Saxagliptin: A Therapy Option in Diabetes and Renal Failure

January 13, 2015

Saxagliptin (Onglyza, AstraZeneca/Bristol-Myers Squibb) is a reasonable choice of glucose-lowering agent for type 2 diabetes patients who also have mild to moderate renal failure, a new analysis of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-TIMI 53 study indicates.

The paper, published in Diabetes Care by Dr Jacob A Udell (University of Toronto, Ontario) and colleagues, examines the outcomes of this large outcomes trial by baseline renal function.

They note that glycemic management in this patient population "is challenging, with few treatment options."

"We probably now have more data on saxagliptin and moderately to severely impaired renal function patients than any other diabetes medicine," one of the study authors, Dr Darren McGuire (University of Texas Southwestern Medical Center, Dallas), told Medscape Medical News.

And "at least in this trial the results seem more similar than different," he said.

"I don't think you can say that saxagliptin is especially beneficial in this patient population, but in the context of this trial that was designed to demonstrate, at a minimum, cardiovascular safety, it looks like saxagliptin appears to perform, both for efficacy and safety, similarly independent of renal function.

We don't have data like this for most drugs for diabetes; most trials have excluded patients with moderate, and certainly with severe, renal dysfunction.

"We don't have data like this for most drugs for diabetes; most trials have excluded patients with moderate, and certainly with severe, renal dysfunction."

He added: "What I take from this clinically is that for diabetic patients with chronic kidney disease [CKD] class 1 through 3, I would be quite comfortable prescribing this drug, but I don't think we have much data to make any comment about stage 4 CKD and end-stage renal disease [ESRD]."

There were only a small number of patients with stage 4 disease in the SAVOR-TIMI 53 trial and ESRD patients were excluded, Dr McGuire pointed out.

Still Exercise Caution with Heart Failure, However

There is another group in whom caution should also be exercised when using saxagliptin, Dr McGuire stressed — those with renal failure and a history of heart failure.

The SAVOR-TIMI 53 results were first reported in September 2013, when an unexpected association between saxagliptin and heart failure emerged: 3.5% of the type 2 diabetes patients on saxagliptin were hospitalized with heart failure, vs 2.8% of those on placebo (hazard ratio [HR], 1.27; P = .007). Doctors have been struggling with the implications ever since; in February last year, the US FDA announced that it would review heart-failure risk associated with saxagliptin.

"The concerns and cautions about heart failure are amplified in the setting of renal dysfunction, which is evidenced in the SAVOR trial," says Dr McGuire.

"The relative risk for heart failure was pretty comparable across the spectrum of renal function, but for the absolute risk, renal function is one of the most potent predictors of development of heart failure in the SAVOR trial, as we have shown in a previous analysis. The absolute risk of heart failure goes up as renal function goes down."

That said, Dr McGuire explained he wouldn't be completely deterred from using saxagliptin in those with a history of heart failure and renal failure:

"I would be cautious....Judicious prescription and close monitoring is probably more the recommendation rather than complete avoidance of saxagliptin."

SAVOR-TIMI 53 by Baseline Renal Function

In the new analysis, the patients in SAVOR-TIMI 53, who had type 2 diabetes and were at increased risk for cardiovascular events, were stratified according to renal function as: normal or mildly impairment (estimated glomerular filtration rate [eGFR] > 50 mL/min/1.73 m2; n = 13,916); moderate renal impairment (eGFR 30–50 mL/min/1.73 m2; n = 2240); or severe impairment (eGFR < 30 mL/min/1.73 m2; n = 336).

The study randomized patients to saxagliptin or placebo, in addition to other background glucose-lowering and cardiovascular therapies and recommendations for diet and lifestyle, at the discretion of the responsible physician. The dose of saxagliptin was 5 mg once daily for those with normal or mild impaired renal function and 2.5 mg daily for those with moderate or severe impairment. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke.

After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions > 0.19).

Overall, the risk of hospitalization for heart failure among the overall population according to the three eGFR groups of patients, independent of study treatment assignment, was 2.2% (referent), 7.4% (adjusted HR, 2.38; P < 0.001), and 13.0% (adjusted HR, 4.59; P < 0.001), respectively.

The fact that the absolute risk for HF goes up as renal function declines "is not surprising or novel," Dr McGuire observed.

But the relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m2 (HR, 1.23), eGFR 30–50 mL/min/1.73 m2 (HR, 1.46), and in patients with eGFR < 30 mL/min/1.73 m2 (HR, 0.94).

Therefore the effect of saxagliptin on heart-failure risk across the classes of renal dysfunction "is more similar than different," Dr McGuire explained.

Major Finding: Increased CV Risk of Patients With Diabetic Nephropathy

The researchers say there are four major findings from this new analysis of SAVOR-TIMI 53.

First, subjects with more advanced nephropathy in the form of progressive renal impairment "had a significantly higher risk of cardiovascular events compared with patients with normal or mildly impaired renal function."

Second, the cardiovascular effect of saxagliptin, including hospitalization for heart failure, in patients with moderate to severe renal impairment was "consistent" with that in patients with normal or mildly impaired renal function.

Third, treatment with saxagliptin resulted in a modest, but significant, improvement in glycemic control, and while saxagliptin also prevented progressive microalbuminuria in patients with moderate to severe renal impairment, it did not affect other renal end points.

And finally, major hypoglycemia, although infrequent, was approximately three times more frequent in patients with nephropathy, with higher rates in all patients treated with saxagliptin compared with placebo, except those with severe renal impairment. This could be due to differences in concomitant antihyperglycemic medications such as sulfonylureas or the play of chance, the authors suggest.

"These findings highlight the increased cardiovascular risk of patients with diabetic nephropathy and provide data on the efficacy and safety of saxagliptin to inform clinicians when formulating treatment strategies for their patients with concomitant type 2 diabetes and renal impairment," they conclude.

Trials for Diabetes Meds in Renal Disease: SGLT2 Inhibitors Promising

Saxagliptin is one of five dipeptidyl peptidase-4 (DPP-4) inhibitors marketed for type 2 diabetes — four of them are renally excreted, including saxagliptin (which is metabolized in the liver, but the active metabolites are excreted via the kidney).

But one DPP-4 inhibitor, linagliptin (Tradjenta/Trajenta, Boehringer Ingelheim), is not renally excreted and so currently has no restrictions or dose adjustments required regarding its use in those with kidney disease.

Dr McGuire said it is impossible right now to compare these different DPP-4 inhibitors, but linagliptin is being tested in a large outcomes trial in a diabetes population with renal dysfunction. The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA) has renal end points as well as cardiovascular safety ones and the estimated completion date is 2018.

These findings highlight the increased cardiovascular risk of patients with diabetic nephropathy.

Another diabetes agent, the injectable glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) has also recently received a positive opinion in the European Union for use in adults with type 2 diabetes and moderate renal impairment, an additional indication, and there are trials ongoing with other new glucose-lowering drugs, including the sodium glucose transporter-2 (SGLT2) inhibitors.

Of note, this class currently has warnings regarding its use in those with renal impairment, said Dr McGuire.

This is the result of a slightly increased risk of side effects like hypotension and volume depletion with SGLT2 inhibitors in patients with increasing degrees of renal impairment who were taking these agents in the registration trials, he explained.

There are a lot of signals…that suggest that renal function may actually be favorably affected over longer periods of time [with SGLT2 inhibitors]."

But now "there are a lot of signals that are possibly even unrelated to the mechanism of action…that suggest that renal function may actually be favorably affected over longer periods of time [with SGLT2 inhibitors]," he said.

Hence, nearly all the companies that market these products are "pursuing some evaluation of renal impairment."

A couple of small studies with SGLT2 inhibitors in patients with type 2 diabetes and renal dysfunction have already been published — the EMPA-REG RENAL trial with empagliflozin (Jardiance, Boehringer Ingelheim) in May 2014 (Lancet Diabetes Endocrinol. 2014;2:369-384) and a study with dapagliflozin (Farxiga/Forxiga, AstraZeneca) (Kidney Int. 2014;85: 962-971).

In addition, the larger Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial, which aims to enroll 3700 participants, and the Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R), which is planning almost 6000 patients, are both under way with canagliflozin (Invokana, Janssen Pharmaceuticals).

And there is also a renewed push for doctors to use an older medication, metformin, more liberally in those with renal impairment, said Dr McGuire — new data indicate it is being underprescribed because of unwarranted concerns about its use in those with mild to moderate renal insufficiency.

The SAVOR-TIMI 53 trial was funded by AstraZeneca/Bristol-Myers Squibb. Dr McGuire reports receiving research grants and honoraria from Brigham and Women's Hospital during the conduct of this study; personal fees from Boehringer Ingelheim, Janssen Research and Development, Merck Sharp & Dohme, Brigham and Women's Hospital, Duke Clinical Research Institute, Cleveland Clinic Coordinating Center for Clinical Research, University of Oxford, Lilly, Novo Nordisk, Hoffmann La Roche, GlaxoSmithKline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, Omthera, AstraZeneca, and Regeneron; and nonfinancial research support from Gilead Sciences. Disclosures for the coauthors are listed in the article.

Diabetes Care. Published online December 31, 2014. Abstract


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