Diabetes Drug Safety Might Be Best Assessed With Real-World Data

Meta-analysis published in JAMA suggests registry-based studies could be alternative to large cardiovascular outcomes trials.

A meta-analysis suggesting comparable efficacy and cardiovascular safety across multiple classes of diabetes drugs may renew questions about FDA's requirement for large CV outcomes studies for new treatments.

The findings point to the need for new thinking about how drugs for type 2 diabetes are studied, including the potential use of real-world evidence and alternatives to large, long traditional clinical trials, the study authors say.

However, given FDA's cautious approach to CV safety assessments for diabetes drugs and the challenges it sees in using real-world evidence for regulatory decision-making, it seems unlikely the agency will be ready ditch its requirement for large CV studies anytime soon.

Randomized trials of diabetes drugs "have been generally insufficiently powered to establish the role of drug treatment for preventing cardiovascular death, limiting the ability of single studies to inform practice and policy," Palmer, et al. said.

The study, which was published in the July 19 issue of the Journal of the American Medical Association, was aimed at determining the most effective medical treatments for type 2 diabetes. Despite widespread use of such drugs, "the comparative effects of glucose-lowering strategies on clinical outcomes, especially mortality and cardiovascular events, are uncertain," Suetonia Palmer, University of Otago Christchurch in New Zealand, and colleagues said.

The authors acknowledge the CV benefits observed in two recent large outcomes studies: the EMPA-REG trial of Boehringer Ingelheim GMBH and Eli Lilly & Co.'s SGLT2 inhibitor Jardiance (empagliflozin) and Novo Nordisk AS' LEADER study of its GLP-1 agonist Victoza (liraglutide). (Also see "Will Novo’s LEADER Trial Move GLP-1 To The Front Line In High-Risk Diabetes?" - Pink Sheet, 4 Mar, 2016.)

These studies were conducted pursuant to FDA's December 2008 guidance requiring CV safety assessments for new type 2 diabetes drugs. In June, an FDA advisory committee narrowly voted in favor of an empagliflozin labeling claim for reduced CV mortality on the basis of EMPA-REG results. (Also see "Can A Safety Study Support A Superiority Claim? Barely, FDA Advisors Say" - Pink Sheet, 4 Jul, 2016.)

Nevertheless, "randomized clinical trials of diabetes medications have been generally insufficiently powered to establish the role of drug treatment for preventing cardiovascular death, limiting the ability of single studies to inform practice and policy," Palmer, et al. say.

Metformin Reigns Supreme

The researchers conducted a random-effects, network meta-analysis of 301 randomized clinical trials involving nine drug classes (see box). The review encompassed 177 trials in which drugs were given as monotherapy, 109 trials in which drugs were added to metformin, and 29 trials in which drugs were added to metformin and sulfonylureas.

The primary outcome assessed was the association of drug treatment with CV mortality. Secondary individual efficacy endpoints were all-cause mortality, myocardial infarction, stroke, HbA1c level, and treatment failure. Secondary individual safety endpoints were serious adverse events, hypoglycemia and body weight.

9 Drug Classes

• α-Glucosidase inhibitor
• Basal insulin
• DPP-4 inhibitor
• GLP-1 receptor agonist
• Meglitinide
• Metformin
• Sulfonylurea
• Thiazolidinedione
• SGLT2 inhibitor

All the drug classes as monotherapy were associated with large proportional reductions in HbA1c. Metformin was associated with lower or no significant differences in HbA1c levels compared with any of the other classes and also fared better in terms of hypoglycemia and impact on weight.

All drug classes were considered to be effective when added to metformin, although SGLT2 inhibitors fared better in terms of weight gain, hypoglycemia and HbAc1 reduction than other classes.

The findings support the American Diabetes Association's recommendation of metformin as a first-line therapy, the authors said.

However, they noted the guidelines also recommend a patient-centered approach that takes into account various factors. "Clinicians and patients may prefer to avoid sulfonylureas or basal insulin for patients who wish to minimize hypoglycemia, choose GLP-1 receptor agonists when weight management is a priority, or consider SGLT-2 inhibitors based on their favorable combined safety and efficacy profile."

Lack of CV Benefit A 'Central Finding'

The meta-analysis results showed no striking differences in CV safety between drug classes.

"Considering cumulative trial data from 118,094 adults with type 2 diabetes, there was no evidence of differences in the associations between glucose-lowering drugs alone or in combination with odds of cardiovascular mortality, all-cause mortality, serious adverse events, myocardial infarction, or stroke," the authors said. "Considerable uncertainty about the association of drug treatment with cardiovascular mortality existed within trial evidence, largely because of few events in most available studies."

The authors called the absence of a benefit in prolonging life expectancy or preventing CV disease a "central finding" that aligns with the large CV outcomes trials of two DPP-4 inhibitors, the SAVOR trial of AstraZeneca PLC's Onglyza (saxagliptin) and the TECOS trial of Merck & Co. Inc.'s Januvia (sitagliptin). (Also see "Sitagliptin Shows No Increased Cardiovascular Risk In Merck’s TECOS Trial" - Pink Sheet, 8 Jun, 2015.)

Takeda Pharmaceutical Co. Ltd.'s Nesina (alogliptin) also demonstrated neutral CV effects in the EXAMINE trial. (Also see "Alogliptin, Saxagliptin Show Neutral CV Effects In Outcomes Studies" - Pink Sheet, 2 Sep, 2013.).

The neutral findings from SAVOR and EXAMINE prompted some experts to question FDA's blanket approach to requiring large outcomes studies. (Also see "Will CV Verdicts For Onglyza, Nesina Cause FDA To Change Its Tune On Antidiabetic Safety?" - Pink Sheet, 9 Sep, 2013.)

Commenting on the EMPA-REG and LEADER studies, Palmer, et al. said: "Although these trials represent emerging evidence of glucose-lowering drug effects on mortality outcomes, none of these trials analyzed treatment as monotherapy or added to metformin. Future trials might prioritize comparisons of SGLT-2 inhibitors against metformin or added to metformin to compare specific dual-therapy regimens."

A Role For Real-World Evidence

The analysis on CV impacts was limited by the amount of data in the studies examined, the authors said.

"Although cardiovascular mortality was included as an outcome because of its central clinical importance and the ongoing uncertainty about drug effectiveness for this endpoint, only a minority of studies reported this outcome, and most had few or zero events," Palmer, et al. said, observing that in the analysis for CV mortality with monotherapy the death rate was considerably lower than in a recent pragmatic trial among adults with previously undetected diabetes.

Consequently, future diabetes drug trials should "consider drug evaluations in real-world settings in individuals with higher morbidity and mortality risks," the authors said. "Randomized trials of sufficient duration and with adequate statistical power are needed to detect treatment effects of diabetes drugs on mortality and include consideration of disruptive trial designs such as registry-based trials to maximize trial efficiency and feasibility."

Industry and other stakeholders are increasingly interested in using real-world evidence – or data generated outside the setting of a traditional controlled clinical trial – as a way of confirming clinical benefit or expanding labeled indications. (Also see "Real-World Evidence May Find A Home On Breakthrough Pathway" - Pink Sheet, 27 Jun, 2016.)

FDA also has taken an interest in real-world evidence and committed to explore its use in the decision-making process under the sixth iteration of the Prescription Drug User Fee Act (Also see "FDA To Join The 'Real World' Under PDUFA VI" - Pink Sheet, 15 Jul, 2016.).

However, the agency remains cautious about ensuring that such evidence is fit for purpose (Also see "FDA's Califf On Real World Evidence: 'Use It For The Right Purposes'" - Pink Sheet, 17 Jun, 2016.).

In a statement, ADA said there is a role for registries and other data sources to support long-term controlled outcomes studies. "We need the long-term data to support what the best treatment options are over the course of that therapy to best preserve health and prevent complications," said Matt Petersen, the group's managing director of medical information.

ADA noted the challenges of assessing drug effects on CV outcomes and mortality but said the drug's other beneficial impacts should not be ignored.

"We can’t lose sight of the fact that lowering blood glucose levels has been repeatedly proven to reduce the rate of microvascular complications of diabetes like eye disease, kidney disease, and nerve damage, and that these effects can often be demonstrated in standard-length clinical trials," Petersen said. "Those complications take a significant financial and human toll, and they should a primary factor in determining whether a particular medication can add to our ability to manage diabetes."