More Data Will Inform Place of SGLT2 Inhibitors in Diabetes

July 16, 2013

The position of a novel class of drugs, the sodium-glucose cotransporter-2 (SGLT2) inhibitors, in the stepwise treatment of type 2 diabetes is currently unclear, but ongoing clinical trials will help better establish the place of these agents, says a new editorial in the Lancet, published online July 12.

Michaela Diamant, MD, PhD, and Linde M Morsink, MD, from the Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands, discuss where SGLT2 inhibitors will fit in to a doctor's armamentarium in their comment, which accompanies the publication of a 52-week, double-blind, phase 3 trial comparing one of the new SGLT-2 inhibitors, canagliflozin (Invokana, Janssen), with the sulfonylurea glimepiride in type 2 diabetes patients who are inadequately controlled on metformin.

SGLT2 inhibitors prevent the reabsorption of glucose from the kidneys back into the blood, leading to increased glucose in the urine and reduced glucose levels in the blood. One of the issues that may hold back use of these agents is the fact that many doctors were trained to think that glucose in the urine is an undesirable thing. SGLT2 inhibitors thus really target a disease manifestation, rather than a cause of type 2 diabetes, and this "may require a change in mind-set and be considered a step backward instead of forward," observe Drs. Diamant and Morsink.

In the study, called CANTATA-SU, canagliflozin provided equivalent or greater reductions in HbA1c than glimepiride and was well tolerated. The findings thereby support use of canagliflozin "as a viable treatment option for patients who do not achieve sufficient glycemic control with metformin," say William T. Cefalu, MD, of Pennington Biomedical Research Center, Baton Rouge, Louisiana, and colleagues. The article was also published online July 12 in the Lancet.

SGLT2 Inhibitors: Good and Bad Effects, More Study

As a drug class, SGLT2 inhibitors have been associated with some favorable effects — as well as the improved glycemia expected for a diabetes drug, they cause weight loss and lower blood pressure with no increase in heart rate, in addition to reducing triglycerides and increasing HDL.

But an increase in LDL cholesterol has also been observed with SGLT2 inhibition, and the significance of this needs to be further investigated. Also, probably because of the glycosuria they induce, SGLT-2 inhibitors increase the risk of genital mycotic infections and urinary-tract infections.

Canagliflozin is the first SGLT2 inhibitor available in the United States, having been approved there in March. A second, dapagliflozin (Forxiga, Bristol-Myers Squibb/AstraZeneca), was already approved in Europe, in November 2012. But the US Food and Drug Administration (FDA) denied approval of dapagliflozin in January 2012 because of concerns about a cancer signal. Other SGLT2 inhibitors are further back in development, including empagliflozin (Boehringer Ingelheim/Lilly), which is in phase 3 trials and has just been filed for approval in the United States, and ipragliflozin (Astellas Pharma) and luseogliflozin (Taisho Pharmaceutical), which are awaiting approval in Japan.

Dr. Cefalu and colleagues do acknowledge that "a longer duration of observation is needed to understand the comparative benefits and risks of these drugs [SGLT2 inhibitors] and the durability of response." Also, studies with other active comparators that are recommended for use after metformin failure "will help to assess canagliflozin relative to other antihyperglycemic drug classes used for this purpose," they note.

Drs. Diamant and Morsink agree. "Available studies suggest that SGLT-2 inhibition could be applied from early monotherapy to advanced disease in combination with insulin," they observe.

However, several issues must first be ironed out before their ideal place is determined, they say. There are the long-term safety concerns, including cardiovascular as well as potential cerebrovascular and cancer risks, and class-related adverse effects on bone health, which will require close surveillance.

A better understanding of the lipid changes seen with canagliflozin should ensue from the ongoing cardiovascular safety study being conducted with the drug, the Canagliflozin Cardiovascular Assessment Study (CANVAS), which is due to complete in 2015.

And other trials mandated by the FDA when it approved canagliflozin in March were: an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, and other adverse events; a bone safety study; and a pediatric pharmacokinetic and pharmacodynamics study and a pediatric safety and efficacy study.

In addition, only "time will tell whether the increased frequency of genitourinary infections will be acceptable for patients with diabetes who are prone to such infection," Drs. Diamant and Morsink observe.

CANTATA-SU: As Expected, Weight Loss and Yeast Infection

In the CANTATA-SU trial just published, Dr. Cefalu and colleagues randomly assigned almost 1500 type 2 diabetes patients with HbA1c of 7.0% to 9.5% already taking metformin, from 157 centers in 19 countries, to canagliflozin 100 mg daily (n = 483), canagliflozin 300 mg (n = 485), or at least 1 dose of glimepiride (n = 482).

The recommended starting dose of canagliflozin is 100 mg once daily, which can be increased to a maximum of 300 mg daily. Glimepiride was uptitrated gradually over the entire treatment period to achieve aggressive glucose targets with the maximum dose allowed in each country (6 or 8 mg per day).

For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was noninferior to glimepiride and canagliflozin 300 mg was superior to the sulfonylurea.

As expected, canagliflozin also led to weight loss, which appeared to plateau at week 26, and there was no evidence of subsequent weight being regained over 52 weeks. "Only subcutaneously administered glucagonlike peptide-1 (GLP-1) receptor agonists provide a weight-reduction benefit as reported for canagliflozin and other SGLT2 inhibitors," note Dr. Cefalu and colleagues. "Sulfonylureas, insulin, and [peroxisome proliferator-activated receptor] PPAR agonists increase weight, whereas [dipeptidyl peptidase-4] DPP-4 inhibitors [gliptins] are thought to have a neutral effect on weight."

But there were a greater number of genital mycotic infections in those taking both doses of canagliflozin: 11% and 14% in the 100-mg and 300-mg groups among women, compared with 2% of females taking glimepiride. For men, these figures were 7%, 8%, and 1%. Also, there were more urinary-tract infections: 6% of those taking both doses of canagliflozin suffered these compared with 5% of those taking glimepiride. And osmotic diuresis-related events, such as pollakiuria, were more frequent among those taking the newer drug.

Other Trials With Canagliflozin Reported at ADA Meeting

Results extending the findings with regard to the 2 doses of canagliflozin compared with glimepiride, out to 104 weeks, have also recently been reported at the American Diabetes Association 2013 Scientific Sessions (abstract 65-LB).

Also presented there were data showing canagliflozin 300 mg is superior and 100 mg noninferior — in terms of glycemic control — to the DPP-4 inhibitor sitagliptin (Januvia, Merck) in patients with type 2 diabetes already taking metformin (abstract 238-OR). "These data suggest that canagliflozin might be more useful than sitagliptin as add-on to metformin in patients with type 2 diabetes," concluded the authors, led by Fernando Lavalle Gonzalez, MD, from University Hospital at Universidad Autonoma de Nuevo Leon, in Mexico.

Dr. Cefalu has served as a consultant for Lexicon Pharmaceuticals, Johnson & Johnson, AstraZeneca, Bristol-Myers Squibb, Sanofi, Halozyme Therapeutics, and Intarcia Therapeutics and has served as principal investigator on research studies with funding awarded to his institution from Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Johnson & Johnson, MannKind, GlaxoSmithKline, and Lexicon Pharmaceuticals. Disclosures for the coauthors are listed in the article. Drs. Diamant and Morsink have reported no relevant financial relationships.

Lancet . Published online July 12, 2013. Abstract Editorial

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