We know through all of the studies we’ve
ever done that if you lower LDL cholesterol levels, you avoid or reduce clinical events. But look what happens in the patients who
were treated with Metformin. There was a smaller subset of patients treated
with Metformin. And from the beginning, those patients have
a significant reduction in myocardial infarction that continues out over time.
And this is really the first sort of inkling that perhaps drugs that don’t cause hypoglcemia that have a different action than to the secretagogues than insulin may be more beneficial
in terms of macrovascular risk reduction. Why haven’t trials shown cardiovascular
disease risk reduction? One of the biggest issues is that we’re seeing lower and lower
event rates. We haven’t had very big differences in glycemic
control and at least not the big differences we’d like because using drugs that cause
hypoglycemia limit our ability to get people down to lower A1c levels. The observation periods tend to be short, but the final thing that I think is incredibly important is that you’ve got to start early
in the natural history of this disease. With diabetes, perhaps more than any other
disease, it really matters what the patient does in their lives that are separate from
us. I want them to tell me what they are concerned
about. And sometimes it is completely unrelated to what I am thinking about. And I also want
to make sure that I have answered their questions and had them set goals. Now this is one the slide that changed how
we all thought in the world of diabetes. And it is the slide that you all must remember. So, at the very top are the two long-term
trials: UKPDS (remember, type 2, newer onset that followed people first for ten years in
the study and ten years and more in the follow-up); and then DCCT/EDIC which was type 1s followed
intensively for about seven years and then for many years in follow-up.
Then these other studies—ACCORD, ADVANCE, and VADT—all type 2 studies, all patients
who already had macrovascular disease. They were at high risk and already had longer-duration
disease. From what I have already said to you, these
are the subtype of patients that you might think you not make much of a difference when
it comes to macrovascular impact by treating glycemia. So, in all of these studies, lower blood sugars
reduce microvascular risk, but the cardiovascular risk data is much more complicated.
So, in the short term, none of the studies showed a reduction in cardiovascular disease
from glucose lowering, but over the long haul, you see a nice reduction independent of anything
else in both UKPDS and DCCT. So, start early, treat aggressively, and patients will do well
over time. No matter what your hemoglobin A1c level,
whether you are in intensive treatment in any of these studies or standard treatment,
having an episode of severe hypoglycemia increases your mortality. It increases your risk of
death by three to five percent. So our glucose targets are an A1c of less
than seven, but we individualize targets. At 65 and over, we now say the target is less
than 7.5, at least according to the American Diabetes Association. Moderate co-morbidities, they say your target
is less than 8.0. And severe co-morbidities, they say your target is less than 8.5. There was only one thing I know for sure…perhaps
two. One is that lifestyle matters. Second of all, metformin is the best characterized
drug. We know all that is good, bad, and indifferent
about it. It has been out since 1957.
And it is the first-line therapy; it’s the first drug to go with. It works. What do you do next? Well, I can’t tell
you. I can’t tell you for two reasons. One, there’s no really good comparative
data that says which one should I take because each of these drugs has been studied, but
not in trials that compares them against each other, really. So, at the County, I can tell you that I go
from Metformin to a Sulfonylurea agent to insulin because those are the steps in the
setting in which I practice. If that second-line therapy doesn’t work,
we have all sorts of third-line combinations where’s even less data on how well these
things work together. And then if that doesn’t work, you can go
to basal insulin. And a lot of what we talk about in the new
guidelines is the fact that we want you to use basal insulin plus a GLP-1 receptor agonist
as opposed to mealtime insulin because mealtime insulin has the highest rate of hypoglycemia
and actually the lowest rate of getting to target. Now, there are some caveats.
If you are not able to tolerate Metformin, you can use any of these as a first-line agent
instead of Metformin. You can use dual therapy if your A1c is higher.
And if somebody’s really sick, you may need to start insulin sooner rather than later. How do I treat to avoid hypoglycemia? This
is my preferred path. So, I start with Metformin and then I add in
a TZD, a DPP-4 inhibitor, SGLT2 inhibitor, and a GLP-1 receptor agonist.
That’s how you avoid hypoglecemia. The least weight gain? You take away TZDs
from that and you get this pathway… And then the lowest cost, you go this way. Is there a dose of weight loss that does reduce
cardiovascular disease risk? And you know what? The answer is “yes.” If you lose ten percent or more of your body
weight and keep it off, you will reduce your risk macrovascular disease. What was associated with weight loss? One in particular that was associated with
weight loss in our East L.A. population was the use of meal replacements. So, in East L.A. it is very hard to go and
tell patients to have healthy food when they can’t afford it, right? It’s expensive to get fresh fruits and vegetables. So in this study, we gave people meal replacements.
It was either SlimFast, Glucerna, or HMR. And they could have meal replacements for
one to two meals a day. And in our site in particular, but in every
site, the more meal replacements you used, the greater your weight loss. So in terms of treating cardiovascular risk,
we obviously do the things we need to do using statins, controlling blood pressure, and aspirin. I personally think that if we use drugs that
don’t cause hypoglycemia or at least try to minimize hypoglycemia, that we’re going
to do better. I think early control is vitally important,
but it should be maintained over time. And I also think that we should never ever
forget the value of lifestyle. I was told that the percentage of my body
that was sugar was 12 percent. Your A1c was 12 percent.
That felt like that was not going to work out. I drank a lot of Cokes. I can tell you that.
There was a lot of sugar in my diet. My mother at night—she would always have
candy out when we were growing up to watch television. So that was sort of love, right? So he has neuropathy which scared you. And we sent him to the dietician and he lost weight. How much did you lose? Like 20 lbs., right? I think so. Yeah. I did lose weight and I
think I was scared into it, you know? So he was scared into it, yes. When did you
start feeling in control of it? I don’t. I mean, I don’t. I still don’t. Ann got me though medications and stuff down
to like below six from the twelve. I walk like four or five miles a day.
Pretty good. I do pretty good. Not fast enough and probably not with enough
cardio where I really enough exerted. Everybody never does good enough. He does
good enough. The point of it—him—is that we started with Metformin.
After Metformin was not working as well …oh, and I put him on a low dose of Actose to help
preserve his beta cells at some point when his blood sugars went up a bit. And then he takes 15 milligrams of Actose a day.
On Metformin and Actose, he did well for maybe eight years. And then his blood sugars started to go up
some and then we put him on a DPP-4 inhibitor, and then you took that for awhile. And then you “out ate” that and then you
did go up to 7.8 which is above any target. And then he’s now on a low dose of an SGLP2-inhibitor
with Metformin, and a little bit of Actose. Correct? I don’t know. Yes. Do you take the pills I give you? Yes.