Tuesday, April 28, 2020

Retrospective #437: Heading for the cliff

“Thelma and Louise,” the 1991 feminist comedy, is most memorable for its ending.  Let me set the scene: Being chased across the desert by a dozen cop cars, with a cliff in front of them, Thelma says to Louise, “Okay, listen; let’s not get caught.” Louise replies, “What’re you talkin’ about?” Thelma replies: “Let’s keep goin!’ Louise replies, “What d’ya mean?” Thelma: “Go” [nods ahead of them]; Louise: “You sure?” Thelma: “Yeah.” And they drive off the cliff.
Now, juxtapose this dialogue, the action that follows, and the consequences, with a current TV commercial for a once-a-week, injectable, type 2 diabetes drug to “activate your within.” This drug works, they say, to “help activate your body to release its own insulin.” Why, they ask? Because “diabetes can be hard to manage. It’s important to remember that diabetes is a progressive disease, which means it usually changes over time. And when it changes, your doctor might have to change your treatment as well.” In other words, your doctor tells you, “Let’s keep goin’!”
But, the pharmaceutical company counsels you, “You are not alone. Millions of people are living with diabetes and going through some of the same things you are.” Now, the image in my mind changes. Imagine you are among millions of lemmings heading for the cliff. “What are you talkin’ about,” you ask? “What d’ya mean?” Well, by the time you’re a candidate for this injectable medicine, you’ve already followed in the footsteps of the lemmings like you who have taken oral antidiabetic medicines, like metformin and sulfonylureas (see below) and have now “progressed” to others. Remember, in the ad, you’ve been assured: “Diabetes is a progressive disease,” and “You’re not alone.”
The medical dogma is that progression of type 2 diabetes from Impaired Fasting Glucose (IFG) to Impaired Glucose Tolerance (IGT), to frank type 2 diabetes is a gradual, decades-long continuum. Ralph A. DeFronzo, described it 12 years ago in his Banting Award keynote speaker address at the 2008 American Diabetes Association meeting.  I chronicled DeFronzo’s remarks 7 years ago in this column, “Natural History of Type 2 Diabetes.” 
 A hyperlink in my old post will take you to the paper in the ADA’s journal, “Diabetes,” in which DeFronzo’s states, “Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function”  Why is this relevant? Because this new injectable drug “activates your body to release its own insulin,” which ultimately will lead to the “loss of your β-cell function.”
Sulfonylureas (SU’s) lower blood glucose “by stimulating insulin release from the Beta cells of the pancreas.” The current generation of SUs, still popularly prescribed (because they’re cheap), include the glimepiride (Amaryl), glipizide (Glucotrol), and glyburide (Diabeta, Micronase, and Glynase). In the ADA paper cited, DeFronzo says,
“Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile [upper third] of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function” (all emphases added by me).
So, if, as Defronzo says in the first paragraph of his seminal paper in “Diabetes,”
“Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1c and progressive loss of β-cell function” (emphasis added), then…
Why, pray tell, if you may already have lost 80% of your pancreatic β-cell function on the drugs you have been taking for years, why would you want, or allow your doctor to prescribe a drug that will ACCELERATE the loss of your remaining β-cells?  Wouldn’t that be like letting you (not your doctor, though), like Thelma and Louise, drive over the cliff? Quoting Louise, “Are you sure?”
Or could it be that the maker of this new medicine, Lilly, and your doctor, have you covered? Lilly also makes and sells insulin, a drug with price increases at 10x the rate of inflation.  And all your doctor has to do is get out his or her pad and write a prescription.

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