Old Habits Die Hard: Newer Diabetes Drugs Slow to be Adopted

Miriam E Tucker

November 16, 2017

When it comes to prescribing drugs for people with type 2 diabetes, old habits die hard.

Findings from a new and comprehensive assessment of trends in prescribing patterns in the United States from 2005 to 2016 for glucose-lowering agents were published online November 6, 2017 in Diabetes Care by Olga Montvida, a PhD candidate at Queensland University of Technology, Brisbane, Australia, and colleagues.

The data reveal a significant increase in the use of metformin as first-line type 2 diabetes therapy, as might be expected per recommendations. However, there was wide variation in the choice of second-line therapies, for which current guidelines are less prescriptive.

And despite the availability of newer agents, sulfonylureas remained the most popular choice for a second agent added to metformin and were among the least likely to be discontinued. The use of insulin as second-line therapy increased over the 11-year study period as well.

"We believe that side effects of old and new antidiabetes therapies are well-known to clinicians. Our study suggests that so far cheaper sulfonylureas are favored over newer drugs at the population level," Ms Montvida told Medscape Medical News.

And, contrary to guidelines advising proactive intensification of therapy when glycemic targets (ie, HbA1c of less than 7% for many) are exceeded, second and third drugs often weren't being added until HbA1c levels had reached 8% or higher.

"Irrespective of drug choice, therapy intensification occurred at elevated HbA1c levels, posing the issue of therapeutic inertia," she noted.

Asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Connecticut, said the findings don't necessarily surprise her.

She pointed out that two trials of newer agents that "shook the landscape" regarding cardiovascular advantage for type 2 diabetes drugs were only just reported and published during the past 2 years of the current study.

These are the EMPA-REG OUTCOME trial with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) and the LEADER study with the glucagonlike peptide 1 (GLP-1) receptor agonist liraglutide (Victoza, Novo Nordisk).

"Definitely it takes a while for trial results to be translated into practice," Dr Lipska said, adding that as this happens, "we may see continued decline in the use of sulfonylureas."

And she noted, "We do not have [cardiovascular-outcomes trial] evidence for sulfonylureas….In the absence of convincing evidence that they are inferior, they are widely used because they are inexpensive, they lower blood sugars effectively, and we have a lot of experience using them.

"I'm not sure that is 'wrong' in every situation, [but] certainly I would not want to use this [sulfonylurea] drug class in someone at high risk of hypoglycemia or someone who is having ongoing hypoglycemia."

More Than 75% Now Prescribed Metformin as First-Line Drug

The new data are extracted from Centricity Electronic Medical Records (CEMR) of primary and secondary ambulatory-care systems, include electronic health records for over 34 million individuals contributed by more than 35,000 physicians and other providers (about 75% primary care) in all US states, and are considered generally representative of the US population.

A total of 1,023,340 people were newly diagnosed with type 2 diabetes and initiated any glucose-lowering medication during a mean of 3.4-year follow-up.

The proportion prescribed metformin for first-line therapy rose from 60% in 2005 to 77% in 2016, while sulfonylureas dropped from 20% to 8% and insulin's share rose from 8% to 10%.

Thiazolidinediones (TZDs) accounted for 11% of first-choice drugs in 2005 but dropped to just 0.7% by 2016 as safety concerns arose for that class. No other drug class was chosen as first line more than 3% of the time. 

For Choice of Subsequent Agents, New Drugs Still Lag Behind Old

For the subgroup of 357,482 who initiated therapy with metformin and then had a second glucose-lowering drug added, their mean HbA1c at the time of the addition was 8.4%, ranging from 7.8% for GLP-1 agonists to 9.3% for insulin.

For the choice of second agent, sulfonylureas did drop — from 60% to 46% — but still accounted for more than half of all postmetformin-therapy intensification initiations across the whole study period.

At the same time, use of insulin as a second agent rose consistently, from 7% in 2005 to 17% in 2016.

Newer drugs as metformin add-ons increased following their approvals.

For example, use of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) as second-line drugs rose sharply from 0.4% in 2006 (following approval of the first in class that year) to 20% in 2016, while for GLP-1 agonists, the increase was from 3% in 2006 to 7% in 2016. And after the first SGLT-2 inhibitor was approved in 2013, the proportion of patients receiving one as a second agent reached 7% in 2016.

Newer Drugs Also More Likely to Be Discontinued

Discontinuation rates within a year of starting second-line agents were just 7% for insulin and 10% for sulfonylureas, vs 25% for SGLT-2 inhibitors, 21% for both GLP-1 agonists and TZDs, and 18% for DPP-4 inhibitors.

"High discontinuation rates of newer drugs, particularly of DPP-4 inhibitors, surprised us," Ms Montvida said, adding, "While higher costs of newer drugs may [explain] cessation rates, more studies designed to assess medication adherence and persistence are needed."

Among those who intensified with a third-line therapy, nine times more patients taking sulfonylureas as their second drug added a third rather than switched, while those ratios were lower when DPP-4 inhibitors or GLP-1 agonists were the second drug (3.8 and 3.2, respectively).

Use of either DPP-4 inhibitors or GLP-1 agonists as second drugs pushed back the time to initiation of a third drug slightly, with 4.1 and 4.2 years, respectively, vs 3.9 years for sulfonylureas.

Similarly, the mean time to starting insulin was also slightly longer among patients taking the newer drugs, 7.1 and 6.6 years for DPP-4 inhibitors or GLP-1 agonists, respectively, vs 6.3 years for sulfonylureas.

Dr Lipska told Medscape Medical News, "A lot goes into a decision to add on therapy — including cost, treatment burden, side effects, and whether the benefits of lowering blood sugars further are substantial for that particular person.

"What I take away from this is that the add-on therapies in particular are changing with availability of new agents and with more [cardiovascular-outcomes trial] data.

"Going forward, it will be important to invest in evidence about the comparative effectiveness of these drug classes and agents on patient-important outcomes, including the older drug classes," she concluded.

Ms Montvida received a PhD scholarship from Queensland University of Technology. Disclosures for the coauthors are listed in the paper. Dr Lipska has no relevant financial relationships.  

Diabetes Care. Published online November 6, 2017. Abstract  

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