If there were a diabetes drug that could help smooth out blood sugar spikes while also prompting weight loss and protecting your heart and kidney health, would you want to take it? Now ask: what if that medication wasn’t officially approved for type 1 diabetes, nor was your doctor confident in writing an “off-label” prescription?
It’s no secret that many in the diabetes community use medications in ways that aren’t FDA-approved and deviate from what the product labeling says, otherwise known as “off-label use.”
In particular, it’s been pretty common for a long time that people with type 1 diabetes take drugs that are only approved and labeled for type 2 diabetes. This is especially true for Metformin, the common T2D pill that helps regulate blood sugars at mealtimes. Now, a growing trend is emerging among the T1D community of using newer classes of T2D drugs like GLP-1s and SGLT2s.
But remember, patients still need a prescription to get their hands on these medications. And physicians are understandably cautious about prescribing T2D medications off-label, due to fears of potential risks like Diabetic Ketoacidosis (DKA) that can appear suddenly without the warning of higher blood sugar levels.
“Being on-label and off-label really doesn’t mean much to people, as long as the medication is safe and effective without a dramatic risk for severe side effects,” says Dr. Steve Edelman, a well-known adult endocrinologist at UC San Diego who also lives with T1D himself. “Type 1s are just looking for something to help them beyond just insulin, but the FDA hasn’t given us that yet, and there is more hesitancy in the medical field to prescribing these (T2D drugs) lately.”
Which Type 2 Diabetes Drugs Are Being Used Off-Label?
First, let’s break down which medications we’re talking about here.
One of the most commonly known oral T2 diabetes drugs out there, it’s been around for over two decades now and is often referred to as the “first line of defence” in treating type 2 diabetes. Metformin has also been used by people with T1D for quite a while. It’s in a class of drugs called biguanides, which help to keep blood sugars steady at mealtimes by decreasing the amount of glucose absorbed from food and limiting the glucose made by the liver.
GLP-1s (Glucagon-Like Peptide) Receptors
These injectable drugs are similar to the natural hormone called incretin, that’s produced in the small intestine. It stimulates insulin secretion and stops glucagon from being released into the body — reducing blood glucose (BG) levels. Shorter-acting versions of GLP-1 receptors can be effective at lowering post-meal BG spikes, whereas longer-acting versions have a more balanced effect over time for both post-prandial (after meal) and fasting glucose readings.
Meds in this category are:
- Byetta/Bydureon (scientifically named Exenatide)
- Victoza (Liraglutide)
- Lyxumia/Adlyxin (Lixisenatide)
- Tanzeum (or Albiglutide)
- Trulicity (Dulaglutide)
- Ozempic (Semaglutide)
SGLT2s (aka “Pee Drugs” for Diabetes)
For the past several years, this new class of oral diabetes drugs called
FDA-approved meds in this category include:
- Invokana (scientific name Canagliflozin)
- Farxiga (aka Dapagliflozin); outside the USA it’s named Forxiga with an “O”
- Jardiance (aka Empagliflozin)
- Steglato (aka Ertigliflozin), approved by FDA in 2018 along with two combos with Metformin and the diabetes drug Januvia (to help slow food metabolism and increase insulin production)
SGLT1-2 Combo (Not USA-cleared Yet)
- Zynquista (scientific name “Sotagliflozin”), a new dual SGLT-1 and SGLT-2 inhibitor from Sanofi and Lexicon Pharmaceuticals. This T2D drug didn’t get through an FDA advisory panel in early 2019, and was turned down by FDA again just recently over concerns about potential risks of increased and sudden DKA for those with T1D. Remarkably (and maddeningly), a week after the FDA panel’s vote, regulators in Europe approved the medication for T1Ds there.
If approved for T1D use soon, Zynquista would become the first-ever pill or tablet officially labeled for T1D alongside insulin in the United States. In fact, this would become just the second-ever glucose-lowering drug besides insulin to be available for type 1 diabetes, after Symlin injections were approved in 2005.
Why Use T2D Meds for Type 1 Diabetes?
“When you put a type 1 on these things, they notice it immediately,” Dr. Edelman says about prescribing these T2D meds, and SGLT2s in particular. “You can’t buy back this effect… they just feel that it’s easier to stay in the zone, insulin dosing is more forgiving, there are less highs and less lows, and for type 1s who are overweight, it’s an added bonus that they can lose weight. The blood pressure impact is another bonus, but that’s not as visible. People just feel that their time-in-range improves, and really the FDA folks just didn’t understand that.”
Take another example: the once-daily Invokana pill. Before Janssen Pharmaceuticals opted to stop studying the impact for T1D specifically, well-known researchers were delving into the idea and said there was a lot to look forward to. Dr. Richard Jackson, then with Joslin Diabetes Center, was one of the key researchers who’d been exploring this SGLT2 class of drugs for use in T1s. He echoed what others had said about the potential for smoothing out post-prandial blood sugars and offering weight loss benefits.
Meanwhile in Toronto, Dr. Bruce Perkins with the Sanai Health System, and a fellow type 1 himself, also delved into that research topic. He published clinical trial findings on Invokana that followed 40 patients for eight weeks alongside daily insulin doses, which led to a mean A1C drop from 8.0% to 7.6% and decrease in fasting glucose levels for everyone.
“We were testing the effects on kidneys and had (the patients) on CGMs to evaluate blood glucose, and it had a beautiful effect on the kidneys and on A1C, with more steady blood sugars and lost weight,” Perkins told DiabetesMine. “The patients had fewer hypos, most likely because they were using less insulin, so this ‘add-on therapy’ seems like it could help all of those. My feeling from this proof-of-concept study is that we should push for this research to be done properly and in bigger randomized clinical studies.”
In fact, study participants said they felt “leaner and meaner” using the SGLT2 inhibitor, and they had less worry about insulin dosing dangers at night, Dr. Perkins reported.
With all of those benefits (and others reported from the D-Community about real-life use of these T2D-labelled meds), why should there be resistance to getting these into the hands of more type 1 patients?
Good question, especially since medical experts — as well as insurers — are becoming more hesitant about prescribing these meds for type 1s, rather than less.
Doctors More Cautious on Off-Label Prescribing
In May of 2015 the FDA
The FDA has also warned about more urinary tract infections,
No wonder some doctors (and patients) have taken a step back from off-label use of T2 meds, even those who are most in-tune with the D-Community and live with diabetes themselves.
“I think it’s put some caution into physicians — even with me,” Edelman says. “I am more careful as to who I prescribe it to. If I have a patient with a higher A1C above 9% and I’m not 100% convinced they’re adherent with their insulin dosing or might be under-insulinized, that would be a higher risk for DKA. And that can be serious. At a minimum, it’s a costly side effect where you can end up in ICU for a couple days. So I think the DKA risk has slowed the prescribing down a bit.”
But there are still many HCPs who aren’t afraid to prescribe T2 meds off-label for T1 patients, of course exercising caution and making sure that patients are well-informed of risks.
“Many meds that are indicated for patients with T2 can benefit patients with T1 as well, but there may be some inherent risks involved,” says Certified Diabetes Educator and longtime T1 Gary Scheiner in Pennsylvania. “I believe that PWDs have the right to utilize and benefit from these medications, but they must educate themselves on proper use, and follow their prescriber’s recommendations carefully. From a healthcare provider’s standpoint, it really bothers me when a professional denies a patient access to something that could help them because of ‘legal reasons’… To me, that’s just them putting their own interests ahead of those of their patients.”
Scheiner says that if a provider takes a few minutes to explain the risks/benefits to their patient, and that individual is willing to assume responsibility, then there’s no reason to deny that patient access. Of course, he notes that goes well beyond just T2D meds for type 1s, and extends to insulin formulations in pumps, CGM use in young children, and even Do-It-Yourself closed loop systems.
“Personally, I am lucky to have an endocrinologist who is open-minded and respectful of my interests,” he says. “I have a chance to try just about everything — which I do partly for my own benefit, and partly to be able to share personal perspective with my patients. As I tell my patients, if your healthcare provider is not meeting your needs, find another one. Your health is too important to be left to someone who puts their own interests ahead of yours.”
In New Mexico, longtime CDE Virginia Valentine at the Clinica Esperanza says that she also sees many patients — particularly those in more rural and under-represented communities — using T2 meds off label for T1D. The added protections of kidney and cardiovascular health are just too positive to ignore, when combined with better meal-time blood sugars. “For the little risk there may be in heightened potential of DKA, people with diabetes can manage that,” she says.
Edelman agrees, saying he has many T1 patients who really love these GLP1s or SGLT inhibitors.
“If doctors see a lot of type 1s and that lot of people are using it, they’ll prescribe, no problem. I’d say even though there is more caution these days because of the whole DKA issue, the risk mitigation exists… it really comes down to education.”
Specifically, Edelman says to keep the following in mind:
- PWDs who are on a strict ketogenic diet maybe shouldn’t be on these drugs, as it can lead to DKA a different way than high blood sugars and not be as noticeable.
- With DKA, you need to also take in carbohydrates, as well as insulin and fluids. When a PWD goes into DKA, the brain is now breaking down fat for energy because there isn’t enough insulin in the body. The minute you take insulin and carbs, it shuts off the brain’s drive to use ketones and the ketoacidosis turns off within minutes, or hours at most. That means being able to avoid the costly ER visits that can result from DKA.
- He does not agree with warnings that say PWDs who exercise a lot or drink alcohol shouldn’t take these T2D meds.
He reiterates that it comes down to a level of awareness. “Education is needed for everyone, whether you’re on SGLT inhibitors or not. DKA can be serious, and insulin pumps can go out or people on MDI can get behind on injections and head into this. A lot of education is needed.”
Insurers Restrict Coverage of Off-Label Diabetes Meds
Even if a healthcare professional is open-minded and willing to prescribe off-label, that doesn’t necessarily mean an insurer (aka payor) is willing to cover that item.
While Medicare has changed its rules to allow for wider coverage of off-label drug uses for cancer in particular, that’s not the norm for private commercial insurers. They often flat-out deny coverage for these off-label uses that are not FDA-approved — because they don’t have the same clinical studies behind them for the federal agency to cite in the drug approval process. The FDA see these as an unproven — and therefore unsafe — uses of a particular product, and the insurers aren’t on board with that when they have approved products already on their formularies.
“With all these combinations now for type 2 medications now, companies just can’t do big studies and get that formal indication from FDA as easily,” Edelman says. And that leads payors to not having actual clinical trial data to rely on in their coverage plans. That’s unfortunate, when there are clear benefits that many believe outweigh the risks.
But a straight-up lack of trial data isn’t the only barrier to FDA approval, apparently; regulators sometimes lack a true understanding of daily struggles of diabetes care. Edelman says he saw that in early 2019, when the FDA advisory panel was considering Zynquista as a first-of-its-kind SGLT1-2 combo drug for T1D.
“They kept saying, ‘Oh wow, a bigger risk for DKA and not much drop in A1C,’ and they just didn’t understand that it’s still significant to see a .4 drop when you’re starting off at 7.7% for example, especially if you’re seeing less highs and lows. The time-in-range is the thing that people feel on a day-to-day basis,” he says.
Still, even if insurers or doctors say NO, that doesn’t stop PWDs from using whatever works best for their lives and health.
Diabetes Peeps Share Off-Label Drug Success
We asked, you answered. Here is a sampling of responses from people with type 1 diabetes to our online queries about using drugs off-label:
“Victoza helped bring mt A1C down and manage my insulin resistance. It’s not covered by my insurance because I’m a T1, so I buy it across the border.” — @theamazingcandie
“Metformin was a game-changer for me. I don’t know why they don’t prescribe that to other diabetics. I am going to Joslin so thankfully my MD is on the cutting edge of research. He was the one who suggested it and prescribed it. My insurance company didn’t give me any problems (and the Rx was very cheap without insurance at about $20/month, which is less than most of my copays). I have only been taking it for a couple of months and have been warned that the efficiency wears off over time. I do think they should prescribe it for periods of time with breaks when the efficiency wears off.” — Jonathan Macedo, T1 in Boston, MA
“I used Victoza for 4 months and just switched to Ozempic due to an insurance change. Yes, I did have issues getting my Ozempic covered on the new insurance because my A1C is below 7% and that was the only factor they decided to deny me on — which I thought was insane. Because I’d already been on Victoza and my A1C was down because of it. My doctor was 100% on board with me wanting to try them, and I’d brought up the possibility to her, not vice-versa. But she helped me fight with the insurance company and got it covered! I am soooo happy with how GLP-1 meds have helped me with my blood sugar control and insulin resistance issues.” — @jenhasdiabetes
“I’m using Metformin because I’ve developed increasing insulin resistance as I’ve aged. It’s brought my insulin doses back to normal for my weight, and my doc also suggested I try an SGLT2 inhibitor… but one of the side effects can be normo-glycemic DKA, and I decided not to risk it. Apparently, Medicare doesn’t object to off-label use of Metformin, either. It makes sense that a T1 can develop insulin resistance, the hallmark of T2D because they’re different diseases and one does not protect you against the other. I know that most insulin-resistant T1s object to the idea that they might also have T2, but the net effect on insulin resistance is the same and should be treated appropriately.” — @natalie_ducks
What to Know: Potential Risks for Using T2D Drugs Off-Label
As always, key messages for any new diabetes management routine are to be prepared, take precautions, and keep in mind that not everyone reacts the same way to the same medications (i.e. Your Diabetes May Vary). From the endos and educators we’ve asked about use of T2D meds for T1D, this is the general consensus on advice they offer:
- Of course, understand the risks before starting a new medication and realize that there may be side effects. Stop the medication if you’re at all concerned.
- Beware of DKA risk: For those taking SGLT2 inhibitors like Invokana, Farxiga or Jardiance, be careful when using these meds if you have a cold or other illness. Or even generally if you feel sick to your stomach. That’s a telltale sign of high ketone levels that can lead to DKA, even if you’re still seeing normal blood sugar readings. Keep ketone strips handy (and these don’t require prescription, so they’re quite accessible at local pharmacies).
- If you come down with any illness: fever, head cold, runny nose, nausea, etc., stop taking the medication and measure urine ketones every 6 to 8 hours.
- If you have urine ketones that are more than trace positive, contact your healthcare provider immediately.
- Don’t restart the T2 medication until you’re well, the ketones are gone and you’ve had a chance to connect with your HCP. You will need to give extra insulin, which is generally the way it goes when you’re sick with insulin-dependent diabetes.
- If you have any doubts or questions, contact your doctor right away. You may be advised to stop the medication, drink lots of fluids, and give insulin regularly.
With anything in diabetes, there’s risk involved — that’s just how we all live, day in and day out. But clearly, going off-label to take T2D drugs has provided significant health benefits for many people with type 1 diabetes. If you’re interested in trying this, find yourself a willing healthcare provider to be your partner in trial-and-error.