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New trials raise bar for CV outcome studies of diabetes therapies
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The CV safety of diabetes treatments has long been questioned by the medical community, in particular the effect of such drugs on the risk for CV mortality, MI and stroke. Now, two new trials addressed the CV safety of dipeptidyl-peptidase IV inhibitors, and the findings have created discussion among cardiologists and endocrinologists.
The SAVOR-TIMI 53 and EXAMINE trials were highlighted at the annual European Society of Cardiology Congress and published in The New England Journal of Medicine in September. In SAVOR-TIMI 53, saxagliptin (Onglyza, AstraZeneca/Bristol-Myers Squibb) added to standard care neither reduced nor increased risk for ischemic events as compared with placebo in patients with type 2 diabetes at high CV risk. In EXAMINE, alogliptin (Nesina, Takeda Pharmaceuticals) added to standard care did not increase major adverse CV event rates as compared with placebo in patients with type 2 diabetes and recent ACS.
Deepak L. Bhatt, MD, MPH, presented data from
the large SAVOR-TIMI 53 trial at the European
Society of Cardiology Congress.
Source: European Society of Cardiology Press office;
reprinted with permission
The trials were designed to satisfy FDA requirements that new diabetes drugs be investigated further to rule out CV risk. The FDA guidelines were developed in 2008 in the context of concerns regarding the long-term CV safety of several antidiabetic medications, such as rosiglitazone (Avandia, GlaxoSmithKline; see sidebar). The new data demonstrate that both SAVOR-TIMI 53 and EXAMINE fulfilled the FDA mandate of demonstrating noninferiority compared with placebo.
“It is important to keep on the radar screen the fact that some of the new diabetes medications can have significant CV effects. It is reassuring that two new trials have come out examining the CV safety of diabetes drugs in patients with diabetes at CV risk. What we are seeing here is a new trend of examining and powering these trials toward studying the CV effects,” William A. Zoghbi, MD, FACC, immediate past president of the American College of Cardiology and William L. Winters endowed chair in CV imaging at the Methodist DeBakey Heart and Vascular Center, told Cardiology Today.
Saxagliptin data
The SAVOR-TIMI 53 trial (n=16,492) was designed to determine whether daily saxagliptin (5 mg or 2.5 mg) was noninferior to placebo when added to background therapy for the primary composite endpoint of CV death, nonfatal MI or nonfatal stroke, Deepak L. Bhatt, MD, MPH, who presented results of the SAVOR-TIMI 53 trial, said at an ESC 2013 press conference.
During a mean follow-up of 2.1 years, the primary endpoint occurred in 7.3% of patients assigned saxagliptin vs. 7.2% assigned placebo (HR=1.00; 95% CI, 0.89-1.12; P<.001 for noninferiority; P=.99 for superiority). An on-treatment analysis yielded similar results (HR=1.03; 95% CI, 0.91-1.17). The major secondary endpoint — a composite of CV death, MI, stroke and hospitalization for unstable angina, coronary revascularization or HF — occurred in 12.8% of patients assigned saxagliptin vs. 12.4% of patients assigned placebo (HR=1.02; 95% CI, 0.94-1.11). A prespecified secondary endpoint of all-cause mortality occurred in 4.9% of patients assigned saxagliptin vs. 4.2% of patients assigned placebo (HR=1.11; 95% CI, 0.96-1.27).
William A. Zoghbi
Of note, saxagliptin-treated patients had more hospitalizations for HF (3.5% vs. 2.8%; HR=1.27; 95% CI, 1.07-1.51). HF requiring hospitalization was defined as admission or ED visit that results in at least a 12-hour stay; clinical manifestations of HF; and additional or increased therapy.
“The higher risk of hospitalization for HF was unexpected, but it was a predefined adjudicated endpoint. Therefore, it does merit further evaluation given the history of other diabetic agents and HF,” said Bhatt, who is professor of medicine at Harvard Medical School, Chief Medical Editor of Cardiology Today’s Intervention and a member of the Cardiology Today Editorial Board. “Additional analyses are ongoing, and preliminary data suggest that the risk is highest in those with elevated baseline clinical risk for HF, such as a history of prior HF and/or elevated [brain natriuretic peptide] levels at baseline.”
Fewer patients assigned saxagliptin required the addition or increase of any new antidiabetic medications (23.7% vs. 29.3%; HR=0.77; 95% CI, 0.73-0.82) or insulin therapy initiation for more than 3 months (5.5% vs. 7.8%; HR=0.7; 95% CI, 0.62-0.79). Reductions in blood glucose were greater with saxagliptin at 2 years (mean HbA1c reduction, 0.5% vs. 0.2%), and more patients assigned saxagliptin achieved or maintained target HbA1c <7% (40% vs. 30.3%; P<.001 for both). More patients in the saxagliptin group reported at least one hypoglycemic event (15.3% vs. 13.4%; P<.001). Hospitalization for hypoglycemia was infrequent and similar between groups (0.6% vs. 0.5%; P=.33).
Additionally, saxagliptin was shown to reduce the development and progression of microalbuminuria.
“It is encouraging that within such a short time, 2 years of follow-up, that saxagliptin has demonstrated a beneficial effect on the kidney,” researcher Itamar Raz, MD, head of the diabetes unit, department of medicine, Hadassah University Medical Center, Jerusalem, told Cardiology Today.
Rates of pancreatitis were similar with saxagliptin and placebo (0.3%; P=.77). Five cases of pancreatic cancer were reported in the saxagliptin group compared with 12 in the placebo group. The incidence of other prespecified safety endpoints were balanced, Bhatt said.
“There is still a great need to bring patients to target HbA1c. Recent epidemiological studies in the United States demonstrated a numeric increase in cases of renal failure and blindness related to unsatisfactory diabetes control. Today, it is generally accepted that only 50% to 60% of diabetes patients are at target,” Raz told Cardiology Today.
“In this study, saxagliptin was shown to be a safe drug that did not cause CV harm, as was shown in the primary and secondary endpoint results. Moreover, saxagliptin did improve blood glucose control; it decreased the need for insulin and did not cause weight gain or an increase in hypoglycemia when added to metformin or insulin. This is the largest outcome study of a diabetic drug that supports both the efficacy and safety of this drug. Similar studies on older antidiabetic drugs are missing and most probably will never be done.”
Alogliptin data
The EXAMINE trial enrolled 5,380 patients with type 2 diabetes and either acute MI or unstable angina requiring hospitalization within the previous 3 months. All were randomly assigned daily alogliptin (6.25 mg, 12.5 mg or 25 mg) or placebo in addition to existing diabetes and CV drug therapy.
During a median follow-up of 18 months, and up to 40 months, the primary endpoint — a composite of CV mortality, nonfatal MI or nonfatal stroke — occurred in 11.3% of patients assigned alogliptin vs. 11.8% assigned placebo (HR=0.96; upper boundary of the one-sided repeated CI, 1.16; P<.001 for noninferiority), William B. White, MD, chief of the hypertension and clinical pharmacology division and professor of medicine at the Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, reported at ESC 2013.
William B. White
Outcomes were similar with alogliptin and placebo for the secondary endpoint, which was a composite of death, nonfatal MI, nonfatal stroke and urgent revascularization, White said.
Glycated hemoglobin levels were significantly lower with alogliptin treatment (mean difference, –0.36 percentage points; P<.001). Incidences of hypoglycemia, malignancies including pancreatic cancer, pancreatitis and initiation of dialysis were similar between the two groups. Rates of withdrawal due to adverse events also did not differ.
“Hence, for patients with elevated CV risk, including those with a recent ACS, who are likely candidates for the drug in clinical practice, it is reassuring that alogliptin does not increase CV morbidity or mortality over a median period of 18 months,” White and colleagues wrote in NEJM.
Commenting on the trial at ESC 2013, Eugene Braunwald, MD, congratulated the EXAMINE investigators for “successfully completing one of the first large trials of a [dipeptidyl-peptidase IV] drug and showing clearly that the primary hypothesis [was] met.”
Eugene Braunwald
For Braunwald, the following questions remain.
“Did [the researchers] look at HF hospitalization? Did the investigators look for or find any changes or reductions in microalbuminuria or some other particular microvascular disease?
“I have to admit with some surprise that the reduction observed in HbA1c was not associated with more hypoglycemic events. Since the outcome of this study showed that alogliptin results were not different from placebo, it would be interesting to learn which co-therapies were added to placebo to make that arm similar to the alogliptin arm. This question is relevant and it’s important because if equality can be achieved with the addition of an inexpensive generic drug, it will be appropriate and important to conduct a cost-benefit analysis of alogliptin in this population. I think it’s important in this high-risk population that these additional questions will be asked,” said Braunwald, who is distinguished Hersey Professor of Medicine at Harvard Medical School, founding chairman of the TIMI Study Group at Brigham and Women’s Hospital and a Cardiology Today Editorial Board member.
Additional results at EASD
At the Annual Meeting of the European Association for the Study of Diabetes in Barcelona, less than a month after ESC 2013, additional safety data on saxagliptin and alogliptin relevant to endocrinologists were presented and further digested by the endocrine community.
Hypoglycemia and pancreatitis subanalyses from SAVOR-TIMI 53 demonstrated saxagliptin was associated with lower mean HbA1c at 1 and 2 years and did not affect the pancreas. The drug was, however, associated with more hypoglycemia, according to Raz. In the subanalyses, saxagliptin showed no signs of risk for pancreatitis or pancreatic cancer.
“In 2-year follow-up, we don’t see any signs that these drugs will cause or accelerate cancer,” Raz said. “Any way we look at it, it doesn’t seem that there is any increase in risk from pancreatitis.”
New data from EXAMINE showed that alogliptin did not cause a significant increase in HF hospitalization and was effective at lowering HbA1c and safe regarding pancreatic health.
“Due to the media and the questions that have been asked [since ESC] of me, my steering committee and the sponsor, we actually analyzed a post-hoc, non-specified evaluation of the EXAMINE study, in which we at least removed the confounding of death,” White said at the meeting. “In none of the analyses, regardless of how they were constructed, did we see a significant difference in any of our endpoints.”
With adjudication, they found a composite of 7.4% in the alogliptin group and 7.5% in the placebo group (HR=0.98, P=.976). Looking at CV mortality alone, the HR was 0.84 (P=.207), and in hospitalization for HF, which also considered those occurring after the primary endpoint, the HR was 1.19 (P=.22). Although the overall study excluded patients with unstable CV conditions, of those randomized, 15% had a history of congestive HF prior to their index ACS event. Of patients with that history, 18% of alogliptin patients vs. 22% of placebo patients met a primary endpoint in this post-hoc analysis, White explained.
A tale of two studies
The new data can be useful in choosing among numerous available diabetes medications when treating patients with type 2 diabetes at very high CV risk.
“What cardiologists might ask is, ‘If a drug is noninferior to placebo, why would I use it, especially if there are issues with cost and other associated side effects?’ I think that is a legitimate question from a cardiovascular perspective and that is why we need, as a field — diabetologists and cardiologists — to do more research to see what we can do to reduce the high rate of macrovascular complications in diabetes. What is clear is that neither of these [dipeptidyl-peptidase IV] inhibitors seems to impact favorably on CV outcomes in the intermediate term,” Bhatt said at a press conference.
David S.H. Bell, MD, told Cardiology Today that the SAVOR-TIMI 53 and EXAMINE data are interesting, especially in light of other recent research. “A meta-analysis that I conducted with colleagues and published in the American Journal of Cardiology last year showed a 55% decrease in ACS with DPP-IV inhibition. A meta-analysis from Europe of all DPP-IVs in general showed an approximate 30% decrease in CV events. Another study from McMaster University found a 75% decrease in CV events with these drugs.”
David S.H. Bell
He acknowledged that the findings in HF hospitalization “need further investigation, as approximately 44% of US hospital admissions for HF are in patients who also have diabetes.” Although the numbers reported are small, “it cannot be ignored and this result should be looked at in higher numbers of patients,” said Bell, of Southside Endocrinology and University of Alabama at Birmingham School of Medicine. “On a positive note, the findings of a low incidence of pancreatitis are especially exciting for endocrinologists.”
Asked to comment on the recent data, Lawrence A. Leiter, MD, professor of medicine at St. Michael’s Hospital, University of Toronto, said, “DPP-IV inhibitors were already a class of medication that had a lot of appeal to prescribers as well as to patients, given the fact that they are easy to take and effectively lower glucose without risk for hypoglycemia or weight gain, both of which may be seen with other glucose-lowering agents. For both physicians and patients, it is important to know that these drugs have now demonstrated cardiovascular safety.”
Carl J. Pepine, MD, Cardiology Today Chief Medical Editor, said he is “gratified by the results from these new diabetes trials,” but expressed concern about the absence of data about other risk factor management. “This is critically important since the percentage of patients achieving all four risk goals — HbA1c, systolic BP, LDL, smoking cessation — in three major federally funded trials (FREEDOM, BARI2D and the diabetes cohort of COURAGE) was only 12% to 20% at 1 year,” Pepine said. “This result was with fact that all trials had protocols to direct risk management for so-called ‘optimal medical therapy.’ So, let’s not forget that we need to do a better job by simultaneously managing multiple risk factors.”
Carl J. Pepine
“We are in a brave new world with diabetes drugs,” Naveed Sattar, MBChb, MRCP, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at British Heart Foundation Glasgow Cardiovascular Research Centre, said at the EASD conference. “The FDA 2008 guidelines have provided us a new approach to diabetes drugs.
“We are faced with the failing reality that in order to reduce CV events in a modest, medium or long term in patients with diabetes, one has to treat them with statins, get the cholesterol and BP to target, and stop smoking. And, reducing glucose … in a small, modest amount … is not going to change CV risk reduction. These trials have allowed us to get closer to the truth quicker. They provide robust evidence on speculation, whether good or bad.”
That said, such trials are expensive to conduct, Leiter said in an interview. “Each trial costs several hundred million dollars, and there are about a dozen such trials currently underway, so billions of dollars are being spent on these trials. It has certainly been questioned whether this is the best way to spend that money.”
Disclosure: The SAVOR-TIMI 53 study was funded by AstraZeneca and Bristol-Myers Squibb. Bell is a consultant and on the speakers’ bureau for AstraZeneca and Bristol-Myers Squibb. Bhatt reports relationships with various pharmaceutical and device companies. Braunwald reports disclosures related to the DPP-IV drugs by AstraZeneca, Bristol-Myers Squibb and Merck. Raz reports serving on an advisory board, consulting and is on the speakers’ bureau for AstraZeneca/Bristol-Myers Squibb. Sattar’s disclosures could not be confirmed at press time. White reports receiving research funding from the NIH and consulting fees for CV safety work from AstraZeneca, Ardea Biosciences, Astellas, Dendreon, EMD Serono, Forest Research Institute, Nycomed, Roche, Takeda Development Center Americas and Teva Pharmaceutical Industries, and compensation from Takeda as a CV safety consultant. Zoghbi reports no relevant financial disclosures.