SGLT2 inhibitors are a class of drugs that are approved to lower the blood glucose levels of people with Type 2 diabetes. Doctors have identified significant secondary benefits to the drugs, and they will only become more popular in the coming years. It is inevitable that SLGT2 inhibitors will be prescribed more and more frequently to people with Type 1 diabetes. Is this a change to be celebrated, or resisted? It’s complicated.
SGLT2 is a protein that works in the kidneys. When the protein is active, it transfers glucose out of urine and back into the bloodstream. A SGLT2 inhibitor blocks this protein from doing its job. This prevents the glucose transfer, and a higher percentage of the body’s sugars are spilled out of the body in the urine, resulting in lower blood glucose levels without any interaction with insulin. The drugs, approved for use to control glucose in people with Type 2 diabetes, are popular with patients and doctors alike.
But they do more than just lower your blood sugar. A great deal of research has focused on this class of drugs, and doctors keep finding more benefits. Studies have shown that SGLT2 inhibitors both trigger weight loss and lower blood pressure. Recent studies have only added to the apparent list of benefits. In the last month, separate investigations showed that SGLT2 inhibitors can prevent kidney failure and reduce risk of heart failure. These benefits appear to be independent of (and in addition to) the benefits of improved glycemic control. A concurrent trial showed that the drugs could improve the outcomes of those living with heart failure, for patients both with andwithout diabetes. Experts aren’t exactly sure why the drugs have these favorable effects, but they’re very excited about them.
Some now argue that the SGLT2 inhibitor should even overtake metformin as the first-line therapy for people with Type 2 diabetes. This month, the European Society of Cardiology and the European Association for the Study of Diabetes updated their care guidelines to recommend SGLT2 inhibitors for a much larger percentage of the Type 2 population. This may be the first significant sign of a sea change in T2 management.
The pharmaceutical companies are understandably eager to see if the drug can be recommended for use beyond the Type 2 diabetes community. The success with patients living with heart failure has led to calls to increase the use SGLT2 inhibitors among non-diabetic patients, and the FDA has put some of these drugs on the fast-track for approval.
Naturally, there has been much speculation about the drug’s efficacy for people with Type 1 diabetes. Many trials have addressed the question, and doctors have begun to prescribe these meds to people with T1 “off-label.”
But SGLT2 inhibitors are potentially very dangerous for patients with Type 1 diabetes. For those in the T1D community: be careful, and read on.
SGLT2 Inhibitors and Ketoacidosis
Few miracle drugs are without their side effects. One gory hazard of the SGLT2 inhibitor is a marked increase in the rate of a genital infection named ‘necrotizing fasciitis of the perineum,’ or, more floridly, ‘Fournier’s gangrene.’ Patients on some versions of the drug appear to have reduced bone integrity, and have sustained an increased number of fractures. Urinary tract infections are not uncommon. But overall, these side effects are considered either very rare or mild and tolerable.
But there is one side effect of lethal relevance to patients with Type 1 diabetes: the risk of ketoacidosis. The mechanism is difficult to explain, but SLGT2 inhibitors can simultaneously increase ketone concentration and mask hyperglycemia, our usually reliable warning sign that the body doesn’t have enough insulin. If these two things happen at the same time, and with enough strength, the sorry patient can experience ketoacidosis that is hidden by low blood sugars, delaying identification and treatment. This can happen to people with T2 as well as T1, but the risk is more acute with patients with Type 1.
While early analyses considered this risk manageable, it would appear that every new study finds that the risk is more significant than previously understood. An analysis of data from 2013-2015 showed that ketoacidosis could occur with blood glucose as low as 90, and as quickly as one day after beginning a course of the drug. A 2018 survey found that some 3% of patients with Type 1 diabetes taking SGLT2 inhibitors experienced a confirmed bout of DKA, “not a trivial problem,” given the seriousness of the potentially deadly condition. A more recent FDA review of an application of one SGLT2 inhibitor for the treatment of Type 1 diabetes found that the risk of DKA increased “between 5- and 17-fold, with a number needed to harm per year between 21 and 31.”
And it’s even worse that that. If we’re predicting what might happen out in the real world, these clinical hazard estimates have to be considered unrealistically low. Patients in such studies are given extensive training as to the risks and identification of ketoacidosis, and are monitored by clinical teams. But when doctors prescribe these drugs casually, patients may be under-informed and underprepared, perhaps dramatically so.
This makes experts nervous. An article this June in Diabetes Carewas titled “SGLT2 Inhibitors for Type 1 Diabetes: Proceed with Extreme Caution.” That author’s conclusion:
The increase in absolute risk of DKA, even in closely supervised patients participating in clinical trials, raises a serious concern that DKA will be even more common if SGLT inhibitors are used in routine clinical practice by practitioners who do not have the expertise and resources of the clinical trialists… It would be prudent to limit adjunctive use of SGLT inhibitors in type 1 diabetes to specialists well versed in the risks associated with such therapy and who have the requisite resources to educate, train, and support carefully selected patients.
This isn’t an abstract concern. Doctors are already prescribing SGLT2 “off-label” to people with Type 1 diabetes without any of the guardrails described above. In one of the many T1 online forums I frequent, a member recently announced that he’d received new prescription for an SGLT2. This adult already had well-controlled blood sugars and was prescribed the drug primarily for its ancillary benefits, such as weight loss. His doctor had only made a single brief mention of the ketoacidosis risk – something along the lines of “watch out for DKA,” with no reference at all to the fact that it could occur despite normal blood sugar levels – and the member was shocked to learn the true magnitude and character of the risk from other members of the forum. Such casual negligence will not be uncommon, and it will send unsuspecting patients to the hospital.
The potential benefits of the SGLT2 inhibitor are impressive. As long as such a large percentage of people with Type 1 diabetes fail to meet glucose management goals using insulin and lifestyle adjustments alone, adjunct therapies have a potential role to play. And it is very easy to understand the attraction of a pill that could also help people with T1D lose weight, reduce blood pressure, and protect against kidney and heart disease. Simply put, there are significant benefits to weigh against the risk of dangerous side effects.
The first of these drugs to apply directly for approved use with Type 1 diabetes is named Sotagliflozin. (It is actually a dual SGLT1 and SGLT2 inhibitor). So far, two of the most important judges in the world have come down on different sides of the issue. In March, a European Union panel approved of the drug, but restricted only to certain specific types of patients and with mandated controls so as to hopefully reduce the risk of ketoacidosis. Later the same month, the FDA rejected the same drug for American use, specifically citing the risk of ketoacidosis. In the following days, diabetes experts weighed in on both sides of the issue, showing that there was no unanimity of opinion in the medical community.
A Final Reason to Doubt
Ketoacidosis, when caused by an SGLT2 inhibitor, doesn’t just usually just happen without warning. These events are typically precipitated by reductions in insulin use, illness, dehydration, vomiting, diarrhea, excess alcohol consumption, or insufficient caloric intake. And some versions of the drug appear to be more dangerous than others. Thorough doctor and patient education, if it were to truly occur, should help mitigate the risk at least to some extent.
But there’s one other DKA trigger that will be of special interest to ASweetLife readers: a low-carbohydrate diet. Studies have shown that patients that take an SGLT2 inhibitor while on a low-carb diet have an enhanced risk of developing ketoacidosis. A low-carb diet naturally produces a small amount of ketones: this is known as nutritional ketosis, and is perfectly safe. But SGLT2 inhibitors also trigger ketone production, and these two ketone sources can combine and spiral out of control, poisoning the blood.
That’s right, the low-carb diet – the single best thing you can do to improve blood sugars, and, now that we mention it, an amazing way to lose weight and lower blood pressure – conflicts with the SGLT2 inhibitor. It can be dangerous to take the drug and eat a low-carb diet at the same time.
Of course, if you’re on a low-carbohydrate diet, you probably don’t need an SGLT2 inhibitor in the first place. You’re probably already enjoying the healthiest blood sugars of your life, and can be confident that you’re already doing your best to reduce the risks of long-term diabetic complications. You’re probably experiencing fewer serious hypoglycemic events than ever before.