Tuesday, January 28, 2020

Retrospective #346: “Glucose lowering in T2D is largely useless.”

I’m a big fan – a devotee you might say – of Jason Fung, MD, a Canadian nephrologist, blogger, and author. His very good book, “The Obesity Code” (2016), has been hugely popular in large part because it is comprehensible to the lay reader. He is also a frequent blogger, and his 2016 post, “Futility of Blood Sugar Lowering in T2D,” like a previous one, “Obesity is Protective,” Retrospective #341, got my attention.
All reasonably well-informed students of diabetes – including clinicians who treat diabetics, endocrinologists, diabetologists, as well as Certified Diabetes Educators (CDEs) and Registered Dieticians (RDs) – are familiar with two large, long-term UK studies, the DCCT and the UKPDS, and the US follow-up, the ACCORD study. What Fung did in his recent blog post was succinctly summarize the findings of those studies and posit, in conclusion, “…that blood glucose lowering in type 2 diabetes is largely useless.” That was a pretty stunning conclusion.
His logic, however, is impeccable. “The DCCT study…had already established the paradigm of tight blood sugar control in Type 1, but whether this held true for Type 2 remained to be seen,” he said. In UKPDS33, he went on, a large cohort of “newly diagnosed T2D patients who failed a 3 month lifestyle therapy trial were enrolled into an intensive group of sulfonylureas or insulin vs. conventional control.”
“The drugs certainly were successful in lowering blood sugars” [to 7.0% vs. 7.9% in the diet group], he said, “but there was a price too. Weight gain was far worse on the drug group….” But over the 10 years of the study, they found no “benefits for the end points that everybody was interested in, i.e., cardiovascular disease (CV). Despite reducing blood sugars, CV disease showed no benefits,” he averred. “Since the majority of deaths are due to CV disease, the primary goal of therapy was reduction in deaths and CV disease, not microvascular disease.”
In a sub-study called UKPDS34, overweight patients with T2D were randomized to either metformin or diet control alone. “Once again, over the space of over 10 years, the average blood sugar was lowered by metformin to 7.4% compared to an average A1c of 8% in the conventional group,” he said, but, “In contrast to the previous study, intensive control with metformin showed a substantial improvement in clinically important outcomes – there was a 36% decrease in death (all cause mortality) as well as a 39% decrease in risk of heart attack.”
“Metformin performed far better than the insulin/SU group despite the fact that average blood sugar control was worse,” Dr. Fung concluded (emphasis his). “What’s the major difference between the two medication groups,” he asked? “Insulin! Insulin and sulfonylureas (SU) increase insulin levels. Metformin does not.”
Refrain, all together now: “Because it does not raise insulin, and insulin drives obesity, metformin does not cause weight gain.
Troubled by the failure of the original UHPDS study to show a benefit from reducing high blood sugar in Type 2s, the U.S. National Institutes of Health (NIH) undertook “an ambitious large trial called the ACCORD study (Action to Control Cardiac Risk in Diabetes).” Two groups with an average A1c of 7.5% were randomly assigned, the 1st to “standard therapy,” the 2nd to “intensive drug therapy,” “…with the goal of seeing whether this intervention would reduce disease.” They were successful in lowering their A1c to 6.5%.
But that was not the primary end point. They “wanted to know whether this made any difference. It sure did,” Dr. Fung says. “When the trial results broke, there was a media firestorm. Why? Because the intensive treatment was killing people! The risk of death increased by a horrifying 21% in the intensively treated group,” he wrote. Then, with 17 months before the scheduled end of the trial, “the safety committee looked at the available data and forced the premature end of the [ACCORD] trial.”
Was the study design flawed because there was no specification of which medications to use to intensify treatment, and the drug Avandia, which was very popular at the time, was included? I took Avandia briefly before I began to eat VLC. Avandia now carries a black label warning that it may cause heart attacks, angina, and heart failure. “Yet, here we sit in 2016, with no better idea of how to treat type 2 diabetes than to lower blood sugars,” Dr. Fung concludes.
But Dr. Fung doesn’t leave the matter there. Check in tomorrow to see what he suggests be done about it.

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