In part 1 of this exclusive interview, DIC publisher Steve Freed talks with Dr. Aaron Vinik about the shift away from rigorous glycemic control in favor of greater focus on the impact of diabetes treatment on the heart.
This is part 1 of a 2-part video transcription.
The full transcribed interview is also available in PDF format.
Steve Freed: You had mentioned that there is a paradigm shift in treating diabetes. That protecting the heart may be more important that tight blood glucose control. Can you explain what you meant by that?
Dr. Aaron Vinik: With the advent of the studies, like the diabetes complications trial, improving glycemic control in type 1 diabetes – they were really showing that improvement of glycemic control would reduce the microvascular complications for diabetes. The long-term outcome of the DCCT , the EDICT study also showed that in people with type 1 diabetes, intensive glycemic control reduced macrovascular events.
Unfortunately, every attempt to show that glycemic control made the difference to macrovascular events in type 2 diabetes failed to achieve success. This all started originally with The United Kingdom Prospective study. And at the end of the study, they were not able to show that they were able to reduce cardiovascular events.
As occurred in the DCCT, with the long-term follow up of UKPS identified a subset of people who were treated with metformin, who did actually have a reduction of macrovascular events. When it came to showing that glycemic control, per se, could reduce major adverse cardiovascular events (MACE) the four major studies that were carried out (ACCORD, ADVANCE, UKPDS and VADT ) in a metanalysis of 27049 patients who had 2370 events failed to show that there was a reduction in cardiovascular events with intensive glycemic control.
And those studies that people are very familiar with, in particular, were trying to reduce MACE, (heart attacks, strokes, death, hospitalization and the need for recanalization of the coronary arteries.) only showed a possible reduction of MI but not cardiac or all cause mortality.
What was even worse was that in the ACCORD study, there was a 22 percent increase in sudden death. And I don’t want to go there because that’s not what has made the headline right now, but indeed, the fact is those were not cardiovascular events that killed the people.
What killed the people was related to the autonomic dysfunction and the fact that they likely died of an autonomic neuropathy complication with the way you try to intensify glycemic control, but that led to a revisitation of how important it is for glycemic control.
Should we be glucocentric and totally focused on the glucose alone? And is it safe to become aggressive in the management of people that have long-standing diabetes, with coronary calcification, and have carotid intimal thickness, and have ischemic heart disease, and may have had a myocardial infarct, or an angina.
All of those people who are at risk for an event, or they’ve had a previous event, or they’ve had bouts of hypoglycemia, which herald a very bad outcome if they intensify control. So what’s now slowly becoming accepted is that this is the era of backing off.
This is the era where the stringent criteria for glycemic control should be tainted with a note of caution, with people with the appropriate elevation of risk, we should be accepting lesser targets for glycemic control, lesser targets for A1c, less stringent control, and less aggression with the management.
So that’s a very big change in the paradigm of how to look after people, backing off, relaxing control, not being as aggressive, and also preaching to your cardiovascular risk status. That’s foreign to a lot of people that are earnest to evaluate the patient’s likelihood of being alive five years hence, what their cardiovascular current risk is, and what should be new goals.
You know, we’ve striven to get to an A1c of 6.5 or 7. And now we’re saying – okay. There are there tiers on which we can manage people, and those three tiers really say that we can go up to 8 or even higher in the A1c. And people are now beginning to address the J curve of managing people who are in this part of the state of susceptibility to a sudden event.
So in the framework of that, they ask the next question which is – well, with all of these new drugs that we’re getting – the 14 new classes of drugs that we have now for managing people with diabetes – has anything emerged that says that what is required is to show that we can impact in a positive way the cardiovascular events.
So that’s not what has been happening in the major studies, such as the TE-COS Study. The question that was asked was not, could we improve on cardiovascular outcomes, but could we not hurt? The ACCORD Study taught us not to hurt. So all the major new studies that have been done have primarily looked at non-inferiority, not to hurt, and not to increase the likelihood of a cardiovascular event.
So within that framework here, the major new drugs, such as the DPP-4 inhibitors, but most recently, the SGLT2 inhibitors are probing the cardiovascular safety not superiority. The SGLT2 agents act to target the kidney to increase glucose passing through the kidney, a mechanism which is antithetic to what nature has designed.
Because nature has designed that the kidney will not give up all of its glucose to the urine. It is very avid for reabsorbing the glucose to utilize it for other purposes. So it has a very efficient transport mechanism. And in people with diabetes, strangely enough, that mechanism is virtually better than normal, nondiabetic people.
So it is antithetic then to paralyze that mechanism, to enhance glucose disposal by the kidney because we all don’t like the notion that we pee glucose, and peeing glucose ultimately increases your likelihood of urinary tract infections in both males and females. But, lo and behold, if you do that in a very large population of people, two major things emerge.
That there is a very significant reduction in cardiovascular events. There is a very significant reduction in mortality, and a reduction in coronary artery episodes, and even more so, a reduction in cardiac failure as has been shown in EMPA-REG.
Steve Freed: Okay. So what you’re saying is that we can be more aggressive with these new treatments?
Dr. Aaron Vinik: No. I’m not saying that, Steve. What I’m saying is if we use an alternative approach – to trying to get glycemic control, it isn’t the glycemic control that’s achieved with an SGLT2. Oh, no. That’s not the factor that is changing anything. Nobody really understands the mechanism of cardioprotection but there is much speculation.
But the mechanism whereby you reduce the the intravascular volume, you decrease the after load on the heart. You decrease the work the heart has to do, is associated with, a reduction in cardiovascular events, and a reduction in congestive heart failure, so that lo and behold, what sounds as if you going after aggressive therapy by choosing a drug that will lower glucose, quite by accident, is doing what people have stopped trying to achieve.
You know the study I quoted were – intensive of glycemic control, getting to know there were some things. So it’s not the glycemic control. It’s something that’s associated with what you’re doing to the kidney to change its mechanism of reabsorption of glucose into the circulation.
That has lots of wonderful consequences, incidentally. The consequences are, the body defends itself furiously, aggressively, angrily, and says – you don’t want to do that to me. I’ve put this in place for your benefit, and now what you’re doing is – you’re poisoning it. And, lo and behold, out of this comes this incredible data which was never before. This was bigger news than the other thing and a prospective study top boot. It was bigger news than the DCCT. And this is only one compound, in a class of compounds, for which there are now several that have the capability of doing this.
But that’s not as easy as it looks, and we can talk about that. I don’t know, Steve. Have I declared that it’s not the glycemic control that’s made this difference, it’s approaching an organ that we were a little frivolous about, in terms of, how much it contributed to diabetes and the complications of diabetes.
And, lo and behold, with this study which was designed primarily as a non-inferiority study comes up with superiority, for the first time.
Steve Freed: So what are your recommendations in the treatment of patients with type 2 diabetes, with elevated blood sugars?
Dr. Aaron Vinik: If you have any of the risk factors I spoke about before, however, you target lesser influence for glycemia because it’s less glycemic control that matters. It’s not in most people, what is going to hurt them or kill them, and it’s not going to get them the benefit.
If they’ve got a longevity of not even five years expected and they have minimal complications, because they’ll target the old dogs, if they have a longevity anticipated that’s less than that and they’ve already had any events, like cardiovascular events, then it behooves us to adopt a much gentler approach.
And I think now, I’m beginning to be convinced that people are hearing that, and they’re listening. But there is another element that has arrived on the scene. And that element is, if I can protect your heart, and I can offload your heart, and decrease the pressure that your heart has to pump against, and you’re a person that’s a candidate for going into a hospital for heart failure, or your have an ambulatory tendency to heart failure, I have another tool.
It’s like the days of the foxglove, Steve, when we did still have a digitalis, and we could get people out of failure with the foxglove. Here we can take people, and get them out of failure, because we offload their hearts. And so, don’t try and promulgate or promote the notion that this is glycemic control.
This is a new discovery – a new direction – quite by accident. We were looking for another one of Ralph DeFronzo’s octets, which is the kidney, to say – well, we should target the kidney like we’re targeting many other tissues right now and at least eight and maybe 10 or more that we target right now, to try and avoid the rampant vascular disease that accompanies diabetes.
So if I’ve got people like that – yes. Whereas, I prescribe these drugs. I warn people about the urinary tract infections. I tell people, if they’ve had that type of problem before, no. I’m not going to use this drug. If you’ve had a tendency to falls and fractures, I’m not going to use this drug.
It can be unsafe for you. It produces hypotension, with a contraction of the plasma volume, with a bit of dizziness, fainting, and a predisposition to falls. I’m not going to use this drug. And, once more, the newest kid on the block is the euglycemia ketoacidotic syndrome. So if you do not feel well test your urine for ketones and do not reduce your insulin dose.
So this drug has given us another lease on life of discovering new physiologies and pathophysiology. I dug up a paper I wrote in 1968, and it was comparing diabetic ketoacidosis and diabetic non-ketotic hyperosmolar syndrome. And at that point in time, we didn’t have the tools.
We couldn’t measure insulin, glucagon, GLP-1, and all these other things that we postulated, that they were very different mechanism, at the disposal of glucose that differentiated these syndromes. And one of them is associated with the release of fatty acids from adipose tissue with markedly elevated ketone production but the sugar was low and spilling through the urine!.
And the second was, there was very little release of fatty acids from fatty tissue, so the blood sugar went up, and you became hyperglycemic hyperosmolar and non-ketotic. Now we’ve gone to the other extreme. The other extreme is we have a syndrome that your blood sugar doesn’t have to go very high And you are severely ketoacidotic.
Blood sugar is 200 to 250 mg/dL, yet you can go into ketoacidotic coma, or stupor. We had one case or two case reports, and then nine case reports, and then 19. And then now that it’s become on the FDA radar, more than 100 cases have been reported and the FDA has now issued a warning!
So we’re learning about new mechanisms for producing ketoacidotic coma, euglycemic coma. And some people are excited because glucagon levels go up if you allow sugar to escape from the urine, and glucagon may be a contributor. But I think there are other mechanisms related to activation of the autonomic nervous system, by contraction of the plasma volume, and creating another form of stress.
Steve Freed: So you’re kind of upbeat with the SGLT2 compounds?
Dr. Vinik: I’m in reversal of being downbeat.