Saxagliptin, Alogliptin Neither Help Nor Harm CV Risk in Diabetics

September 02, 2013

AMSTERDAM Saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) and alogliptin (Takeda Pharmaceuticals), two oral antihyperglycemic agents, did not increase the risk of cardiovascular events in patients with type 2 diabetes mellitus in two major trials presented here today at the European Society of Cardiology (ESC) 2013 Congress [1,2].

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) study, however, saxagliptin was associated with a significant 27% increased risk of hospitalizations for heart failure, a component of the prespecified secondary end point.

In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) study, there was no increased risk of heart failure with alogliptin, but investigators said the database was locked just five weeks ago, and nonprespecified secondary cardiovascular end points have not yet been analyzed.

While saxagliptin and alogliptin significantly reduced glycated hemoglobin levels, there was some debate about the role of the drugs, which are dipeptidyl peptidase-4 (DPP-4) inhibitors, in clinical practice.

Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA), a co–principal investigator of SAVOR-TIMI 53, said that most cardiologists will want to know why they should use either of these two drugs, given their lack of effect on cardiovascular end points and the increased risk of heart-failure hospitalizations. Indeed, some early analyses had suggested that the DPP4 class of drugs might actually improve CV outcomes.

"Okay, so a drug is noninferior to placebo, why should I use it, especially if there is a cost and other associated side effects that are present with all drugs?" said Bhatt during an ESC press conference. "It's a legitimate question from a cardiovascular perspective. That's why I ended saying that as a field, with diabetologists and cardiologists, we need to do more research and see what we can do to reduce the high rate of macrovascular events, such as heart attacks and strokes, in diabetic patients. What's clear is that neither of these drugs, and I would be willing to say that none of the DPP-4 inhibitors, seem to impact favorably on cardiovascular outcomes in this intermediate-term follow-up."

Speaking during the morning press conference, lead EXAMINE investigator Dr William White (University of Connecticut School of Medicine, Farmington) also addressed whether or not clinicians should use alogliptin. He said first-line therapy for diabetic patients is metformin, but the second drug is not yet clear. "I think when you have data such as [EXAMINE] supporting a lack of safety signal in a very high-risk population, it gives enhanced credibility to use a DPP-4 inhibitor as a second drug in addition to metformin."

White said alogliptin lowers the glycemic index significantly, and such reductions can reduce the risk of microvascular complications. "I think there is that benefit," said White. "Now, we don't have benefit in these shorter-term trials, but we know from the prior literature that it might take five years-plus before we determine a microvascular benefit."

FDA Requires Cardiovascular Safety Studies

Both saxagliptin and alogliptin emerged in the new Food and Drug Administration (FDA) era that requires all diabetes drugs to conduct a cardiovascular end point study to show the drugs are safe.

In SAVOR-TIMI 53, researchers randomized 16 492 patients with type 2 diabetes at high risk for cardiovascular events or who had a history of cardiovascular events to saxagliptin 5 mg/day or placebo. Patients were followed for a median of 2.1 years.

The primary end point--a composite of cardiovascular death, MI, or ischemic stroke--in SAVOR-TIMI 53, which was designed as an event-driven trial, occurred in 613 patients treated with saxagliptin and 609 patients treated with placebo. Statistically, saxagliptin met the primary end point of noninferiority, with the drug no worse than placebo. Glycated hemoglobin levels were reduced with saxagliptin, down from 8.0% at baseline to 7.7% at the end of the trial (p<0.001 vs placebo). In addition, more patients in the saxagliptin arm had glycated hemoglobin levels reduced to less than 7.0%.

As noted, there was a significant 27% increased risk of hospitalizations for heart failure compared with placebo, or a 0.7% increased risk in terms of absolute numbers. In addition, the risk of hypoglycemia, including hypoglycemia that required assistance in the intervention, was also higher with saxagliptin.

In the EXAMINE trial, 5380 patients with diabetes and an acute MI/unstable angina requiring hospitalization were randomized to alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The primary end point of the trial was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke, and like SAVOR, the study showed alogliptin no worse than placebo. Glycated hemoglobin levels were significantly reduced with alogliptin, a mean difference of -0.36%.

The EXAMINE researchers did not observe any increase in hypoglycemia or any increase increased risk of cancer or pancreatitis.

Industry Hurdles

Rosiglitazone was first approved in 1999, but 11 years later the FDA restricted access, given a 2007 meta-analysis showing the drug increased the risk of MI and death from cardiovascular causes. The data, however, have been parsed again this past summer, and an FDA advisory panel recently suggested restrictions on the drug should be eased.

However, given the uproar that followed the meta-analysis and the subsequent years of confusion and debate, all new diabetic agents must first rule out excess cardiovascular risk, leading to the SAVOR-TIMI 53 and EXAMINE studies.

In an editorial accompanying the publication of the new trials online September 2, 2013 in the New England Journal of Medicine [3], Dr William Hiatt (University of Colorado, Aurora), Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles), and Dr Robert Smith (Brown University, Providence, RI) write that saxagliptin and alogliptin appear to be relatively safe, but it is disappointing neither drug showed a benefit.

Adding a New and Costly Drug to the Toolbox

Speaking with heartwire about the results, Dr John Harold (Cedars-Sinai Heart Institute, Los Angeles, CA), who was not affiliated with either trial, said the studies, at first glance, don't appear to offer much to cardiologists. For starters, there was no benefit shown, and second, the one trial hints at an exacerbation of heart failure, with SAVOR-TIMI 53 suggesting that heart-failure hospitalizations occurred in those at highest risk for heart failure or patients with higher baseline brain-natriuretic-peptide (BNP) levels.

"At the end of the day, the rosiglitazone story raised the specter of excessive cardiovascular morbidity and mortality, but now we see that maybe that is less relevant with some of these newer agents," said Harold. "To the extent that they are adding to the armamentarium of practicing physicians, especially since it is an expensive agent, is the controversy."

Harold, the president of the American College of Cardiology, said physicians treating these high-risk diabetic patients are often in a difficult spot in trying to lower glycated hemoglobin levels without increasing the risk of hypoglycemia, or worse, cardiovascular events. "I don't think these agents will be used commonly by cardiologists, but we will get to see patients who are treated with these drugs," said Harold. "The issue now will be a little bit closer surveillance for heart failure."

Regarding microvascular end points, Harold noted that saxagliptin reduced the development and progression of microalbuminuria. However, neither study was designed to address the drug's effects on end points such as retinopathy or nephropathy.

Speaking with heartwire , ESC spokesperson Dr Johanne Silvain (Pitié-Salpêtrière University Hospital, Paris, France), who was also not affiliated with the studies, said there is a different focus for endocrinologists treating diabetic patients. Whereas cardiologists focus on cardiovascular end points and might look at these trials in a negative light, endocrinologists will be pleased with the reduction in glycated hemoglobin levels and the safety of the drugs in SAVOR-TIMI 53 and EXAMINE.

"This is why we need collaboration with diabetologists, because we don't see the same thing," said Silvain. While he does not treat patients for diabetes, if his CVD patients are being treated with either saxagliptin or alogliptin, these studies show the agents are safe in terms of cardiovascular events. "I wouldn't have any negative opinion about them." He added that he is unconcerned about the 0.7% absolute increase in the risk of heart-failure hospitalizations, especially since all-cause and cardiac mortality was not increased in either trial.

In their editorial, Hiatt, Kaul, and Smith say the optimal approach for reducing cardiovascular risk in diabetic patients is the aggressive management of cardiovascular disease risk factors rather than aggressive glycemic control.

The SAVOR-TIMI 53 study was sponsored by AstraZeneca and Bristol-Myers Squibb. The EXAMINE study was sponsored by Takeda Pharmaceuticals. Bhatt reports receiving grants to his institution from AstraZeneca and Bristol-Myers Squibb for his role as co-principal investigator for SAVOR-TIMI 53; research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi, and the Medicines Company; unfunded research grants from FlowCo, PLx Pharma, and Takeda; fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, the American College of Cardiology, Cardiosource, Belvoir Publications, Slack Publications, WebMD, and Elsevier Practice Update Cardiology; and fees paid to his institution from Medscape Cardiology, Regado Biosciences, and the Boston VA Research Institute. White reports personal fees from Takeda Pharmaceuticals during the conduct of the study; personal fees from Ardea Biosciences, AstraZeneca, Dendreon Pharmaceuticals, EMD Serono, Forest Research Institute, Palatin Technologies, Roche, Salix Pharmaceuticals, St Jude Medical, Shire Pharmaceuticals, and Teva Industries, grant support from the National Institutes of Health, and other support from the American Society of Hypertension. Disclosures for the coauthors are listed on www.nejm.org .

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