Expectations High for Insulin GLP-1 Combinations in Diabetes Care

Evidence-Based Diabetes Management, September 2016, Volume 22, Issue SP13

Two competing insulin / GLP-1 combinations, one from Sanofi and the other from Novo Nordisk, are under review at FDA.

Pills that combine metformin with some other class of medication for type 2 diabetes (T2D) have been around for more than a decade. There are now more than a dozen on the market, but their total impact on outcomes has been as modest as the difference between swallowing 1 pill or 2.

Expectations are higher for 2 injectable combinations that currently await approval from the FDA. Analysts expect annual sales of more than $1 billion from Sanofi’s iGlarLixi (formerly called LixiLan) and IDegLira, to be marketed by Novo Nordisk as Xultophy, which both mix a basal insulin with a glucagon-like peptide 1 (GLP-1) receptor agonist in a way that would be hard for patients to do on their own.

“The results of the IDegLira trials I’ve participated in have been very impressive. The percentage of patients who get A1C levels into the target range is high, while the risk of hypoglycemia or weight gain is low,” said John Buse, MD, PhD, a professor at the University of North Carolina School of Medicine and director of the university’s diabetes care center. “I’m not yet sure that the combination is always superior to a GLP-1 alone, but I am convinced it is superior in all cases to basal insulin alone,” Buse said in an interview with Evidence-Based Diabetes Management. “In a world where price was not an issue, it would quickly and entirely supplant insulin in the treatment of type 2 diabetes.”

The race to be first has been fierce—and costly. Sanofi announced in late August that FDA approval of iGlarLixi would be delayed until November while regulators reviewed additional information, not on the therapy itself, but on the pen delivery system. At first, it seemed Sanofi had essentially wasted a $245 million priority review voucher it had redeemed to jump ahead of Novo Nordisk.1 But over Labor Day weekend came word that FDA had extended the review period for IDegLira from September to December.2

IDegLira combines 2 medications with distinct advantages over some of the competition—insulin degludec, sold as Tresiba, and liraglutide, which is formulated for diabetes as Victoza. Insulin degludec lasts nearly 2 days, so patients can take their daily dose at different times.3 It also keeps blood sugar significantly more stable than older insulins, and there’s some evidence that it reduces the risk of hypoglycemia.4,5 As for liraglutide, it is only the second diabetes medication (after empagliflozin) to demonstrate cardiovascular (CV) benefit.6

Together, the 2 medications have shown themselves generally superior to insulin or GLP-1 monotherapy.

In one phase 3 trial,7 investigators randomized 1663 metformin-using adults with glycated hemoglobin (A1C) levels of 7% to 10% to 26 weeks of IDegLira, insulin degludec, or liraglutide. Mean A1C levels fell by 1.9 percentage points (to 6.4%) in the IDegLira group, 1.4 percentage points (to 6.9%) in the insulin group, and 1.3 percentage points (to 7.0%) in the liraglutide group. Subsequent analysis found IDegLira noninferior to insulin degludec (estimated treatment difference, —0.47%; 95% confidence interval [CI], –0.58 to –0.36; P <.0001) and superior to liraglutide (estimated treatment difference, –0.64%; 95% CI, –0.75 to –0.53; P <.0001).

As for adverse events, IDegLira essentially averaged out the performance of its component parts. The number of confirmed hypoglycemic events per patient year were 2.6 for insulin degludec, 1.8 for IDegLira, and 0.2 for liraglutide. The percentage of users reporting nausea was 19.7 for liraglutide, 8.8 for IDegLira, and 3.6 for insulin degludec. “IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycemic control compared with its components given alone,” the investigators wrote.

Results from a 26-week extension of that original trial further supported the conclusion.8 Some 1311 of the original patients kept taking whatever medication they had started, and IDegLira maintained its advantage over its component parts. At the end of a full year of treatment, mean A1C levels were down 1.84 percentage points in the IDegLira group, 1.40 percentage points in the insulin group, and 1.21 percentage points in the liraglutide group. Some 78% of IDegLira users—but only 63% of insulin users and 57% of liraglutide users—got A1C levels below 7%. When investigators compared IDegLira users to insulin degludec users, they found that IDegLira users, on average, took less daily insulin (39 units vs 62 units), lost an additional 2.8 kg body weight, and suffered 37% less hypoglycemia.

IDegLira fared even better in a trial that compared it to insulin glargine (Lantus). Investigators randomized 557 patients between the 2 treatments for 26 weeks.9 Mean A1C levels fell 1.81 percentage points in the IDegLira group and 1.13 percentage points in the insulin glargine group (estimated treatment difference, —0.59%; 95% CI, –0.74% to –0.45%; P for non-inferiority <.001; P for superiority <.001). IDegLira was also associated with weight loss while insulin glargine was associated with weight gain (–1.4 kg for IDegLira vs +1.8 kg for glargine; total difference, –3.2 kg; 95% CI, –3.77 kg to –2.64 kg; P <.001). What’s more, IDegLira users had fewer confirmed hypoglycemic episodes (episodes/patient-year exposure, 2.23 for IDegLira vs 5.05 for glargine; estimated rate ratio, 0.43; 95% CI, 0.30 to 0.61; P <.001).

“We saw very robust efficacy, and very good lowering of A1C, and you see the mitigation of side effects,” said Todd Hobbs, MD, chief medical officer at Novo Nordisk North America. “If I have a patient for whom adding a next single agent is not going to get him to goal, this would be a great choice.”

IGlarLixi has also demonstrated superiority over its component parts.

Investigators in the LixiLan-O trial10 recruited 1479 patients, some whose T2D was inadequately controlled by metformin monotherapy, some whose diabetes was inadequately controlled by metformin and a single, additional oral therapy. During a 4-week run-in, they kept eligible patients on metformin (but discontinued other oral agents) and randomized 1170 of them to 30 weeks of iGlarLixi, insulin glargine 100 units/ml (Lantus) or the once-daily GLP-1 receptor agonist lixisenatide (Adlyxin). Mean A1C levels fell 1.6 percentage points (to 6.5%) in the iGlarLixi group, 1.3 percentage points (to 6.8%) in the insulin glargine group, and 0.9 percentage points (to 7.3%) in the lixisenatide group (P <.0001). Some 74% of iGlarLixi users—compared with 59% of insulin glargine users and 33% of lixisenatide users—saw their A1C levels fall under 7%. IGlarLixi users tended to lose weight (—0.3 kg) but not so much as lixisenatide users (–2.3 kg), while insulin glargine users tended to gain it (+1.4 kg).

Unlike IDegLira, iGlarLixi did not produce significantly less hypoglycemia than its component insulin. It occurred in 25.6% of iGlarLixi patients (1.44 events per year), which was not significantly different than in the insulin glargine group (23.6% of patients; 1.22 events per year). The combination did produce fewer adverse gastrointestinal events than lixisenatide, however. Nausea was reported by 3.6% of insulin glargine patients, 9.6% of iGlarLixi patients, and 24.0% of lixisenatide patients. Vomiting was reported by 1.5% of insulin glargine patients, 3.2% of iGlarLixi patients, and 6.4% of lixisenatide patients.

The results of that trial were reported orally at the annual meeting of the American Diabetes Association (ADA) in June, as were the results of the combination’s second pivotal test, the LixiLan-L trial.11 That second study pitted iGlarLixi against insulin glargine 100 units/ml for 30 weeks in patients whose diabetes was inadequately controlled by insulin and up to 2 oral agents. Some 1018 eligible patients underwent a 6-week run-in period, during which the insulin dose was optimized and oral medication except metformin was discontinued. Among the 736 patients who were randomized to treatment, mean A1C levels fell 1.1 percentage points (to 6.9%) among iGlarLixi users and 0.6 percentage points (to 7.5%) among insulin glargine users (P <.0001). Some 55% of iGlarLixi users—but only 30% of insulin glargine users—saw their A1C levels fall under 7% (P <.0001). IGlarLixi users also tended to lose weight (—0.7 kg) while insulin glargine users tended to gain it (+0.7 kg; P <.0001).

Again, there were no significant differences in hypoglycemia rates between iGlarLixi users (40% of patients; 3.0 events per year) and insulin glargine users (42.5% of patients; 4.2 events per year).

“Despite all the advances we’ve seen recently in treatments for type 2 diabetes, A1C is still uncontrolled in 50% of all patients,” said Rachele Berria, MD, PhD, the head of Sanofi’s US Diabetes Medical Unit. “This combination brings [A1C] down further and faster than any individual injection that’s currently available. These trials show that it can usually get [A1C] down to target levels for patients who have tried and were unsuccessful on other treatments.”Both Sanofi and Novo Nordisk say they have been negotiating with pharmacy benefits managers (PBMs) to secure favorable coverage should the FDA approve iGlarLixi or IDegLira, but neither company would discuss the specifics of such negotiations.

Excluded from Formulary Lists

PBMs have made news of late by taking aggressive steps to curtail spending on diabetes treatments. CVS Caremark, the nation’s second-largest PBM, announced12 last month that it would exclude Lantus and Toujeo, a new Sanofi basal insulin that lasts longer and keeps blood sugar steadier. (CVS Caremark users will be able to get a Lantus biosimilar called Basaglar.) Express Scripts, the nation’s largest PBM, announced13 that it would exclude 3 insulin formulations (Novolin, NovoLog, and Apidra), 2 dipeptyl peptidase-4 (DPP-4) inhibitors (Nesina and Onglyza), 2 combination pills that incorporate the excluded DPP-4 inhibitors (Kazano, Kombiglyze XR), and generic forms of alogliptin.

Perhaps more surprisingly, Express Scripts also announced that it would keep liraglutide off its list of diabetes treatments, except for patients who can prove a “specific need” for the drug. Company policy, according to an e-mail from its senior director of corporate communications, is to exclude medications only because “there is at least one clinically equivalent (or superior) product on the market that is more affordable for our clients. We will never exclude a product if it is clinically superior.” Express Scripts does cover 3 GLP-1 agonists—Bydureon, Byetta, and Trulicity—but none of them have demonstrated CV benefits. Liraglutide, on the other hand, reduced cardiac events by 13% and CV death by 22% in a large trial that was presented at the ADA meeting.6

Such decisions suggest that PBMs will not feel obligated to cover both iGlarLixi and IDegLira should 1 medication cost them significantly more than the other. The real question is whether PBMs will feel obliged to cover either combination, or whether they would counter what they view as unsatisfactory prices by rejecting both and telling patients to use separate basal insulins and GLP-1 receptor agonists. Neither Express Scripts nor CVS would return requests for comment about what value they see in FDA-approved, fixed-dose combinations.

Recreating such combinations at home would be tricky, even if a PBM let patients buy its component parts separately. Liraglutide, for example, comes in a pen that is labeled every 0.6 mg, but the standard dose escalation when titrating IDegLira is 0.12 mg. It is possible to judge the dose by ear—the pen makes a soft clicking sound every time it dispenses 0.06 mg—but error would be easy. Combining different basal insulins and GLP-1 agonists would involve guesswork because no trials have determined optimal ratios.

Anecdotal evidence suggests that a significant number of physicians are already engaging in such guesswork and prescribing both types of medications to some patients,14 but total numbers are unclear as is the demand among such patients for a single product that would save them a daily injection and a monthly copay. Hobbs said Novo Nordisk’s presentation before the FDA advisory panel emphasized the need for a range of options. “Patients and clinicians need that—they need individualized therapy,” he said.

Strategies for Patient Compliance

A number of studies support the intuitive hypothesis that patients dislike injecting themselves and wish to minimize the need to do so. For example, a 2011 paper15 based on survey responses from 15,16 T2D patients reported that 73.1% of daily-injection users would switch to weekly injections if their doctors recommended such a treatment.

On the other hand, both of the inhalable insulins that have won FDA approval have failed to generate significant revenues. Pfizer brought Exubera to market in 2006 but withdrew it just a year later because of poor sales. Afrezza, which came to market last year, has fared even worse thus far. Sales of the drug, which saves a typical user more than 1000 injections per year, barely exceeded $5 million during its first 9 months on the market.16

Even if PBMs don’t feel obligated to pay a premium for the new combination injections, the prospect of increased patient compliance might make them consider spending extra money.

There is significant evidence that treatment adherence increases as medication frequency decreases. A 2009 review of 20 studies found a significant negative correlation between doses-per-day and treatment-regimen-adherence in all 20 studies,17 though the studies in question examined the impact of consolidating several oral doses given at various times rather than 2 injections taken right after each other. There’s also some hope that combinations will increase real-world adherence by saving patients the worst side effects of either insulin or GLP-1 monotherapy.

“We did patient reported outcomes; they were generally beneficial, indicating the patients preferred the combination,” Hobbs said of his company’s IDegLira trials, noting that some of that preference likely stemmed from the fact that combinations produce less nausea than GLP-1 monotherapy. “We want to do everything to help patients stay on therapy. If patients are not taking therapy, then it’s not going to help.” Novo Nordisk may soon have some hard numbers about real-world compliance. IDegLira has been on sale in some European countries for more than a year now, and Novo has been tracking both usage and outcomes, though it has yet to report any numbers.

Reports that have already come from Europe may hint at Novo Nordisk’s strategy for US IDegLira pricing. The company apparently sells the combination for significantly less than it sells similar quantities of iDegLira’s component parts.18 IGlarLixi has yet to go on sale in any market, so there’s no public evidence of either its real-world performance or Sanofi’s pricing strategy.

Analysts apparently expect many PBMs to cover iGlarLixi and many patients to use it. Consensus annual sales projections for 2020 are $1 billion, according to analysts polled by Thomson Reuters.19 Expectations, on average, are similar for IDegLira,20 though some who have experience with it expect it to have even greater impact.“If I had the option right now, I’d advise most patients who were failing on metformin alone to consider just 3 options: empagliflozin, liraglutide, or IDegLira,” said Buse. “I’d say empagliflozin and liraglutide are right for people who want to maximize weight loss and minimize hypoglycemia risk, but that Xultophy is right for people who to reduce blood sugar as much as you can with any well-studied treatment.”


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6. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes [published online June 13, 2016]. N Engl J Med. 2016; doi: 10.1056/NEJMoa603827.

7. Gough SC, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label randomized, 26-week, treat-to-target trial in insulin-naïve patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014;2(11):885-893. doi: 10.1016/S2213-8587(14)70174-3.

8. Gough SC, Bode BW, Woo V, et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26- week main trial. Diabetes Obes Metab. 2015;17(10):965-973. doi: 10.1111/dom.12498.

9. Lingvay I, Manghi FP, Garcia-Hernandez P, et al. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial. JAMA. 2016;315(9):898-907. doi: 10.1001/jama.2016.1252.

10. Rosenstock J, Aronson R, Hanefield M, et al. Clinical impact of titrable fixed-ratio combination of insulin glargine/lixisenatide vs. each component alone in type 2 diabetes inadequately controlled on oral agents: IGlarLixi-O trial. Diabetes. 2016;65(suppl 1):186-OR.

11. Aroda V, Rosentock J, Wysham C, et al. Efficacy and safety of the insulin glargine/lixisenatide fixed-ratio combination vs. insulin glargine in patients with T2DM: the IGlarLixi-L trial. Diabetes. 2016;65(suppl 1):238-OR.

12. 2017 standard formulary list of removals and updates. CVS Health website. http://investors.cvshealth.com/~/media/Files/C/CVS-IR-v3/documents/02-aug-2016/2017-standard-formularylist- of-removals-and-updates.pdf. Published August 1, 2016. Accessed August 2, 2016.

13. 2017 Preferred National Formulary. Express Scripts website. http://lab.express-scripts.com/lab/insights/drug-options/2017-national-preferred-formulary. Published August 1, 2016. Accessed August 2, 2016.

14. Carris NW, Taylor JR, Gums JG. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations. Drugs. 2014;74(18):2141-2154. doi: 10.1007/s40265-014-0325-2.

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16. Smith A. Sanofi pulls plug on Afrezza deal, putting drug’s future in doubt. The American Journal of Managed Care website. http://www.ajmc.com/newsroom/sanofi-pulls-plug-on-afrezza-dealputting-drugs-future-in-doubt/. Published January 6, 2016. Accessed August 26, 2016.

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19. Blamont M, Regan J. Sanofi says LixiLan drug trials meet targets. Reuters website. http://www.reuters.com/article/us-sanofi-diabetes-idUSKCN0YY10F. Published June 12, 2016. Accessed August 26, 2016.

20.Carroll J. In a showdown with Sanofi, FDA questions Novo’s phase III data for IDegLira. Fierce-Biotech website. http://www.fiercebiotech.com/a-showdown-sanofi-fda-questions-novo-s-phiiidata-for-ideglira. Published May 20, 2016. Accessed August 26, 2016.