SGLT2 Inhibitors as First-line Therapy for Diabetes With CVD?

December 11, 2017

ABU DHABI, United Arab Emirates — Whether a newer class of drugs, the sodium glucose cotransporter 2 (SGLT2) inhibitors, should now be considered as first-line therapy in patients with type 2 diabetes was the topic of a good-humored debate here at the International Diabetes Federation (IDF) Congress 2017 last week.

On the one hand, André J Scheen, MD, of the University of Liège, Belgium, presented some compelling arguments for this new drug class as initial therapy, primarily in type 2 diabetes patients with existing cardiovascular disease (CVD), based on recent cardiovascular-outcomes trials.

"Everybody agrees these compounds [SGLT2 inhibitors] act beyond glucose lowering," he stressed.

But in rebuttal, Guntram Schernthaner, MD, Medical University of Vienna, Austria, said: "Metformin should remain the foundation therapy for type 2 diabetes." He cited a long list of reasons why, including cost, side effects, discontinuation rate, and long-term experience with the drugs.

And it would seem that the American Diabetes Association agrees with Dr Schernthaner.

Just days later, it issued its new standards, sticking with metformin as the first-line therapy in type 2 diabetes patients. However, the ADA did recommend that SGLT2 inhibitors and another group of agents, GLP-1 agonists, could now be elevated to second-line therapy in type 2 diabetes patients with established CVD who don't meet blood glucose targets with lifestyle modification and metformin, as reported by Medscape Medical News.

Strong Argument for SGLT2 Inhibitors First Line in Some of Those  With CVD

There "is a strong argument supporting SGLT2  inhibitors as first-line therapy" in type 2 diabetes patients with established cardiovascular disease, on the back of recent CV outcomes trials such as EMPA-REG and CANVAS, Dr Scheen told attendees, noting that the FDA has added a claim for mortality reduction to the label for empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) based on the EMPA-REG results.

He argued that there is actually little direct evidence that metformin — the generally agreed first-line treatment for type 2 diabetes patients worldwide — is protective in all patients, and particularly not in those with cardiovascular disease, as most conclusions regarding metformin were drawn from the results of the UKPDS 34 trial. The patients in that trial were obese, newly diagnosed with diabetes with low cardiovascular risk, and were not taking current standard cardiovascular protective therapy such as statins, he emphasized.

And there have been "consistent" results in a few trials where SGLT2 inhibitors were used first line, as monotherapy, in addition to diet and exercise, Dr Scheen told the meeting — including reductions in HbA1c, fasting blood glucose, systolic blood pressure, and body weight, although this drug class does come at the expense of more genital infections, he acknowledged.

Add to this "some advantages" shown for the newer drug class in the only trial to compare metformin with an SGLT2 inhibitor head-to-head (metformin vs canagliflozin; Diabetes Care. 2016;39:353-362), and this can only lead to the conclusion that metformin use "should be reconsidered as first-line therapy for every patient," Dr Scheen said.

SGLT2 inhibitors "are protective in patients with type 2 diabetes with established CVD (as recognized by the ADA, FDA, ESC, and EMA), to reduce major cardiovascular outcomes, to reduce CV and all-cause mortality, to prevent hospitalization for heart failure, and to prevent renal outcomes," he emphasized.

Therefore, there is a "strong argument" supporting SGLT2 inhibitors as first-line therapy, at least in patients with established CVD, he urged, making a plea for a personalized, patient-centered, approach.

"Current algorithms for the management of type 2 diabetes based primarily on HbA1c values ought to shift toward a new paradigm that incorporates patients' CV risk and their likelihood of realizing a CVD benefit into the glucose-lowering drug-selection process," Dr Scheen concluded.

Metformin Is a Very Safe Drug That Has Been Used for Decades

In rebuttal, Dr Schernthaner presented a long list of reasons why he feels metformin must stay the drug of first choice in type 2 diabetes for the foreseeable future, despite the fact "I have presented more than 100 lectures about SGLT2 inhibitors…and that I believe this class is the best after metformin."

Relevant questions include HbA1c lowering, which is "much better" with metformin, he said, the durability of that effect, effects on body weight and blood pressure, discontinuation rates, side effects, CV protection in low-risk patients, whether use is possible in patients with renal impairment, long-term experience, and costs.

Arguments for Metformin Should Remain First-line Treatment for Type 2 Diabetes

Characteristic Metformin   SGLT2 inhibitors
HbA1c lowering High Intermediate
Durability Good Good
Discontinuation rate 8% per year 25% per year
Side effects Lactic acidosis (very rare) DKA, amputation, bone fractures, genital infection
Can be used in CKD (eGFR 30) Yes No, only when eGFR > 60
CV protection in early diabetes UKPDS No data in randomized controlled trials
Long-term experience 60 years 3–5 years
Costs Very low High

Citing a recent study of more than 800,000 patients with more than 1 year of follow-up, the discontinuation rate of the first-line antidiabetic agent within 1 year was threefold higher with SGLT2 inhibitors vs metformin, which is "very different," he noted (Diabetes Care. 2017; DOI:10.2337/dc17-1414).

Next, he emphasized "experience with metformin is extremely long (60 years) — it's a very safe drug used for decades — but relatively short with SGLT2 inhibitors (3–5 years)."

Potential adverse effects associated with SGLT2 inhibitors are many: increased risk for urogenital infections, dehydration risk in elderly, acute renal failure, and FDA warnings on diabetic ketoacidosis and increased risk for bone fractures and for foot amputations.

In addition, there are numerous combination therapies with metformin in them, including ones with each approved SGLT2 inhibitor (empagliflozin, canagliflozin, and dapagliflozin), thereby illustrating the generally accepted notion of metformin first, followed by another drug, he noted.

Slow Uptake of Newer T2D Drugs, "Striking" Cost Differences

And even though Dr Schernthaner says he himself believes it's important to use SGLT2 inhibitors as second-line therapy, data published just last month show that doctors are simply not using any of the newer agents in any great numbers just yet, he noted.

In an analysis from a US database of more than one million patients with type 2 diabetes who started on any glucose-lowering drug, to the end of 2016, 77% of patients took metformin as first-line therapy, 8% used sulfonylureas, 10% insulin, and 5% others.

And when it came to second-line therapy after metformin, almost half (46%) of the patients were getting the older sulfonylureas, 20% got dipeptidyl peptidase 4 (DPP-4) inhibitors, 7% insulin, and just 7% got SGLT2 inhibitors and 7% glucagonlike peptide-1 (GLP-1) agonists, as reported by Medscape Medical News.

"The uptake of these drugs [SGLT2 inhibitors] is much lower than expected despite the brilliant results [of EMPA-REG and CANVAS]," said Dr Schernthaner.

He also pointed out that in EMPA-REG and CANVAS, patients were already taking metformin; it was already in the mix of therapies to which SGLT2 inhibitor or placebo was added.

"If I were a company, I would do a head-to-head study [of my SGLT2 inhibitor] with metformin," he noted.

But probably the biggest obstacle to adoption of novel agents is cost, Dr Schernthaner told IDF Congress attendees, explaining that the current relative annual costs differences between metformin and newer drugs "are striking."

Metformin costs less than $50 a year, compared with about $4800 for SGLT2 inhibitors and around $9300 for GLP-1 agonists, he noted.

Therefore "a change in the first-line therapy to SGLT2 inhibitors in 100 million patients with type 2 diabetes would dramatically increase the cost of drug therapy from about $50 million per year to about $4.8 billion," he explained.

Dr Scheen did acknowledge that cost "remains a major concern in many countries" and conceded this may "limit widespread use of SGLT2 inhibitors."

"There is no doubt that metformin should remain the first-line glucose lowering therapy and should not be replaced by SGLT2 inhibitors," Dr Schernthaner concluded.

Dr Scheen reports receiving lecture, advisor or investigators fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Sanofi, and Takeda. Dr Schernthaner disclosed grants for scientific or clinical research, honoraria for advisory board meetings, and lectures from: Abbott, Amgen, Andromeda, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, DeveloGen, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, MSD, and Novartis. He has been principal investigator in more than 40 studies and involved in three FDA cardiovascular-outcomes studies with new antidiabetes drugs.

International Diabetes Federation (IDF) Congress 2017. December 5, 2017; Abu Dhabi, United Arab Emirates. Abstracts 163 and 164

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