by the FDA.
In recent evidence from the Journal of Clinical Investigation, there were two studies with a small number of patients that demonstrated the effectiveness of canagliflozin and empagliflozin (not approved in the United States) on glycemic control. In the studies, both agents increased glucose excretion in the urine. However, both studies demonstrated an increased endogenous glucose production through elevations in glucagon levels. This new evidence may be preliminary data showing a compensatory increase in glucagon secretion, which would contradict the class’ theoretical mechanism of action.
Providers will either prescribe or wait to write a prescription for these products as they become available on the market. However, there may be some reluctance especially as more evidence is evolving that may counteract the proposed theories for canagliflozin and dapagliflozin.
Last week, I attended a presentation by 1 of the 25 research scientists for JDRF. We have a great group of support staff here in San Antonio; they are committed, caring and really go the extra mile for their members.
Their tagline is “Turn type 1 into type none.” Their plan is to create a future with:
The speaker, who has had type 1 diabetes (T1D) since he was 14 years old, shared several areas of research which JDRF is funding:
Artificial Pancreas: This will eliminate blood glucose testing and carb counting by monitoring glucose values and automatically releasing insulin as needed. He reported that the artificial pancreas is done, but they still need to improve the technology. Studies continue to look at current platforms such as smartphones, CGMS and pumps. The system is ready and being marketed and sold by Medtronic in Europe. The European market has shown good data, especially in the area of eliminating overnight low glucose.
Encapsulation: This would detect glucose in the blood, secrete insulin to control glucose and protect beta cells from an immune system attack. It would avoid immunosuppression, which often causes problems of its own.
Smart Insulin or Glucose Responsive Insulin: This would activate only when glucose goes up.
Restoration: This would be a biologic cure for T1D. This will involve the creation of new insulin producing cells.
Prevention: This would slow or stop the progression of T1D before beta cells fail and insulin dependence occurs. The long term goal is to create a vaccine that would eliminate the risk of anyone developing T1D.
Medications: This would slow or stop the progression of the complications associated with diabetes.
I read in another article today that there are over 30 drugs in development for T1D – either for prevention, regeneration of insulin producing cells or to treat complications.
The information I found most fascinating was that researchers are now finding that beta cells often “recharge” and that the pancreas will have occasional “bursts” of insulin. The speaker stated this might be an explanation for the honeymoon where beta cells resume functioning for varying lengths of time after the onset of T1D. This may explain why it is so difficult to control T1D; just when things seem to be going well and glucose is under good control, the person will experience hypoglycemia.
The only thing I could think to say about this presentation was “We’ve come a long way, baby!” For those too young to remember, this was a tagline for a cigarette for women – it might not be appropriate in that context, but we certainly have come a long way in our attempts to “turn type 1 into type none.”
I have to admit, I love insulin. It is such a cool drug. It has few side effects (potential for hypoglycemia being the biggest concern), it works quickly to bring blood glucose levels under control, and it is relatively easy to deliver with insulin pens and pumps. It has a great track record, beginning with the first dose in 1922. I have studied it’s mechanism of action, role in metabolism, and how to coach dosing for food, exercise and emotional as well as physical stress. I talk to people about it each and every day. It’s of course the only option for folks with type 1 diabetes, but is often put on the back burner for later use with individuals with type 2 diabetes long after (in my opinion) it should have been started. After explaining its power, and the ease of tiny needles and insulin pens, I rarely have a patient who is not willing to try insulin and almost always reports amazement at how effective it is, especially after the frustration of using multiple oral medications for longer than their power lasts.
It was wonderful for me to see basal insulin as a second line of therapy option for patients with an A1C of ≥ 7.5% in the 2013 AACE Comprehensive Diabetes Management Algorithm. Not that it is for everyone, but it is an option! The guidelines also recommend basal insulin plus orals when A1C is ≥ 9.0%.
So it was such an absolute treat for me to read an article in the February 2014 issue of Diabetes Forecast, written by Dan Fleshler, a 51 year veteran of diabetes. The article is titled “Abracadabra: the lessons of insulin.” His description of learning more about insulin, the drug he has used for years, and recognizing the true wonder of the drug is delightful. The term “Abracadabra” reflecting the magic of this drug of drugs, a term Fleshler found to describe insulin as he scoured websites for a better understanding of insulin’s role in the human body. Remember, it was less than 100 years ago, that type 1 diabetes was a death sentence, and now it is “merely” a frustrating, tedious inconvenience.
I hope no diabetes educator is standing in the wings, afraid to recommend insulin to a patient or primary care provider, or perhaps even worse, afraid to work with insulin and the patient. I hope you too are loving the drug, teaching its role in the drug treatment for type 1 diabetes of course, but also a recognizing it as a clear options for individuals with type 2 diabetes. And perhaps you will look at insulin in a bit different light – perhaps using Fleshler’s very delightful and descriptive word “Abracadabra” as you teach patients to inject, just as he does when injecting himself with this life sustaining fluid.
While reading one of my favorite nutrition newsletters, Nutrition Action Health Letter, I came across a new approach to insulin therapy using intranasal insulin to boost cognitive ability.
In the January/February 2014 issue, the feature article, “Trouble Ahead? How to Keep Your Brain Sharp” highlights this research through a sub-article called “Insulin, by a Nose.” After realizing that patients with prediabetes had low insulin levels in their brain (despite high insulin blood levels), they started giving insulin nasal sprays. Researchers at Wake Forest with the Study of Nasal Insulin to Fight Forgetfulness (SNIFF) tested patients with mild memory impairment or Alzheimer’s disease. They found that there is a strong connection between insulin and memory. (Click here to read the article)
As diabetes educators, we know that insulin has receptors in the brain working on glucose metabolism. What I didn’t realize is that those insulin receptors also work closely with memory formation and retention. When there is a problem with those insulin receptors, memory is affected.
I found out that they are now recruiting patients for the next phase of the SNIFF study to administer intranasal insulin and look at the effect on patient’s abilities to complete memory tests and improvements on daily functions.