James K. Rone, MD, FACP, FACE

DIABETES PROGRESS—A TALE OF TWO STUDIES

April 27, 2014

Tags: Diabetes

It was the best of times, it was the worst of times…
—Charles Dickens

By coincidence I was recently honored with an invitation to lecture on a topic of my choosing for my local AARP chapter (it was strongly suggested diabetes be the focus), and in the process of preparing what I titled TYPE 2 DIABETES UPDATE: 2014, I pondered a question I didn’t know the answer to…Since the early 1990s have we really improved outcomes—that is, improved glucose control, and rates of complications, such as eye, kidney, and nerve damage in diabetes sufferers?

The early 1990s were a watershed for diabetes: the DCCT was published in 1991—this was the study that at long last conclusively proved strict blood-glucose control and low hemoglobin A1c’s of <7.0, prevented complications. This had a profound impact on diabetes management in the years and decades to come. A short time later, in 1994, metformin was approved by the FDA in the United States. Metformin had been available in Europe for decades, but at that point became the first drug for diabetes available to the US market other than insulin and sulfonylureas, the latter being pills that stimulate insulin release by the pancreas. In other words, before metformin, all we could offer in the realm of drug treatment for diabetes was more insulin, either in the form of a shot or a pill (as my father would say: “six of one, half-dozen of the other”). Metformin was the first really new thing in diabetes drugs since the 1920s, and eight totally new classes of drugs have been introduced to diabetes management since, the last in 2013.

In other words, in 1990 we had 2 drug classes for diabetes: insulin and sulfonylureas. In 2014, we have those, plus metformin, plus eight others, some shots, some pills. A total of 11 options to mix and match in our diabetes patients, not to mention radically new insulin types.

In practical terms, this means diabetes management today is a lot more complex and costly than it was almost a quarter century ago. What have we gotten in return? The coincidence I referred to above was that I was asked to give that AARP talk, which led me to ponder this question, which I wasn’t sure there was a known answer to. Yet, less than 1 week after my talk, two scientific papers appeared—one in the NEW ENGLAND JOURNAL OF MEDICINE (NEJM), the other in ANNALS OF INTERNAL MEDICINE (AIM)—which directly answered my questions about whether we’re seeing better control and fewer complications.

The complications issue was addressed in the NEJM study and the answer was overwhelmingly positive. Between 1990 and 2010, among Americans with diabetes, there were 68% fewer heart attacks, and 64% fewer deaths due to a high-glucose crisis, such as diabetic ketoacidosis. There were 53% fewer strokes and 51% fewer leg and foot amputations, and a 28% reduction in severe renal failure.

Those data are of course very good; however, in that same period, the number of people with diabetes tripled from almost 7 million to almost 21 million. And if you look at those same diabetes complications and express them as a percentage of all Americans, rather than as a percentage of just Americans with diabetes, it turns out that there were still fewer diabetes-related heart attacks and hyperglycemic crises, but no improvement in amputation, stroke, or kidney-failure rates. Kind of supports the old adage about being able to prove anything with statistics. Yes, we have greatly improved the lot of the individual person with diabetes—reduced for example that person’s risk of having to have a leg amputated—but we haven’t reduced the number of diabetes-related leg amputations in the United States, see?

What about blood-sugar control? The AIM paper addressed that. A few definitions are in order: HbA1c is a blood test that effectively tells what a person’s average blood sugar was like over the past month or two. A HbA1c <7 is considered good, and <8 is considered fair. The AIM paper compared the percentage of American diabetes patients getting HbA1c’s <7 and <8 in the period from 1988 to 1994 (the “pre-metformin era”) to the period from 2005 to 2010. Note that this study covers roughly the same span of time as the NEJM paper, but looks at different kinds of outcomes.

Here goes: HbA1c was <7 in 51% of diabetics in the 1988/94 period and 59% in 2005/10. It was <8 in 67% and 79%, respectively. If we just look at diabetes patients taking medication to control their disease—which gets more to the heart of the question I formulated getting ready for the AARP, are we doing any better with 11 classes of drugs than with 2?—40% achieved a HbA1c <7 in 1988/94 and 55% in 2005/10. And HbA1c <8: 59% and 78%, respectively.

So, to summarize the AIM paper, in all cases we are doing better now. That’s not surprising, that’s what I guessed for the purposes of my talk, but I also surmised in the talk that though we’re doing better, we’re not doing all that much better. And that is what this data shows. For diabetics taking drugs to get under control, the percentage getting under excellent control improved by only about a third (55% divided by 40%), and the percentage achieving at least fair control increased by just about the same degree. That’s good. I’m very happy we’re doing that, but I don’t think a 1/3 improvement is all that impressive stacked up against the fact that the number of classes of drugs for diabetes has quintupled, and some of those newer drugs cost hundreds of dollars per month. (To be fair, not all of those 11 classes were available in the study period ending in 2010, but most were.)

There is something else to consider—prior to 1991 there was no definitive proof that getting the HbA1c to <7 was important. I was in my training in that period before the DCCT trial and I can attest to there having been far less aggressiveness on the part of many physicians’ diabetes management. So, we are seeing a 1/3 improvement in the percentage of diabetics on drugs getting under control, at a time when we have 5X the number of drugs to do the job, and a greater understanding that it is important to try. See what I mean? If you were to factor out the doctors who didn’t even try in 1988, something that might be malpractice today, I bet the improvements would be even less impressive.

What do we learn if we combine the findings of these two papers? Seems to me that we are doing a much better job of preventing most complications, including heart attacks and death from diabetes, at least in the individual diabetic—we’re not doing so good with the population because we’re doing a lousy job of preventing new cases of diabetes, which have soared. Anyway, we’re reducing complications despite less impressive improvements in actual blood-sugar control. Which tells me that it isn’t all about blood sugars.

Glucose control is important but it is not necessarily more important than other challenges diabetes patients face, such as high blood pressure, high cholesterol, insulin resistance, vascular inflammation. I think we’re doing at least as good a job and probably better controlling these things as we are controlling blood sugars. Especially LDL cholesterol, with the introduction of the statin drugs at about this same time in the early 1990s. These are the real lifesavers, I believe. The prevention of heart attack and stroke and amputations in diabetics owes at least as much to better blood pressure and cholesterol medicines as it does to better glucose control.

So what about those 9 newer classes of diabetes drugs? Are they worth the added cost and complexity? You might’ve been expecting me to say no, considering the tone of this posting to this point. But, as I said, it’s not all about blood sugar. Those shinier newer drugs might not be doing that much better for blood sugar, but what they are doing, they are doing in different ways compared to what was available pre-1994 when all we did was increase insulin levels. We’re reducing insulin resistance, systemic inflammation, glucagon levels, appetite stimulation, altering fat-cell metabolism, and cholesterol profiles—all with just our newer diabetes medicines. There may even be a lower overall cancer risk with the newer versus the older drugs.

So, yes, we are better off paying top dollar, when we can afford to, for these newer drugs and drug combinations. Like with anything: you get what you pay for. They may not be showing that much more bang for the buck when it comes to blood sugars, but when you factor in how they do what they do, and the side benefits beyond blood sugar control, it is the best of times for those with diabetes.

Now we need to work on prevention, because it is still the worst of times in that arena.

Dr. Rone

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