Among the dirty little secrets of the older diabetes medicines was that they usually made you gain weight, they could cause low blood sugar suddenly and unexpectedly, and they had no particular benefit to the most important consequence of type 2 diabetes (T2D) – heart disease.
All that changed with the release of two newer classes of diabetes medicines. The first are called GLP1-RA’s (to be explained, below) which include brand names Byetta, Victoza, Bydureon-BCise, Trulicity, and Ozempic. The second are SGLT2i’s (ignore that too, for now) named Invokana, Jardiance, Farxiga, and Steglatro. Whew – that’s a lot of names and choices. And there’s more to come! That’s what happens when you have a good thing going.
Here are some of the good things they do:
- They don’t cause low blood sugar by themselves.
- Although the details of research studies are always nuanced, and different drugs have different levels of study outcomes, in general the evidence is very strong that these medicines significantly decrease risk of death from all causes, heart attacks, sudden death, and stroke. SGLT2’s also prevent hospitalization for heart failure. Guidelines from diabetes and heart disease societies name these meds specifically as first choices to treat people with T2D who have established cardiovascular disease (CVD). Since there is no official definition of “established CVD”, it can be argued that all adults with T2D should be treated with SGLT2 inhibitors and/or GLP1-RA’s.
- These medicines also lower body weight by 3-7%, and the weight stays off for many years of follow-up. The weight lost is mainly from fat, not fluid or muscle, though there is always some of that too. The amount of weight loss varies widely, and while these are specifically not supposed to be weight drugs, this percentage of weight loss is significant for metabolic health.
- The medicines lower systolic blood pressure by about 5 mmHg, which is about as much as most blood pressure agents. Systolic is the higher number on blood pressure. Lowering blood pressure is one of the most important ways to prevent CVD and especially stroke.
- While the definitive studies are soon to be released, it appears these drugs prevent the usual decline of kidney function with age, which everybody has but which people with T2D have twice as fast. Preventing chronic kidney disease (CKD) may be the most significant contribution since it greatly increases risk for CVD and is among the biggest drains on the U.S. healthcare budget.
While the old, inexpensive generic drug metformin is still typically used first for T2D, many argue the benefits of GLP1-RA’s and SGLT2 inhibitors are more than worth the money and that they ultimately save money. I still support metformin because of many other virtues that it has, but would argue against using sulfonylureas because of risk of hypoglycemia and weight gain, and maybe even worsening risk for CVD. Too bad today’s insurance goes for cheapest in the short term instead of the most value in the long term. Regardless, most people with T2D will eventually require combinations of these meds anyway.
So How Do They Work?
Well this is cool too, and they are very different.
GLP1-RA’s are “glucagon-like peptide receptor agonists” because native GLP1 physically resembles glucagon even though its actions are almost opposite. GLP1 is co-secreted with insulin in normal physiology and in many ways has actions that are complementary to insulin. It enhances the actual secretion of insulin in proportion to glucose, inhibits levels of the actual hormone glucagon (which would raise glucose), slows the otherwise faster stomach emptying of T2D, and, remarkably, signals the brain when you’ve had enough food, so most people eat less and lose weight. GLP1-RA’s act like GLP1.
GLP1-RA’s have to be injected, like insulin, but they still are really easy to live with because they can be taken anytime daily (Victoza) or weekly (Bydureon-BCise, Trulicity, and Ozempic), come in easy dose pens, and have needles so small you can hardly feel them if you don’t use alcohol to prep the skin. Byetta has to be used twice daily and timed before meals, so although it was the original GLP1-RA from San Diego-based Amylin Pharmaceuticals, it is used less often today. An oral GLP1-RA has been developed and is in the later stages of review by the FDA.
SGLT2 inhibitors are once-daily tablets that cause the kidneys to release glucose into the urine, generally 65 to 100 grams daily (100 grams is roughly 400 calories, if you wondered). The kidneys have a system to absorb glucose from the urine called the “sodium-glucose-luminal-contransporters 1 and 2”, and SGLT21’s inhibit that absorption. You would think that losing 400 calories per day would reduce a person to dust in no time, but the body has many compensatory mechanisms so the weight eventually plateaus and some people, somehow, don’t lose much weight while others lose 10-15 lbs.
What Are the Side Effects?
As you might guess from the way they work, people taking SGLT2i’s pee more urine at first, and so should increase water intake by about a quart daily for the first week or so. After that it tends to return to a normal steady state. And because the urine is full of sugar, you have to be careful with good hygiene around urination, especially for women, to avoid yeast infections. If yeast infections do happen, it’s rarely more than once and is easily treatable with over-the-counter remedies for three days (not one, because of diabetes itself).
The GLP1-RA’s have to be started at low dose and built up slowly over a few weeks to minimize gastrointestinal side effects like nausea or diarrhea. Once stable, those side effects don’t occur.
Every person is unique, however, so one always needs to be cautious with any new medication.
Good News for Those with Type 1 Diabetes?
Although not approved for use in people with type 1, there is very promising research that has been done showing benefits of both classes of agents, especially the SGLT2i’s, to smooth out glucose variability, especially around meals, and to somewhat decrease insulin requirements. We are still working out the safety issues and the best strategies for introducing these agents to avoid diabetic ketoacidosis, but I anticipate their use in type 1 soon.
Good News for People Who Don’t Have Diabetes?
Perhaps. SGLT2i’s are being tested for those at risk for congestive heart failure, in particular, and both classes for heart and kidney preservation as well. We should know more in a few years, but stay tuned. There is an enormous amount of research interest in these meds and in the lessons they are teaching about human physiology.
If these agents are so good, why isn’t everyone on them and why do we still have so much poor diabetes control and diabetes complications? It’s beyond the scope of this piece to tackle that, but we need to do it as a community and as a nation. Dr. Edelman and Dr. Polonsky have contributed important work in this area, and the ADA has held consensus conferences to address this gap between possibility and reality. But knowledge is power, and now you have more knowledge about these exciting medications. And always remember that good nutrition, keeping fit, sleeping well, maintaining purpose, reveling in humor, and embracing friends and loved ones remain the mainstays of any plan to be healthy.
GREAT, INFORMATIVE ARTICLE. Thanks Dr. E.
Thank you Ed!
How to get medication
You’ll need to speak with your provider, who can recommend the best medication for you and write the prescription.
Very informative, thanks
Where does metformin fit in this?
Metformin is the first oral medication of choice around the world because it’s effective and also inexpensive. It also works well with all other medications for type 2 diabetes. However, it does not lead to weight loss and has not been shown to protect the heart like the newer classes of medications such as SGLT inhibitors and GLP-1 medications.
I was on Metformin at first, for about 5 years, then my kidney function started acting up so they took me off. It was wonderful and controlled my t2d. Kidney function are controlled now but doctor says I will never get to go back on it. The insulin I am on now doesn’t seem to be doing the job for me. Do you agree that Metformin should never be used again once kidneys are affected?
It all depends on the level of your kidney function. I would run this by your endocrinologist or whoever you see that’s an expert in diabetes management, as we are using metformin quite a bit in folks with kidney problems. It just depends.
Thanks for the great information. I love seeing all the rapid advancements in work on multiple components. I am confident that diabetes is on it’s way out and better health is taking it’s place.
Thanks Sally, we hope so too. 🙂
Great information. I need to keep reading…
So much to learn.
Glad you found it helpful!
Thanks so much for this article. As newly diagnosed this was so helpful to take in whem I talk to my Doctor about medications!!
Glad to hear that, Angela! 🙂
I’m taking Bydureon once a week. My doctor just put me on Metformin ER 500 MG 4 tablets a day. Is this too high a dosage with taking the Bydureon also? My A1C is 6.8.
2000mg a day is the preferred and most common dose folks are on. The long-acting form only comes in 500mg tablets so you have to take 4 in the morning.
Thank you, Daniel for sharing your valuable information about diabetes medicine. My father is also suffering from diabetes because it’s in our family genes. I’ll share this post with him because the medicine he is taking is not effective and he is allergic to that. So, I guess this post will help him.
Is there any component of Jardiance that is similar to (or acts as) an extended release medication? For unknown reasons, I get serious muscle twitching when on any extended release medications and therefore would need to know this information.
Good question. My opinion is there is no relation to other long-acting medications, but you should reach out to Lilly/BI on the Jardiance website to get an official answer. Here’s the link: https://www.bi-druginforequest.com/?
Thank you for the reply. I will reach out to Lilly/BI as you suggested.
I am a late onset T1. Recently found I had CVD and needed a stent. My cardiologist wanted me to take Jardiance for the help it gives with your heart. Endocrinologist said no because of the ketoacidosis issue. For someone with a serious heart issue isn’t it worth the chance?
Both of your physicians have their points. As for your heart issues, I would make sure your blood pressure, cholesterol and weight are at goal and then look at other things. Your endo is worried about a side effect seen primarily in type 1s. I think you should get them on the phone for a conference to measure out the pros and cons. Good luck.
Thanks for providing this and give such important facts from this content
I’m very excited about the newer medications. When I asked my Kaiser physician if these are available to Kaiser patients I was told no, that Kaiser is staying with (my current list of meds) Metformin, Glipizide, Lisinopril, Atenolol, Atorvastatin, 1 baby aspirin, Humulin. I’m 65 year old male. Diagnosed at age 50. Same regimen for 15 years. A1C’s taken every 6 months average 6.8%. Keep hoping Kaiser will consider offering more to Type 2 diabetics.
What are your thoughts on janumet ER, VS metformin & starlix? Is the janumet better? I have been researching, although I am unable to find solid information. I have recently asked my PCP to refer me to an endocrinologist.
Janumet contains metformin and Starlix is under a completely different class of agents. Which one is best for you depends on your diabetes and individual needs. Hopefully your new endo can help. There’s also a lot of great information in our TCOYD book which you can download for free when you attend our virtual events (which are also free).
My father has been diagnosed by diabetes type 2 at age of 48 he is losing his weight quickly which ,his sugar level is mostly 208-230 or sometimes normal moreover his cholesterol level is also high is metformin best for his health and kindeys,or he should avoid medication and improve only his diet and lifestyle?
As a physician, hearing about quick weight loss is a big concern. He needs to speak to his healthcare provider for a weight loss workup. Not to alarm you, but his healthcare provider needs to make sure he doesn’t have cancer.
Do SGLT-2 inhibitors and GLP-1 RAs have notable interactions vs. taking one or the other, particularly in T1 patients?
No interactions that I know of – there are none in type 2s and we use them very commonly together.
In T1 patients, can Symlin be used in conjunction with SGLT-2 inhibitors?
Another article on TCOYD (https://tcoyd.org/2019/10/strike-the-spike-controlling-blood-sugars-after-eating/) points out the overlap in the benefits of Symlin and GLP-1 RAs, so could it be worth it for a T1 patient to take both?
It’s a good thought, but I would not recommend it because it gets way too complicated. Two drugs that cause nausea, one drug is not approved for type 1 so you have access issues, and it adds a tremendous cost to the diabetes care. I would think a good GLP-1 would be all that you’d need.
I have growths on my thyroid. What would be the best medication for my type 2 ? On met Forman and glypizide now. Took byetta and victors 10 years ago.
The growth on your thyroid does not affect any choice of medication for type 2 diabetes. In the package insert it says “if you have medullary thyroid carcinoma, then you should not take a GLP-1”, however, that’s not what you have. But you should check with your doctor.
Thanks for the great information, diabetes persons and also a normal person will found this article very usefull.