Diabetes in 2025: Drug choice
McMaster Perspective Extended

Hertzel C. Gerstein, MD, endocrinologist and professor at McMaster University and Hamilton Health Sciences in Hamilton, Canada, joins Roman Jaeschke, MD, to discuss the evolving landscape of diabetes management and provide advice for physicians on how to navigate this field and tailor treatment to individual patients, considering factors like glucose control, cardiovascular and renal risk, weight, and cost.

This is part 2 of the interview. Watch part 1.

This video offers playback speed control and subtitles.

Outline

1. The complex landscape of diabetes medications.
2. Core principle: treat the patient, not the disease.
3. Understanding the meta-analysis.
4. Traditional vs new drugs in risk-stratified treatment approach.
5. Practical takeaways and cost considerations.

Transcript

Roman Jaeschke, MD, MSc, DPharm: Let’s go to the other part, which is something called network meta-analysis, which is essentially trying to compare everything with everything, generating a comparison which goes through whatever is considered standard treatment to alpha-glucosidase inhibitors, basal insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, and so forth. Now, I remember the time when we had insulin, sulfonylureas, and metformin. Obviously now the field changed completely. How do you navigate it these days? We’ll show the data from this meta-analysis down the road, but how do you orient yourself and your patients in this maze?

Hertzel C. Gerstein MD, MSc: I think the most important thing is one needs to treat the patient, and not treat the disease or treat according to an algorithm. So I think I’m going to go right back to basics, Roman. I think we need to do a history and a physical examination and evaluate the patient to say what are this patient’s major problems and what is the goal of therapy.

I think if we say the patient is at high risk for cardiovascular, kidney disease, it’s really important that that person has either a cocktail of cardio- and kidney-protective drugs as part of their regimen. So in addition to the ACE/ARB-type drug, statin-type drug, blood pressure control, et cetera—the non–diabetes focused things—I think there’s a real place in that person’s therapy for a GLP-1 receptor agonist, an SGLT2 inhibitor, or both. And everything we know shows that these work independently, so that they can be combined, obviously one at a time.

The advantage of these new drugs, the SGLT2 inhibitor and the GLP-1 receptor agonist, is you get glucose lowering with added benefits. And the added benefits are cardioprotection and renoprotection. The GLP-1 receptor agonists lower glucose more and they also lower weight more than the SGLT2 inhibitors. But they have different side effect profiles. But, as I said, they can be used together and they have both glucose [lowering] and other effects. Metformin is an excellent glucose-lowering drug.

Roman Jaeschke: Dr Gerstein, let me jump into this, because you are going now through the table, effectively comparing different drugs. So let me, for the purposes of our listeners, explain that colorful areas are those where we have strong evidence: green is evidence for benefit, and reddish is highlighting potential side effects. And then we have these more neutral areas, which are effectively saying that those classes of drugs are neutral in comparison to, I don’t know, standard treatments, or even slightly harmful.

What strikes me when I look at it is that we have those two classes of drugs which have majority of greens, which means beneficial, and beneficial in terms even of all-cause death, and cardiovascular death, and myocardial infarction, and nonfatal, and admission for heart failure. And you can keep going. They also have distinct areas of untoward effects. But there is the whole slew of other medications which we were talking about: sulfonylureas, and DPP-4, and metformin, and whatnot, alpha-glucosidase inhibitors, which seems neutral in this area. So my overall question is: we started by talking about those two new classes of drugs. Where is the place for the “old” drugs?

Hertzel C. Gerstein: One of the big problems with this meta-analysis and with this table is that there is no column for glucose lowering and there is no column for weight changes. Now, of the two, from a diabetes perspective, glucose lowering is a real benefit, because we know clearly that glucose lowering clearly reduces future eye disease, kidney disease, nerve disease, and myocardial infarctions from meta-analyses that have been done independent of its other effects. So I think that is missing from this. I understand that they’re looking at the hard clinical outcomes in this table, but I do think that’s an important point to make.

As I said before, if the goal is glucose lowering, the person’s at low risk for other problems, and there’s no particular concerns about obesity and kidney disease, et cetera, then it’s perfectly reasonable to start with a drug like metformin, because it will lower glucose and it even can affect the course of diabetes.

In people who are in the prediabetes range, it does prevent future diabetes from happening. But if we’re getting into a patient who has high risk for kidney, cardiovascular, or related diseases, heart failure for sure—which is one important cardiovascular disease that people forget about asking—then we’re talking about the two top ones on this list: the SGLT2 inhibitors, especially if there’s a heart failure concern, and the GLP-1 receptor agonists, and both of them have kidney effects. The SGLT2 inhibitors have more heart failure, kidney effects, the GLP-1 receptor agonists have more cardiovascular but also have kidney effects and heart failure effects as well. And you get the added benefits of weight lowering, et cetera.

I’ll go back to what I said before. When you look at it this way, it looks confusing. When you look at it from the prism of a doctor with a patient across from them, it’s much easier. What does this patient need? So you ask about in my view… There’s very little place anymore for sulfonylureas and meglitinides in our therapeutic armamentarium or arsenal, because we have other drugs that do the job in a better way. The DPP-4 inhibitors also, there’s not a big place for them unless your only job is glucose lowering, in which case they should be combined with metformin.

But if you’re talking about organ protection, especially in people who have some evidence of damage, the higher risk people, you should be talking about the top. Insulin always has a place. You need insulin for glucose lowering if the other drugs are not lowering glucose sufficiently. But interestingly, in type 2 diabetes these other drugs are allowing us to use less meal insulin and allowing us to spend, if we’re using insulin, it’s more basal insulin as opposed to meal-related insulin.

But in the end, you’ve got to treat the patient. What’s their glucose level? What’s their cardiovascular risk? Have you optimized their cardioprotection? What’s their kidney protective risk? Have you optimized their glucose levels? Have you optimized their A_1c and is weight an issue? And then I think you put it together and you can come up with a tailored regimen that is best for each patient, the one across from you. So you don’t treat the disease, you treat the patient. You don’t treat the guidelines, you treat the patient. The guidelines and the evidence inform the clinical judgement that you need to apply to the patient in front of you.

Roman Jaeschke: Okay. So if I understand correctly, you have to pay attention to a few things at the same time. You have to lower the glucose level and aim for reasonable hemoglobin A_1c. You have to look at the risks of renal and cardiovascular effect. You have to look at the patient’s weight and choose the drugs according to the patient’s profile.

Hertzel C. Gerstein: And quality of life, and the ability to afford the medications, which is an important issue as well, of course.

Roman Jaeschke: Right. So affordability and availability is an issue as well.

Well, I hope that your discussion does to our listeners what it does to me. It clearly will help me next time I see the patient with diabetes to make decision about choosing the appropriate drugs.

You mentioned affordability here. If I understand correctly, GLP-1 and SGLT2 would be more expensive than other classes of drugs, maybe except insulins.

Hertzel C. Gerstein: The SGLT2… People always talk about cost, and obviously cost is extremely important. The nice thing about cost is that it changes every year. SGLT2 inhibitors are now going generic. So there are going to be nonproprietary SGLT2 inhibitors out there very soon—I think there already are some—that actually are cheaper. And so the cost is going to change. I mean, you and I both remember when thiazides were expensive drugs, and beta-blockers were expensive drugs, and ACE inhibitors were.

Roman Jaeschke: Absolutely.

Hertzel C. Gerstein: And as costs fall, it becomes less and less of an issue. Even GLP-1 receptor agonists, in the United States the first GLP-1 receptor agonist that I’m aware of has become generic or become a biosimilar. And so this is going to happen as well. But the reality is we’re seeing the patient today and cost is part of your assessment of the patient. And you have to prescribe a regimen that works, because they can afford it. That’s part of the clinical medicine.

Roman Jaeschke: Hertzel, it’s a great pleasure to live with you through the revolution in diabetic management. We clearly lived through it. It’s similar to the heart failure revolution and rheumatoid diseases revolution. I mean, the world is changing and thankfully for diabetic people, for the better. I really appreciate your every-few-years update for us and for the McMaster Textbook of Internal Medicine. My real appreciations, and thank you.

Hertzel C. Gerstein: It’s always a pleasure. Thank you very much.