Ten years ago, I was considered the physician who would intensify insulin and many clinicians would send me patients or they would realize that that’s what we did back then to really get people to tight control, to prevent complications with their diabetes. We would use multi daily insulin injections using two or three different kinds of insulins and we would use insulin pumps if the patients didn’t want to receive shots. We used a lot of insulin because we didn’t have many choices besides metformin and a class of medicines called Thiazolidinediones—sometimes shortened to TZDs or glitazones, or the Sulfonylureas, to take care of diabetes. So, it often ended up with insulin since that was the most powerful driver of lowering blood sugars.
Since then, we’ve had the advent and the discovery of many compounds, including those classified as GLP-1 or SGLT2, that have helped reduce the requirement for insulin, and in some ways may have misled us to think that maybe we won’t need insulin. Many of these new medicines have helped keep me from using a lot of insulin, which has its own complications, including low blood sugar and weight gain. Some of these Type 2 diabetics are very insulin resistant. So, in some patients, insulin has a very marginal, if any, effect as we try to get to a given endpoint on their sugars.
GLP-1s have been around for a long time, starting with BYETTA, and that was a twice daily medication. It has evolved over the years to many Companies figuring out how to produce this compound. Today, we have different versions of those GLP-1 medicines, so we only have to give one shot per week to patients.
These medicines do the opposite of insulin in terms of helping those patients require less insulin to get their blood sugars to goal. It helps to stop the liver from making so much glucose, which is a counterproductive measure that happens in Type 2 diabetics. The patients make more glucose than they should, especially after a meal. And so, these hormones actually help stop that and prevent all that extra glucose. We call that hyperglucagonemia and is generally the cause for that. And GLP-1s also assist with decreasing a patient’s appetite so they don’t tend to want to eat as much, and many Type 2 diabetics want to eat too much. Part of the neurohormonal problem with diabetes is that patients are hungry, and GLP-1s help with the hunger part of that. And in a glucose dependent way, it helps make more insulin. The pancreas make insulin if the sugar’s high but does not make more insulin if the sugar’s not high. So we call these kind of smart hormones, where they decrease the glucagon, which is what’s causing the high sugars out of the liver, and they increase the insulin, both of which are glucose dependent. So they are just great hormones and have helped us manage many Type 2 diabetic patients. In my practice, I feel like it has reduced my insulin use by half compared to what I used to do. And I’m still getting really good results with A1c levels.
SGLT2s, or sodium-glucose co-transporter 2 inhibitors, are even more new in terms of their advent of use and introduction as a treatment option for Type 2 diabetics. SGLT2s are really interesting because we used to think that sugar in the urine was a bad thing because that meant you’re diabetic and you must have pretty high sugar if your kidneys couldn’t hold onto the sugar and you are excreting it through your urine.
Somewhere along the way, someone recognized that SGLT2s cause you to excrete glucose out of the urine. They target certain receptors in the kidneys to allow the floodgates, so to speak, to open so that the higher the sugar level, the more glucose, and the more sugar got excreted through the urine. And so, that was almost a linear response in terms of helping diabetics who have severe high blood sugars to allow it drain out through the urine. Because of that, both GLP-1s and SGLT2s help people lose weight, which is the first time in my generation of medicine that we’ve seen diabetic medicines actually help people lose weight, which is what many patients need to help their diabetes be more well-controlled.
The SGLT2 class of medicine helps lose weight because you’re draining out calories through glucose during the day. We have found that that SGLT2’s and GLP-1s, working together, have really, really provided us help keep these patients under control.
Both classes of medications have their own risk profile, but most of us find that the risk is much outweighed by the benefits that it provides these patients over time.
Side Effects of GLP1s and SGLT2s that Patients Should Know
Let’s talk about the side effect profile for each of these classes of medications. In the primary care world, the more of these types of medicines that get introduced, the more complicated it is for the physician to keep up with all these advancements and to try to figure out which one to use in which patient.
With SGLT2 medicines, since they allow you to drain out glucose through the urine, it makes you urinate more. Because of that, they work as a diuretic, like a LASIX for hydrochlorothiazide. They also lower blood pressure, not to a large degree, but they definitely lower blood pressure. And they lower fluid volume, so there’s a lot of ongoing clinical studies that are looking at preventing heart failure using these types of medicines, because you’re always draining more water out of your body. Because the more glucose comes out, more water has to follow.
Yeast infections are also common because you’re draining out glucose in the urine. So, you can imagine if there’s glucose there is going to be yeast infections, and an increase in urinary tract infections. And then the final side effect is if you are draining off more water, as a diuretic would, you might put a strain on the kidneys temporarily, because of dehydration. There is some concerns with people that do have baseline kidney insufficiency or renal insufficiency. We have to be careful not to drain too much fluid off, or it might actually stress the kidneys too much. It is important to monitor all of these side effects with your physician.
GLP-1s are a little more complicated, because they’re injections. So as much as we love these medicines, and as much as patients are getting better and better at giving themselves shots, there’s still some reluctance for a lot of patients to want to give themselves shots. That could be for many reasons, it might not just be for the fact that they’re afraid of needles, but they might just feel like their diabetes is at the end of the rope, because of what happened to their family members, and they don’t want to get shots because they are used to following the same routine and path as their relatives who might have lost their feet, or might have gone into kidney failure, and that was about the time they started taking injections. So we, as physicians, have to do a better job to review the side effects with patients but also talk about the great benefits that these medications provide to diabetic patients.
We now have not only daily versions of GLP-1s that last all day, but we have weekly versions, one shot per week, as well. The needles are tiny and they are pretty easy to administer, and when we give patients their first injection in the office, they can’t believe that they were worried about actually getting a shot.
With any medication, It is always important to understand that there always are some risks and we always go over with these patients. For the GLP-1 class of medications, we do not use those in patients who have had pancreatitis. We should not use it in patients who have a high risk of pancreatitis, whether it be because their alcohol intake is too high, they have gallstones that need to be removed, or maybe they have high triglycerides. Those patients on GLP hormones do have a small increase in the risk of getting pancreatitis while they’re on the medicine. But diabetics in general, even who are not on GLP-1s, also have a little bit of a higher risk than the normal population to have pancreatitis. Sometimes you’re doctor doesn’t want to have that conversation with you but it is important that they know this information so they can make the right decision on what medication to prescribe.
One other side effect of GLP-1s, is that they almost all cause GI side effects, like nausea, and sometimes vomiting. So we really do have to prepare patients, when we put them on these medicines, to go slow and to realize that they may be nauseated, and to convince them that that’s probably not a bad thing, and that they usually will get used to that, and that eventually is part of why it helps them lose weight, it decreases their appetite. And it really is a good thing. But that’s a discussion and it takes some time to get through that.
The final thought about GLP-1s is that there are warnings about thyroid cancer, medullary thyroid carcinoma, but it was only found in the clinical trials in the long-acting, the once a week version, the longer acting, not the shorter acting. And it only occurred in the rodents and rats in the clinical trials. We don’t have a lot of human data to support any connection to the risk of that thyroid cancer. But that risk is out there, so we really don’t use it in patients who either have that history of thyroid issues or a strong family history of thyroid cancer, and in those patients, we prefer not to prescribe them.
Those are the things that we really need to address with every patient before we start the medicine. And it takes a little bit of time. But after I review these with them, I tell them about the benefits, and typically the benefits outweigh all of that so much that they’re hooked on starting the medicine unless they qualify for one of those risks that I mentioned.
Understanding Insurance Coverage for Diabetic Medications
So, with all the benefits that I have discussed about these newer diabetic medicines, comes the curse of cost. And just about every patient that we put on a SGLT2, or GLP-1, or even some of our newer, really good insulins, have trouble financially at some point. Their insurance company will make them switch, or they won’t cover a particular medicine. It can get very complicated financially, and to keep patients on a regimen that actually keeps their sugars controlled without being forced to go back to the old fashioned medicines that did the opposite. The old medications caused weight gain. They might have caused low blood sugars, but they did the opposite in terms of contributing adversely to the diabetic condition, instead of positively.
I will tell you that it seems to be getting easier with coverage. There are now a lot of resources for patients. I think insurance companies and payers are finding the benefits, and ultimately lower costs, of long-term control, and they are covering some of these more expensive meds a little more freely. At TRIHEALTH, where I practice and where we see a lot of diabetic patients along with other chronic diseases, we help patients as much as possible navigate these waters.
TRIHEALTH is a rather large institution. It has a lot of PCPs and in addition to a lot of specialists, there are a lot of mid-level providers, RNs, NPs, Pas, and others. We treat a lot of diabetes at TRIHEALTH and we have a prior authorization department that has done wonderfully to help address some of the challenges that patients face in terms of getting the right medicines covered.
TRIHEALTH has focused on the quality of care that we provide our patients, especially for our chronic disease patients, like our diabetics. Making sure that their A1cs are controlled, making sure that their blood pressures are controlled, making sure that we’re keeping up on their surveillance measures, like their eye exams, and their urine proteins, to make sure that they’re not in the midst of, or evolving into, kidney failure. Large institutions like TRIHEALTH, if not already focusing on these measures, should be, and TRIHEALTH is really doing a great job of keeping our communities healthy.
For me, I am very proud to work with TRIHEALTH and I am happy that they have focused on their population health efforts and really pushed all of the physicians be part of and maintain our Patient Centered Medical Home Practice (PCMH) accreditation, which leads to better patient care, better patient happiness, a much healthier patient, and one who costs the system less money because they’re healthier and in good shape.