(R)evolution of pharmacologic therapy for diabetes mellitus

Dr Ally Prebtani, professor of medicine in the Division of Endocrinology and Metabolism at McMaster University and coauthor of the Hypertension Canada’s 2018 and 2020 guidelines for adults and children, connects with Dr Roman Jaeschke to discuss the recently published meta-analysis of the use of SGLT-2 inhibitors and GLP-1 receptor agonists in diabetes.

For a recent Publications of the Week article discussing the use of SGLT-2 inhibitors and GLP-1 analogues in diabetes, click here.

Roman Jaeschke, MD, MSc: Good afternoon, welcome to another edition of McMaster Perspective. I would like to introduce to you Dr Ally Prebtani, professor of medicine and endocrinology at McMaster University and section editor in the McMaster Textbook of Internal Medicine. In addition to being a clinician and endocrinologist, Dr Prebtani also specializes in international health and applications of evidence to different international settings.

The stimulus for our recording was a recently published British Medical Journal (BMJ) meta-analysis of using 2 drugs, the names of which—or classes of which—I hoped never to learn because they are real tongue twisters: sodium-glucose cotransporter 2 (SGLT-2) [inhibitors] and glucagon-like peptide 1 (GLP-1) receptor agonists. However, it sounds like internists and all primary care practitioners need to know something about them. And that is why I’m going to the expert. Dr Prebtani, the floor is yours.

Ally P.H. Prebtani, MD: Thank you, Dr Jaeschke, for the kind introduction. I just wanted to start off by saying that this is bread and butter for most endocrinologists who do diabetes, that is, the use of GLP-1 analogues and SGLT-2 inhibitors; so, far from being an expert, I think we all deal with these medications for quite some time.

I just also wanted to state that they are pretty well new kids on the block, but they are not that new, as they have been around now for about a few years and they have been widely used. In fact, we have incorporated them into our clinical practice guidelines for Diabetes Canada—both SGLT-2 inhibitors and GLP-1 analogues—and we’ve graded them and based on the level of evidence [decided] to apply them to our patient that is in front of us.

Roman Jaeschke: Okay. As a person, as I said, who is new to the area, how should I incorporate it in my practice?

Ally P.H. Prebtani: That is a really good question. Everyone uses a lot of metformin, which is a wonderful drug. It’s got very good efficacy in terms of reducing glycated hemoglobin (A_1C), it is safe, and it costs pennies. That is probably the main reason—along with the test of time—that we are using metformin as a first line. But there is no real good evidence that metformin on its own, independent of glycemic control, reduces cardiovascular disease. Although there was borderline improvement in the reduction of cardiovascular disease in the (UKPDS) UK Prospective Diabetes Study, but the P value is only .05 so, again, pretty borderline.

When you are considering using these new therapies, either the SGLT-2 inhibitors or the GLP-1 analogues, there’s a few questions that we need to ask ourselves and to the patient that’s sitting in front of us. Number 1: What is their A_1C [level] or what is their current glycemic control? As I mentioned earlier on, metformin is very efficacious and these drugs are pretty efficacious, but probably not as efficacious in terms of reducing glycemia versus metformin. The second question we need to ask ourselves is what is the cardiovascular risk and what is the renal risk.

I would like to break up the cardiovascular risk into what is the atherosclerotic disease risk and what is the heart failure risk. And once you answer those questions, along with convenience (do they want an injection with GLP-1 analogues versus do they want to take it orally, like SGLT-2 inhibitors), taking into account the cost, the risk of hypoglycemia—which is very low with both these agents—and, at the end of the day, the patient’s preference, we make a decision of what therapy to use. I will give you an example. If someone has mainly an atherosclerotic risk, especially if they have had an event already, the GLP-1 analogues are much more effective in reducing cardiovascular risk, whereas if the risk is mainly heart failure, or the risk is mainly renal—based on their profile—then SGLT-2 inhibitors are much better in terms of reducing renal and heart failure risk. That is why we need to ask all these questions before popping up that therapy in front of our patient.

Roman Jaeschke: If I can interject here, because this is the paper I am talking about, and it actually compares… The first surprise that I found here is really how large the benefit is. We are talking about SGLT-2 inhibitors and in a very high-risk [group] we are talking about 5% absolute mortality reduction after 5 years; mind you, the lower the baseline risk, the lower this absolute risk is, but it strikes me as quite substantial. And the relative risk in lowering those events is 20% to 25%, actually similar to statins, which may generate another question. The only thing where SGLT-2 inhibitors do not perform as well is actually nonfatal stroke, where they do not seem to be effective at all, whereas GLP-1 analogues seem to be working particularly well in reducing stroke. I don’t know whether it is a play of chance or whether that is real.

This paper also provides a comparison of SGLT-2 versus GLP-1 and in most categories the SGLT-2 is similar or slightly better, whereas for stroke, again, the GLP-1 seems to be better. I do not think we are yet talking about using both of them on top of metformin. We are talking about one as a routine, correct?

Ally P.H. Prebtani: Most of the studies that use these therapies were add-on to metformin.

Roman Jaeschke: Okay.

Ally P.H. Prebtani: And I just wanted to quickly answer the question about the statins. Mostly the studies had patients already on optimal therapy—whether it was a renin-angiotensin system (RAS) blockade with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), or [whether it was] a statin—they were already included. So, those confounders were actually looked at carefully because I think it would be somewhat unethical to come to [the same] conclusion when someone is not on a statin at a large scale [without optimal background therapy] and to make these conclusions with these SGLT-2 [inhibitors] or GLP-1 analogues.

Another point that I also wanted to answer, Dr Jaeschke, is one that you already mentioned. The most benefit from the cardiovascular point of view was in patients who had already had an event in the past. So, most of the data, whether renal or cardiovascular, was for secondary prevention rather than primary prevention. There are primary prevention studies that showed benefit, but the benefit was much higher, in general, for secondary prevention. [That’s] number 1. Number 2, despite having multiple agents of each class, each drug had different outcomes depending on the study that was done. It is hard to compare one GLP-1 analogue to another GLP-1 analogue because they were [not directly] compared… some of them were more beneficial for primary prevention in that study and others were more powerful in terms of reduction in secondary prevention. So there were some differences.

That is why when we incorporated these in the guidelines not only did we include the class, but we also specified the specific drug with its grading and its level of evidence. Although I believe that [internally, within each class] both classes are pretty equivalent in terms of the drugs, there are some differences with the actual specific drug in terms of renal and cardiovascular outcomes.

Roman Jaeschke: Well, the amount of information that mere mortals can accommodate is probably limited, so at the moment I am looking at them as class action, but obviously on an expert level there may be a little bit more information than that. Could you comment on long-acting GLP-1 [analogues]? Because that sounds like a newer [thing].

Ally P.H. Prebtani: Yeah. Right now we have 2 most commonly used long-acting GLP-1 analogues on the market. The first one that has been around for quite long is semaglutide, and the brand name is Ozempic; and then we also have dulaglutide, which is Trulicity. They are both injected once a week. Semaglutide was studied in a big randomized controlled trial called the SUSTAIN-6 trial (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and this showed no inferiority in cardiovascular outcome reduction [against placebo, there was evidence of superiority]. The benefit of that in our province is that it is covered. It is the only GLP-1 analogue that’s actually covered on the formulary and the one that’s been indicated to be used in secondary prevention for its outcomes.

Dulaglutide—also known as Trulicity—which is not covered, showed improvement in some major adverse cardiac events (MACE) outcomes, mainly really acting at the reduction of nonfatal stroke. It was the main outcome that was powerful in primary prevention with dulaglutide.

Roman Jaeschke: I see it every day on CNN. There is this advertisement these days. It is quite amazing. But it is also probably an exciting time for endocrinologists, isn’t it?

Ally P.H. Prebtani: Yeah. I think you make it… I wanted to add on that. This is the first time in the history of diabetology where we have 2 classes of drugs or therapies that reduce cardiovascular or renal risk independent of glycemic control, which was never heard of until these 2 classes of drugs. So these are almost like cardiac drugs and renal drugs in a sense. They are almost like the analogy of using statins, where they give multiple bangs for the buck and in addition to glycemic control they also improve cardiovascular and renal risk, depending on the patient profile.

Roman Jaeschke: It is sure exciting. Could you estimate—I know that you will say that it all depends on the profile of patients—in your type 2 diabetic population, what is the proportion? How common are those drugs in your practice? That is number 1; and number 2: Is it only type 2 [diabetes] or would you consider using them in type 1?

Ally P.H. Prebtani: I will start off with SGLT-2 inhibitors. In type 1 diabetes SGLT-2 inhibitors are for the most part contraindicated because there is a risk of euglycemic diabetic ketoacidosis (DKA). Right now they are off-label and they are contraindicated, so I am not going to say too much about SGLT-2 [inhibitors] in type 1 [diabetes].

GLP-1 analogues, again, are indicated in type 2 [diabetes]. There is 1 GLP-1 analogue, liraglutide or Victoza, which is also indicated in obesity, independent of diabetes, but the doses are much higher. Semaglutide is currently being studied and so far the preliminary results look promising, but it is not actually officially indicated yet for obesity, although it’s in the working.

Roman Jaeschke: Okay.

Ally P.H. Prebtani: So, generally speaking, in terms of diabetes they are mainly indicated for type 2 diabetes mellitus, not for type 1 diabetes mellitus, because the mechanism is based on the profile of what is going on mechanistically in type 2 diabetes pathogenesis.

Roman Jaeschke: You mentioned there may be extra benefit for obese people.

Ally P.H. Prebtani: Yes.

Roman Jaeschke: So, what do you think: A quarter of your patients? Half of your patients? Three quarters?

Ally P.H. Prebtani: I see sicker patients because we are in a tertiary clinic being in a teaching institution, so we are often combining them with people on insulin and metformin. I would say for GLP-1 analogues—you know, this is a very rough estimate, Dr Jaeschke—but I would say ~25% to 30% of my patients are on a GLP-1 analogue and SGLT-2 [inhibitors] often… they are already on it because they had been put on it by primary care practitioners, whether a nurse practitioner, an internist, or a family doctor. I would say it is ~50% to 60% to 75%, somewhere around there because they are easier to prescribe and they are all covered by formulary and they are oral. So they are much easier to use.

I wanted to make one more point about SGLT-2 inhibitors. Although they have the heart failure reduction mainly in secondary prevention and the renal reduction mainly for renal risk patients, their glycemic effect does not work as well when the glomerular filtration rate (GFR) drops <60 in terms of the estimated GFR (eGFR). That is the one of the limitations. Although they are great for preventing outcomes in terms of glycemic reduction, they only work really well if the eGFR is >60 because they require renal excretion.

Roman Jaeschke: You mean for glycemic control or for cardiovascular control?

Ally P.H. Prebtani: For glycemic control.

Roman Jaeschke: Okay.

Ally P.H. Prebtani: They work well regardless of the eGFR for renal reduction in the appropriate patients and for heart failure reduction, but for efficacy for A1C in glycemic reduction, once you get below the eGFR of 60, they do not work as well for A_1C reduction despite the clinical reduction in terms of cardiovascular and renal reduction.

Roman Jaeschke: It is fascinating. It is exciting in your specialty. Thank you for teaching me on them. I will feel much more comfortable now following those patients or even starting them on it. Thank you very much, Dr Prebtani.

Ally P.H. Prebtani: My pleasure. Thank you very much for having me.

Roman Jaeschke: Goodbye.