2014 was the year of the SGLT2 inhibitors in diabetes management.
This year brought two new sodium glucose co-transporter 2 (SGLT2) inhibitors to the market, giving physicians more options in a class that has been touted for not only its glucose-lowering effects but also for weight loss and blood pressure reductions.
In January, the FDA approved dapagliflozin (Farxiga) after a series of setbacks, and then gave the OK to empagliflozin (Jardiance) in August. These drugs joined canagliflozin (Invokana), which has been on the market since March 2013.
More evidence has mounted that the SGLT2 class can improve HbA1c while helping patients lose weight and lower their blood pressure -- including a meta-analysis of 55 studies reported at this year's European Association for the Study of Diabetes meeting in Vienna in September.
Before reviewing the year in SGLT2 advances, some history and context is in order. Each day, the kidney filters some 160 to 180 grams of glucose, almost all of which is reabsorbed and put back into circulation. SGLT2 is the main transporter protein involved in that process.
In a 2014 review published in Drug Design, Development, and Therapy, Michael Nauck, MD, of Diabeteszentrum Bad Lauterberg in Germany, notes that SGLT2 inhibitors had their origin in phlorizin -- a naturally occurring glucoside in the root bark of fruit trees.
The natural compounds weren't suited for clinical development because of their poor oral bioavailability and potential systemic effects, Nauck wrote. But pharmaceutical companies continued to pursue derivatives that were less likely to be broken down by the gut and that had SGLT2 selectivity.
Development of O-glucosides such as sergliflozin and T-1095 were halted, but C-glucosides appeared to work -- leading to the current family of SGLT2 inhibitors.
Nauck noted that SGLT2 inhibitors only stop 30% to 50% of the filtered glucose load, or 50 to 80 of the nearly 180 grams of glucose filtered per day. This is due to the fact that SGLT1 works overtime to reabsorb glucose when SGLT2 inhibitors are impaired.
This leaves the possibility of developing other agents that can inhibit a larger proportion of filtered glucose and further reduce HbA1c levels, Nauck said.
The Data Thus Far
At the 2014 EASD meeting in Vienna, Apostolos Tsapas, MD, PhD, of Aristotle University Thessaloniki in Greece, and colleagues updated a 2013 meta-analysis, analyzing a total of 55 studies comparing SGLT2 inhibitors with placebo.
They found that the drugs offered a a better reduction in HbA1c (-0.69%), greater weight loss (1.87 kg or about 4 lbs), and a larger reduction in blood pressure (4.19 mm Hg) compared with placebo.
The benefits did appear to come at the expense of an increased risk of hypoglycemia (HR 1.13, 95 % CI 1.03 to 1.25), as well as the well-known side effect of urinary tract infections (RR 1.21, 95% CI 1.06 to 1.38) and genital tract infections (RR 3.70, 95% CI 2.88 to 4.76).
Six trials that also compared the newer agents with metformin revealed a similar reduction in HbA1c, greater weight loss (1.31 kg or 2.9 lbs), and greater reduction in blood pressure (3.11 mm Hg), along with a trend toward more hypoglycemia that wasn't statistically significant.
When Tsapas and colleagues compared the three drugs approved in the U.S., canagliflozin offered the best reduction in HbA1c (-0.81% versus -0.56% for dapagliflozin and -0.65% for empagliflozin), they reported.
But in his review article, Nauck noted that no head-to-head trials of the three agents have been done.
"At present, there is no evidence suggesting preference of any one SGLT2 inhibitor over another," Nauck wrote. "Any differences between individual SGLT2 inhibitors may be revealed when clinical head-to-head comparator studies are carried out, although no such studies are currently reported to be underway."
Pills that combined an SGLT2 inhibitor with metformin also made it to market this year. Canagliflozin plus metformin (Invokamet) was OK'd by the FDA in August, followed by dapagliflozin plus metformin (Xigduo) in October.
It is not clear how either the drugs alone or as combination pills are fitting into individual patient regimens, but clinicians have noted that the weight loss seen with these agents may make them preferable.
"The properties of SGLT2 inhibitors present for the first time the possibility of a triple combination, i.e., metformin, DPP-4 inhibitor, and SGLT2 inhibitor, with the expected net effect of weight reduction and freedom from hypoglycemic episodes," Nauck wrote in his review. "This could be particularly attractive in Europe, where triple oral combinations have not been popular, presumably because at least one of the combination components introduced undesired adverse events, such as weight gain or hypoglycemia."
A Role for Monotherapy?
The SGLT2 inhibitors are indicated as monotherapy, and researchers have been exploring the drugs' efficacy in this role.
In May at the annual meeting of the American Association of Clinical Endocrinologists, William Canovatchel, MD, of Janssen Pharmaceuticals, reported findings that canagliflozin may be effective as monotherapy in type 2 diabetes patients who fail to control their disease with diet and exercise.
In a phase III study, patients had significantly greater reductions in HbA1c with either of two doses of canagliflozin compared with those on placebo, they reported.
Daniel Einhorn, MD, of Scripps Memorial Hospital in La Jolla, Calif., who was not involved in the study, told MedPage Today during the meeting that the study results were promising.
"The amount of glucose reduction is about as good as with any single oral agent we have," Einhorn said in May. "Whenever you have something that doesn't cause hypoglycemia, that gives you weight loss and not weight gain, and is easy to use orally, that is very encouraging."
But Sue Kirkman, MD, of the University of North Carolina at Chapel Hill, said they may be more common as second-line agents.
"Although the FDA indication is only as monotherapy, I doubt there's much first-line use at all," she told MedPage Today. "I tend to add them to other oral agents or to insulin."
When Tsapas and other panelists were asked at an EASD press briefing whether clinicians may come to favor SGLT2 inhibitors as the primary add-on after metformin failure, they emphasized that treatment of type 2 diabetes should be highly individualized, choosing the best agent for each particular patient.
When SGLT2 inhibitors were being evaluated for approval, the primary concern about side effects related to genitourinary tract infections. Tsapas' and other studies have shown expected rates of these conditions, which experts say have not been a major complication of the drugs' use.
Others have raised concerns about volume depletion and hypotension, as well as bone fractures, but studies have not turned up a major signal for these complications, Nauck wrote in his review.
While SGLT2 inhibitors have favorable effects on cardiovascular risk factors by reducing hyperglycemia, body weight, and blood pressure, Nauck noted that changes in lipid profiles have caused some concern, and "information on major cardiovascular outcomes such as stroke, heart attack, and other vascular complications is currently limited."
Several large, long-term studies with cardiovascular endpoints are ongoing and will provide data in the next 2 to 6 years, Nauck added. Those include the DECLARE-TIMI58 for dapagliflozin (expected in 2019), CANVAS for canagliflozin (2018), and EMPA-REG OUTCOME (2015).
2014 SGLT2 Inhibitor Timeline
Nauck disclosed financial relationships with Berlin-Chemie/Menarini, Eli Lilly, Merck Sharp and Dohme, Novartis, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Lilly Deutschland, MetaCure, Roche Pharma, NovoNordisk, Tolerx, Amylin, Bristol-Myers Squibb, Diartis Pharmaceuticals, Hoffman-La Roche, Intarcia Therapeutics, MannKind, Sanofi, Takeda, Versartis, and Wyeth.
Last updated 12.11.2014
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