Issue: May 2021
Disclosures: Grunberger reports no relevant financial disclosures.
May 18, 2021
3 min read

Should SGLT2 inhibitors be first-line therapy for type 2 diabetes?

Issue: May 2021
Disclosures: Grunberger reports no relevant financial disclosures.
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Yes. It is not right to put everyone on metformin and wait until it fails.

George Grunberger

As far as SGLT2 inhibitors for first-line therapy in type 2 diabetes, the question should be, why not? What other drug class, apart from insulin, can be prescribed and it works immediately, without the need for titration? SGLT2 inhibitors are insulin-independent. There is no risk for hypoglycemia. There is no risk for weight gain. They work for everyone, as long as you have a kidney.

Metformin has been around for decades, costs pennies per day, and has become the go-to first-line therapy for type 2 diabetes. However, people forget that one-quarter to one-third of patients cannot tolerate the full dose of metformin because of gastrointestinal adverse effects. The dose also needs to be titrated.

Every other class of antihyperglycemic medication has its disadvantages. With thiazolidinediones, you measure full response in months. GLP-1 receptor agonists have to be titrated, plus there can be adverse gastrointestinal effects. Sulfonylureas have their own issues. With SGLT2 inhibitors, the first pill you swallow works — the response is measured in hours. The only adverse effect to discuss is risk for genital mycotic infections, which can be mitigated.

Questions like this, of course, are always hypothetical and unanswerable. There will never be a large-scale, randomized controlled trial with all the many combinations of drugs we have for type 2 diabetes looking at long-term, meaningful outcomes. Everything should be patient-centered.

The American Association of Clinical Endocrinology and other groups have stated that if a person with diabetes is the right candidate for SGLT inhibitors, those patients should be started on them immediately, regardless of current or target HbA1c.

As for out-of-pocket cost of drug acquisition, that should not be a reason to avoid prescribing this class of medications. We are talking about treating patients for the rest of their lives and, once generic, the cost will come down as it did for metformin. I try to remind people that about 80% of the entire societal cost for diabetes is related to long-term complications, hospitalizations, revascularization procedures, dialysis, etc. These complications would be prevented if we did the right thing — prescribing a drug like an SGLT2 inhibitor — from the very beginning.

George Grunberger, MD, FACP, MACE, is chairman of the Grunberger Diabetes Institute in Bloomfield Hills, Michigan.


No. Our patients are already well served with metformin first.

Daniel Einhorn

As a practical matter, therapy choices in type 2 diabetes eventually become “and” rather than “instead of.” The debate is when, not whether, to initiate SGLT2 inhibitors for the right patient.

What is the rush? If we are discussing treating patients for type 2 diabetes, not heart failure, the argument to bypass metformin is a tempest in a teapot.

There are no data that beginning metformin as a first-line therapy is harmful. For most patients, metformin is without drama — affordable, well understood, without bad press, safe, prescribed with confidence, not frightening for the patient or their family, and possibly beneficial for the heart. VA-IMPACT is a federally sponsored cardiovascular outcome trial for metformin vs. placebo that will be available by 2024. For now, we rely on older studies where CV benefit was not the primary outcome. Six are reasonably good, looking at death and hospitalization for heart failure. In every study, the signal for metformin suggests CV benefit and never harm. And, of course, studies of SGLT2 inhibitors are mostly on a background of metformin therapy.

Understandably, it may be galling to some physicians to base the choice of first diabetes agent on historical precedent and cost. But to what end would one suggest bringing the current medical system to its financial knees by insisting on SGLT2 inhibitors only as the first therapy for all patients with type 2 diabetes?

The first prescription of any medication telegraphs to the patient and their family that they have a medical problem serious enough to warrant intervention. That alone may trigger the lifestyle changes that alter the course of type 2 diabetes better than any medication. I have personally witnessed this many times. If that intervention is not enough based on HbA1c, or if an SGLT2 inhibitor is valuable for CV or renal reasons independent of HbA1c, then begin the SGLT2 inhibitor after a few months of metformin.

Clinical endocrinologists were prepared to get ahead of the data for combination therapy because there was a need. I do not see the need to get ahead of the data here.

Daniel Einhorn, MD, FACE, FACP, is a clinical endocrinologist with Diabetes and Endocrine Associates and medical director of Scripps Whittier Diabetes Institute in La Jolla, California.