Creators of drug-approval trials strive for clinical homogeneity when choosing inclusion criteria for the patient-participants. The too old, the too sick generally remain outside the chosen parameters, not only for safety reasons, but because their illnesses and conditions can challenge and obscure the legitimacy of the tested therapy. Too much heterogeneity threatens regulatory approval. 

Too much homogeneity, however, creates its own problems; a thorough understanding of how real patients in the real world will respond to the treatment — risk vs benefit — isn’t likely to be ascertained in a clinical trial. Once a drug is approved, its use may not mirror the approval label. 

But a trial based on real-world data — the kind buried in a health system’s electronic medical records, in nationwide data banks, in PBM-based prescriptions — can answer questions not asked in a gold-standard, randomized controlled trial. While a real-world trial will not directly connect cause and effect, where so-called noise exists in abundance, it can expand the population that the therapy was created to help in the first place. 

“It is often the case that the treatment dilemmas we face in the clinic do not align perfectly with the current evidence base. This presents a problem,” said David K. Ryan, MBChB (Hons), MRCP, MSc. “Frequently, there is a gap between what is studied in an RCT and the decisions physicians must make in everyday clinical practice.” 

Ryan is doctoral fellow, Institute of Health Informatics and ST4 Doctor in Clinical Pharmacology and Therapeutics, University College London. “There is growing appreciation for using alternative sources of data to give more complementary insights into a drug's treatment effect,” he said.

Irl B. Hirsch, MD, professor, diabetes treatment and teaching chair, University of Washington School of Medicine and UW Medicine Diabetes Institute, is a fan of real-world trials. He agreed they can produce real value; the results are broader, in terms of reaching more patients, than found in the gold-standard trials. 

“What you see in real-world evidence is something that [pharma] can do something about,” he said. 

Gregg Fonarow, MD, director of the Ahmanson-UCLA Cardiomyopathy Center, helped establish the American Heart Association’s Get With The Guidelines Heart Failure (HF) program in 2005, “in response to persistently poor outcomes associated with HF hospitalizations and high estimated mortality rates,” with about 1 in 3 patients dying within 1 year post-hospitalization with acute HF. The program now has 626 hospitals nationwide and its own registry linked to data at CMS. 

This program, said Fonarow, the Eliot Corday Chair in Cardiovascular Medicine and Science at UCLA, “has shown how guideline‑directed therapies perform in everyday hospitals — community, academic, rural, and urban — not just in highly selected trial populations.” 

Clinicians, he said, can be confident that using “evidence‑based therapies for heart failure at scale is safe, well tolerated, and truly improve outcomes, including lower 30‑day mortality and better long‑term survival.”

Real-world studies also can:

• Inform on the use of medical devices, like continuous glucose monitors and automated insulin delivery systems.
• Make head-to-head comparisons of drugs: SGLT2 inhibitors perform better than metformin in preventing delirium in diabetes patients.
• Can explain behaviors, exposing the reasons, for example, why patients with diabetes stop, restart, and switch GLP-1 receptor agonist (RA) medications and SGLT2 inhibitors.
• Determine if primary care physicians in the UK are prescribing GLP-1s and SGLT2 inhibitors per National Institute for Health and Care Excellence (NICE) guidelines.

In Europe, NICE has expanded the use of SGLT2 inhibitors. Based on a review of the medical records of 590,000 people, it recommended that SGLT2 inhibitors, designed to help control blood glucose levels, be used as a first-line treatment, along with metformin, for those with diabetes. The earlier guideline said patients should have existing cardiovascular problems or the potential for them. 

Real-world studies also can expose disparities. The NICE study showed that more men than women received prescriptions, as did White people and those under 60 years of age. 

The issue, of course, is reaching primary care physicians with this real-world information. 

“The next challenge is ensuring that these guideline changes translate into real-world patient benefit,” said Ryan, particularly because of the disparities in prescribing. “We know from RCTs and accumulating real-world evidence that these drugs are effective, so it is important to address systemic barriers to ensure equitable access to evidence-based diabetes care.”

Real Data, Usable Information 

PubMed is chock-full of real-world data studies. In the last few months alone: 

• Researchers have reported on patients with diabetes who have died from pneumonia; they found that patients with fasting blood glucose of ≥ 130 mg/dL had a 2.5-fold risk of dying from pneumonia.
• Countering concerns regarding lung disease, real-world data showed that inhaled insulin produced one case of pulmonary disease — COPD, chronic bronchitis, emphysema — among 647 controls culled from millions of health records. The 1,830 controls produced two lung cancer cases and 27 COPD cases. The FDA had issued warnings, based on small studies, that patients with lung problems should avoid inhaled insulin.
• Using data from a pharmacy benefit manager, Hirsch and colleagues looked at 74,679 patients with type 2 diabetes who were treated with noninsulin, basal insulin, or prandial insulin who later switched to a continuous glucose monitor for up to 1 year. A sub-analysis of 6,030 patients showed glycated hemoglobin reductions across the board at 3 months that remained post-index. A second study involving a different database looked at different outcomes, including healthcare costs. CGM users required fewer hospital visits and had better odds of reducing A1c levels below 9.

“CGMs bring you down more than a SGLT2 inhibitor and as much as metformin. It protects you from hypoglycemia if you are on metformin. A CGM is another part of the tool kit,” Hirsch said. 

The Ryan study, involving 62,503 people with diabetes over an 8-year period, set out to discern the real-world effects of those who were taking the SGLT2 inhibitor empagliflozin; the controls were taking dipeptidyl peptidase-4 inhibitors. 

“One of our key findings was that fewer than 20% of real-world users of empagliflozin would have been eligible for the original EMPA-REG trial,” published in 2015, Ryan said. 

In the original study, participants had to have established CVD. In the Ryan study, 70% did not have CVD. (You can view the details here.) The real-world study results were consistent with the all-cause mortality findings of the 2015 trial, while showing the effect was seen in a much broader and more diverse population, he said.

In the NICE guidelines comparison study, researchers compared GLP-1 RA dose titrations in patients with type 2 diabetes between NICE guidelines and real-world data. The researchers found that patients were not prescribed the GLP-1 RA until they had tried three or more glucose-lowering therapies, which paralleled NICE guidance at the time. 

In 2018, when guidelines were changed to recommend SGLT2 inhibitors for those with obesity and at high risk of or with existing cardiovascular disease, about half of patients, regardless of CVD status, were prescribed SGLT2 inhibitors with GLP-1 therapy. The researchers analyzed medical records of 29,780 patients between 2007 and 2023. 

“Post-2018, most GLP-1RA initiators received SGLT-2 [inhibitors] concomitantly,” the researchers wrote. “However, CVD history did not influence prescribing patterns, underscoring missed opportunities to optimize the prevention of cardiovascular events and slow the progression of CVD.”

These same researchers also conducted a GLP-1 RA discontinuation and titration study in patients with type 2 diabetes; it involved 8,200 people who began taking a GLP-1 RA over a 5-year period. The researchers wanted to understand how primary care physicians were prescribing GLP-1 RAs by evaluating persistence and dose titration. The researchers stratified the patients by therapy, history of cardiovascular disease, obesity status, and sex at birth. 

The researchers found that the 1-year discontinuation risk of dulaglutide or semaglutide averaged 41.1% but was higher for those without obesity. 

“Only 58% of subcutaneous/oral semaglutide initiators reached recommended maintenance doses after 4 weeks, while 21% remained on starting doses,” the researchers wrote. 

In the real world, said Hirsch, patients do not get the close contact and hand-holding that occurs in trials. “In the real world, patients are bumped up when they are barely tolerating the first [dose] ... and then they stop the drug.”