www.ajmc.com/compendium/diabetes

Diabetes Compendium

In This Issue

P 3 As Metformin Combinations Proliferate, Questions Arise About Value

P 6 Discussions of High Costs for New Therapies Raise Questions About an Old One: Insulin

P 7 Studies Support Robust Real-World Efficacy, Adherence, Persistence, Quality Measure Attainment With Canagliflozin

P 9 Intensive Diabetes Management Adds Years to Life, Study Finds

P 9 Military’s Problem With Obesity Getting Worse, Report Finds

P 10 Sleep Disorders Linked to Heart Disease Risk in AHA Statement

P 11 Minorities, Southerners in Medicare Less Likely to Take High Blood Pressure Medication

OctOber 2016

NEWSLE T T ERTHE AMERICAN JOURNAL OF MANAGED CARE®

®

Managed Care/Moderators: Bruce A. Feinberg, DO, Joseph Alvarnas, MD

• Value in healthcare

• Panel: How patient-centered are payment models?• Panel: Managing cancer care costs while ensuring

adequate outcomes and quality of care• New cost sharing models being evaluated by

pharmacy benefit managers• Lack of diagnostic testing coverage: a barrier to

patient recruitment• Does cost sharing influence patient adherence and

outcomes in oncology?

Policy/Moderator: Bruce Feinberg, DO• Telehealth in palliative care• CMS coverage of outpatient palliative care services• Panel: Oncology care 2017

TOPICS:*

16

5th Anniversary

#AJMCLive

November 17-18, 2016 • Baltimore, MD

To register, visit ajmc.com/meetings/PCOC16

5th Annual

*subject to change

Clinical/Moderator: Joseph Alvarnas, MD• Immunotherapy update

• Chimeric antigen receptor T-cell update

• Panel: Immuno-oncology vs precision medicine: where is cancer care headed?

• Patient education on IO toxicities

• Keynote speaker

• Networking reception

• Patient reception speaker

DAY 1 DAY 2

PCOC16_HouseAd_Asize.indd 1 9/26/16 1:54 PM

As Metformin Combinations Proliferate, Questions Arise About ValueAndrew Smith

E arlier this year, when the FDA grant-ed initial approval to Jentadueto (lina-

gliptin/metformin HCl) XR and a first-line indication to Invokamet (canagliflozin/met-formin HCl), it gave fresh momentum to an entire category of medications: single pills that combine metformin with some other treatment for type 2 diabetes (T2D).

Several recent studies suggest that phy-sicians should employ combination thera-py faster and more aggressively than they have in the past. Indeed, a growing body of evidence supports immediate combina-tion therapy for many patients. There are questions, however, about the benefits of physically combining medications. Study results show that fixed-dose combinations improve patient adherence to treatment reg-imens. There is less evidence, however, that patients fare better over time with combina-tion pills rather than their component pills.

Although a number of payers declined requests from Evidence-Based Diabetes Man-agement™ (EBDM™) to discuss how much value they see in the physical combination of existing oral medications, their formular-ies suggest they see some. Most pharmacy benefits managers cover most combinations.

“There’s some value in 1 pill instead of 2. We just don’t know exactly how much,” John Buse, MD, PhD, a professor at the University of North Carolina School of Medicine and the director of the university’s diabetes care center, told EBDM™ in an interview.

No new trials were required for the approval of Jentadueto XR. The approval hinged on pre-existing validation of its method of delayed drug release and trial re-sults from the immediate-release version of Jentadueto, which combines the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta) and metformin hydrochloride.

Investigators in the immediate-release medication’s pivotal trial1 randomized 791 pa-tients to twice-daily treatment with 6 regimens:

• 2.5-mg linagliptin + 1000-mg metformin

• 2.5-mg linagliptin + 500-mg metformin

• 2.5-mg linagliptin monotherapy

• 500-mg metformin monotherapy

• 1000-mg metformin monotherapy

• Placebo

Mean changes in glycated hemoglobin (A1C) from a baseline of 8.7% were:

• –1.7 percentage points (95% CI, –2.0 to –1.4 percentage points) for linagliptin + 1000-mg metformin

• –1.3 percentage points (95% CI, –1.6 to –1.1 percentage points) for linagliptin + 500-mg metformin

• –1.2 percentage points (95% CI, –1.5 to –0.9 percentage points) for 1000-mg metformin monotherapy

• –0.8 percentage points (95% CI, –1.0 to –0.5 percentage points) for 500-mg metformin monotherapy

• –0.6 percentage points (95% CI, –0.9 to –0.3 percentage points) for linagliptin monotherapy

(all P<.0001).

Hypoglycemia occurred at a statistical-ly similar rate with combination therapy (1.7%) and metformin monotherapy (2.4%). Adverse event rates were comparable across treatment arms, as was the absence of any significant change in body weight.

Invokamet, which combines metformin with the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana), was originally approved as a second-line treatment in 2014. Earlier this year, after re-viewing evidence from a new phase 3 trial,1

In addition to research showing that combination pills increase treatment adherence, there is much research demonstrating that treatment adherence improves long-term outcomes.

Publishing Staff

Senior Vice President of Operations and Clinical AffairsJeff D. Prescott, PharmD, RPh

Senior Clinical Projects ManagerIda Delmendo

Clinical Projects ManagerCindy Spielvogel

Project ManagerJessica Toye

ProofreadersGriselda Demassey Maggie Shaw

Managing EditorMary K. Caffrey

Clinical EditorMichael R. Page, PharmD, RPh

DesignerJulianne Costello

Associate PublisherJustin T. Gallagher

Director of Sales Sara Belanger

National Account Managers Gabrielle Consola Michael Costella

Corporate

Chairman and CEOMike Hennessy, Sr

Vice Chairman Jack Lepping

PresidentMike Hennessy, Jr

Chief Financial Officer Neil Glasser, CPA/CFE

Chief Marketing OfficerWarren Dardine

Chief Digital Strategy OfficerSteve Ennen

Vice President of Editorial Services and ProductionKerrie Keegan

Vice President, Digital MediaJung Kim

Chief Creative Officer Jeff Brown

Director of Human Resources Shari Lundenberg

Copyright ©2016 by Managed Care & Healthcare Communications, LLC

4www.ajmc.com/compendium/diabetes

the FDA approved the drug as an initial treatment for patients with T2D who have A1C levels greater than 7.5%.

Investigators in that trial randomized 1186 untreated patients to 26 weeks of cana-gliflozin 100 mg + metformin, canagliflozin 300 mg + metformin, canagliflozin 100-mg monotherapy, canagliflozin 300-mg mono-therapy, or metformin monotherapy. Mean A1C levels, which started at 8.8% for all groups, fell by 1.77 percentage points in the 100-mg combination group, 1.78 per-centage points in the 300-mg combination group, 1.37 percentage points in the 100-mg monotherapy group, 1.42 percentage points in the 300-mg monotherapy group, and 1.3 percentage points in the metformin monotherapy group. Moreover, members of both combination therapy groups lost significantly more weight than metformin group members and were significantly more likely to attain A1C levels below 7%.

These results led the investigators to conclude that patients who resemble the trial population would fare better if they started treatment on Invokamet rather than metformin alone. “Initial therapy with canagliflozin plus metformin was more ef-fective and generally well tolerated versus each monotherapy in drug-naïve T2D,” they wrote in Diabetes Care.2

It was not the first time study authors had suggested that some newly diagnosed patients would be better off skipping met-formin monotherapy and moving straight to combination therapy. The trial that won Jentadueto’s approval in 2012 used it as a first-line treatment. The investi-gators who ran the trial concluded that the combination performed better than the monotherapy. “Initial combination therapy with linagliptin plus metformin was superior to metformin monothera-py in improving glycemic control, with a similar safety and tolerability profile, no weight gain, and a low risk of hypoglyce-mia,” they wrote at the time.

Even before that, researchers who had tested several other metformin combina-tions had reached similar conclusions. A 2006 piece that appeared in Treatments in Endocrinology made a case for first-line

combination therapy.3 “The glycosylated hemoglobin goal in patients with T2D should be to achieve as low a value as can be obtained without causing significant or frequent hypoglycemia. This is best achieved by utilizing agents that lower glucose levels without causing hypoglyce-mia (thiazolidinediones and metformin),” wrote David S.H. Bell, MB, FACP, FACE, the piece’s author. “Utilizing small doses of 2 drugs will also result in a decreased incidence of adverse effects compared with a large dose of a single drug.”

The results of a number of recent large studies have shown significant advantages to starting newly diagnosed patients on various types of combination therapies.

“We decided to test the [American Diabe-tes Association] algorithm, which was, ‘We put you on metformin. When you fail, and you will, I’ll add [another oral medication]. When you fail, and you will, I’ll add basal insulin.’ We chose [to put it up against] a triple-therapy algorithm, which was a GLP-1 receptor agonist, low-dose pioglitazone … and metformin,” said Ralph DeFronzo, MD, professor of medicine and chief of the Diabetes Division at the University of Tex-as Health Science Center in San Antonio, at an MD Magazine Peer Exchange®, while describing a trial he’d worked on.

“They all started with A1C of about 8.8%, and A1C came down in both groups to about 6.3%. Now, with the ADA algorithm, at the end of 3 years, they’re up to 6.7%. With the triple-therapy algorithm, they’re at 5.9%. The incidence of hypoglycemia was 7.5-fold greater with the ADA algorithm, but our A1C is 5.9% and theirs is 6.7%. We measured beta cell function and, at the end of 3 years, we had perfectly normal beta cell function with the triple-therapy algorithm. With the

ADA algorithm, they’d lost about 90% of beta cell function. You also saw, with the triple-therapy algorithm, a 60% increase in insulin sensitivity and no change with the ADA algorithm. Weight gain with the ADA algorithm was 3.7 kg. Weight loss with the triple-therapy algorithm was 3 kg. This is total destruction of the ADA algorithm.”

There is, however, far less evidence to show that patients who use early combi-nation therapy to control A1C experience better outcomes than others, according to a 2016 review published in the Journal of Di-abetes and Its Complications.4 “Support for improvement in microvascular and mac-rovascular outcomes with early, aggressive therapy is conflicting. [UK Prospective Di-abetes Study] supports the use of intensive therapy to improve long-term microvascu-lar and macrovascular outcomes, although significant improvements in [myocardial infarction] and death from any cause did not materialize until 10 years post trial,” wrote Steve Milligan, MD, the author of the review, citing Holman et al.5

On the other hand, “The ORIGIN trial was the first key evaluation of long-term [cardiovascular] outcomes in patients with T2D. Participants had [impaired fasting glucose], [impaired glucose tolerance], or newly diagnosed T2D, but insulin glargine therapy targeting near-normal [fasting plasma glucose] levels did not sig-nificantly reduce the risk of macrovascu-lar outcomes,”6 Milligan added.

Still, barring strong evidence to the con-trary, professional societies assume that fast-acting, long-lasting blood sugar con-trol will eventually improve outcomes. The newest guidelines from the American Asso-ciation of Clinical Endocrinologists and the American College of Endocrinology call for metformin monotherapy in patients whose T2D is newly diagnosed and who have A1C less than 6.5%, dual therapy for new patients with A1C ranging between 7.5% and 9.0%, and triple therapy for the newest patients with A1C levels exceeding 9.0%.7

Even the ADA guidelines now say doc-tors should consider starting new patients with combination therapy, although only with 2 agents and only in patients with

Efforts to measure the effect of combining multiple pills into single pills (rather than extending the release of a single medication) have also reported improved patient compliance.

5

A1C greater than 9%. (For other patients, ADA guidelines still recommend at least 3 months of metformin monotherapy before beginning combination therapy.8) Guidelines from both organizations, moreover, urge the use of combination therapy whenever monotherapy fails to get patients below A1C targets, because it is clear that most types of combination therapy reduce A1C more than monother-apy in most patients.

A 2014 meta-study9 looked at 15 ran-domized, controlled trials with a total of 6693 subjects whose characteristics var-ied considerably. The mean baseline age ranged from 48.4 to 62.7 years, the mean baseline duration of disease ranged from 1.6 to 4.1 years, and the mean baseline A1C ranged from 7.2% to 9.9%. The medication classes paired with metformin also varied considerably and included thiazolidine-diones, insulin secretagogues, DPP-4 in-hibitors, or SGLT2 inhibitors. The only thing that didn’t vary much was the out-come. Combination therapy reduced A1C more (weighted mean difference, –0.43 percentage points; 95% CI, –0.56 to –0.30 percentage points) and increased the chance that patients would get A1C under 7% (relative risk, 1.40; 95% CI, 1.33-1.48).

The evidence that combination therapy controls blood sugar better than monother-apy is overwhelming. The evidence that physically combining pills produces better outcomes than prescribing patients several pills is less dramatic. There are, however, many studies that find patient adherence increases as the effort required to adhere to treatment regimens decreases. For ex-ample, a 2009 review of 20 studies found a significant negative correlation between doses per day and treatment-regimen ad-herence in all 20 studies10—although 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.

Efforts to measure the effect of com-bining multiple pills into single pills (rather than extending the release of a single medication) have also reported improved patient compliance. A 2008

study11 of patients who were prescribed metformin and a sulfonylurea before Au-gust 2000 and Glucovance (which com-bines the 2 medications) after that date used information from claims data to see whether the switch increased the num-ber of days that patients at least had both medications on hand. The study authors found a 12.8% improvement in adherence.

Another pharmacy claims–based study of treatment adherence by patients with diabetes found an even greater effect.12

“Among the 1815 previously treated pa-tients receiving glyburide or metformin monotherapy who required the addition of the alternative agent, resulting in combina-tion therapy, adherence rates were signifi-cantly lower (54.0%; 95% CI, 0.52-0.55) than in the 105 patients receiving monotherapy who were switched to fixed-dose combina-tion therapy (77.0%; 95% CI, 0.72-0.82). The 59 previously treated patients receiving combination therapy who were switched to fixed-dose combination therapy had a significant improvement in adherence after the switch (71.0% vs 87.0%; P <.001).”

(Another paper13 notes a potential pitfall with metformin combinations: many such combinations use immediate-release met-formin, which requires twice-daily dosing. Replacing 2 pills that need to be taken once daily with 1 pill that needs to be taken twice daily does not reduce the pill burden.)

Much of the research into the effects of fixed-dose combinations on treatment ad-herence focuses on cardiovascular disease and hypertension, and it typically reaches similar conclusions. A 2010 meta-analysis of 6 studies of 30,295 patients combined the data to report that fixed-dose com-binations were associated with a 29% increase in compliance compared with individual pills.14 A 2011 meta-analysis of 7 other studies that estimated compliance through medication possession found that a combination doubled the risk ratio of patient treatment persistence.15

In addition to the research showing that combination pills increase treatment adherence, there is much research demon-strating that treatment adherence improves long-term outcomes. There is not, however,

much direct evidence that the use of combi-nation pills improves long-term outcomes. Indeed, the few studies so far that have ex-amined how the increased adherence as-sociated with combination pill use affects known risk factors have found only small effects, although still significant ones.

A 15-month trial that pitted a 4-pill combination against 4 separate pills in 2004 patients found only modest practical improvements.16 “Among patients with, or at high risk of, cardiovascular disease, use of a fixed-dose—combination strategy for blood pressure, cholesterol, and platelet control versus usual care resulted in sig-nificantly improved medication adherence at 15 months (86% vs 65%) and statistically significant, but small improvements, in sys-tolic blood pressure (−2.6 mm Hg; 95% CI, −4.0 to −1.1 mm Hg; P <.001) and low-density lipoprotein cholesterol (−4.2 mg/dL; 95% CI, −6.6 to −1.9 mg/dL; P <.001).”

Without concrete evidence about the effects on long-term outcomes, it is impos-sible to calculate the cost-effectiveness of combination pills that cost more than the sum of their component parts. In many cases, however, combinations cost less than the sum of their component parts, so they are, by definition, cost-effective.

References1. Haak T, Meinicke T, Jones R, Weber S, von Evnatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycae-mic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Dia-betes Obes Metab. 2012;14(6):565-574. doi: 10.1111/j.1463-1326.2012.01590.

2. Rosenstock J, Chuck L, Gonzalez-Ortiz M, et al. Initial combination therapy with canagliflozin plus metformin versus each component as monother-apy for drug-naïve type 2 diabetes. Diabetes Care. 2016;39(3):353-362. doi: 10.2337/dc15-1736.

3. Bell DS. The case for combination therapy as first-line treatment for the type 2 diabetic patient. Treat Endocrinol. 2006;5(3):131-137.

4. Milligan S. Combination therapy for the improve-ment of long-term macrovascular and microvas-cular outcomes in type 2 diabetes: rationale and evidence for early initiation. J Diabetes Complica-tions. 2016;30(6):1177-1185. doi: 10.1016/j .jdiacomp.2016.03.010.

5. Holman RR, Paul SK, Bethel A, Mathews DR, Neil AW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589. doi: 10.1056/NEJMoa0806470.

6. Gerstein HC, Bosch J, Gagenais GR, et al;

6www.ajmc.com/compendium/diabetes

ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328. doi: 10.1056/NEJMoa1203858.

7. Garber AJ, Abrahamson MJ, Barzilay JI, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE). Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84-113. doi: 10.4158/EP151126.CS.

8. American Diabetes Association. Approaches to glycemic treatment. Diabetes Care. 2016;39(suppl 1):S52-S59. doi: 10.2337/dc16-S004.

9. Phung OJ, Sobieraj DM, Engel SS, Rajpathak SN. Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and

meta-analysis. Diabetes Obes Metab. 2014;16(5): 410-417. doi: 10.1111/dom.12233.

10. Saini SD, Schoenfield P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009;15(6):e22-e33.

11. Pan G, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on adher-ence to prescription medications. J Gen Intern Med. 2008;23(5):611-615. doi: 10.1007/s11606-008-0544-x.

12. Melikian C, White TJ, Vanderplas A, Dezii CM, Chang E. Adherence to oral antidiabet-ic therapy in a managed care organization: a comparison of monotherapy, combination therapy and fixed-dose combination therapy. Clin Ther. 2002;24(3):460-467.

13. Blonde L, San Juan ZT, Bolton P. Fixed-dose combination therapy in type 2 diabetes mellitus.

Endocrin Pract. 2014;20(12):1322-1332. doi: 10.4158/EP14259.RA.

14. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combina-tions of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-407. doi: 10.1161/HYPERTENSIONAHA.109.139816.

15. Sherrill B, Halpern M, Khan S. Zhang J, Panjabi S. Single-pill vs. free-equivalent com- bination therapies for hypertension: a meta- analysis of health care costs and adherence. J Clin Hyperten. 2011;13(12):898-909. doi: 10.1111/j.1751-7176.2011.

16. Thom S, Poulter N, Field J, et al; UMPIRE Collaborative Group. Effects of a fixed-dose com-bination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013;310(9):918-929. doi:10.1001/jama.2013.277064.  ●

Discussions of High Costs for New Therapies Raise Questions About an Old One: InsulinRobert A. Gabbay, MD, PhD, FACP

I n June, I had the opportunity to lead a symposium at the Scientific Sessions

of the American Diabetes Association (ADA) called “Follow the Money—How Costs and Payments Impact Diabetes Care.” Much of the discussion involved new payment models, which can provoke lively debate on their own. But when the talk turned to the price of insulin, that’s when the sparks started to fly.

A speaker asserted that over the long term, the share of nonelderly patients who spend large shares of their income on insulin isn’t as large as it seems. But the endocrinologists were having none of it. As Irl Hirsch, MD, of the University of Washington, warned earlier this year, the price of insulin and the increased talk about diabetic ketoacidosis are high-ly connected.1 During the bloom of the EpiPen saga this summer, Hirsch sounded the alarm that the crisis over insulin pric-ing is just as dire, even if it has unfolded more gradually.2

Work by Elbert Huang, MD, of the University of Chicago, along with re-searchers from the University of Michi-gan and the University of Melbourne in Australia, appeared in JAMA in April 2016.

The researchers found that the price of insulin has more than tripled over the past decade, from $231 a year to $731 per patient. By contrast, costs for other med-ications, including those commonly used in type 2 diabetes (T2D), have stayed flat or declined.3

To be sure, modern insulins offer su-perior control, often with less hypogly-cemia and potentially less weight gain. But rising insulin costs have enormous implications; for those with type 1 diabe-tes, the hormone is needed to stay alive. We also know that if individuals with T2D live long enough, they likely will need in-sulin therapy as a result of ongoing beta cell decline. But because of the cost, pay-ers may resist reimbursing for insulin or other newer classes of diabetes therapy.

Who is to blame? As our colleagues who treat cancer and rare diseases have understood for years, nobody’s completely guilty, but nobody’s completely innocent either, which makes solutions challeng-ing. An informative paper appeared last month in JAMA, by Aaron S. Kesselheim, MD, JD, MPH; Jerry Avorn, MD; and Ameet Sarpatwari, JD, PhD. It offers both a roadmap to how we arrived here and

some solutions.4 In the short term, the authors say, solutions include rethinking our reward system for exclusivity rights for new drugs, giving government payers meaningful negotiating power, and doing more to get generics to market. Providers and health systems are increasingly incen-tivized to ensure high-value healthcare, pharmaceutical companies are challenged with the high cost of bringing new drugs to market, and payers (which includes the federal government and therefore all of us) need to control healthcare spending. Unfortunately, at the present, patients are caught in between.

In diabetes care, we have many pa-tients who are not at goal; there is clear-ly great unmet need. Therefore, we do need new treatment options. Our most recent ADA meeting also brought news about combinations of insulin and glu-cagon-like peptide-1 receptor agonists, which are discussed in this issue of Ev-idence-Based Diabetes Management™. The FDA will likely act on these applications before the end of this year. The question is, will patients have access? There was a time when this idea would have seemed absurd, but those days are over.

COMMENTARY

7

It seems easy to blame payers. But when we see pharmaceutical companies set high prices—or raise prices on older drugs in ways that seem illogical—it’s not so straight-forward. Today, new benefit designs reveal to consumers what drugs actually cost (which is a reason the EpiPen uproar happened and why many believe insulin is next.) More and more Americans now have high-deductible plans—up to 40% of those under age 65, ac-cording to a new report from the CDC.5

The downside, however, is that rising healthcare costs that were once spread among everyone, through higher premi-ums, are being borne directly by those with life-threatening, chronic conditions

who need life-sustaining medications. Some with diabetes, who, for years, were unable to gain coverage, finally did so un-der the Affordable Care Act. But now, once again, they find themselves struggling each month to scrape together ever-increasing out-of-pocket costs for insulin—a drug discovered nearly a century ago.

Dr Gabbay is chief medical officer at Jos-lin Diabetes Center and editor in chief of Evidence-Based Diabetes Management.

References1. Hirsch IB. Ranting in 2016—a medical system in crisis. Diab Technol Thera. 2016;18(2):111-112. doi: 10.1089/dia.2015.0435.

2. Rege A. EpiPen isn’t the only drug with a price hike: insulin prices skyrocket. Becker’s Hospital Review website. http://www.beckershospitalreview .com/supply-chain/epipen-isn-t-the-only-drug-with-a-price-hike-insulin-prices-skyrocket.html. Published August 24, 2016. Accessed September 5, 2016.

3. Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P. Expenditures and prices of antihy-perglycemic medications in the United States, 2002-2013. JAMA. 2016;315(13):1400-1402. doi:10.1001/jama.2016.0126.

4. Kesselheim AS, Avom J, Sarpatwari A. The high cost of prescription drugs in the United States. JAMA. 2016;316(8):858-871. doi:10.1001/jama.2016.11237.

5. Cohen RA. Martinez ME, Zammitti MP. Health in-surance coverage: early release of estimates from the National Health Interview Survey, January–March 2016. National Center for Health Statistics website. https://www.cdc.gov/nchs/data/nhis/earlyrelease/insur201609.pdf. Published and Accessed September 7, 2016.  ●

Studies Support Robust Real-World Efficacy, Adherence, Persistence, Quality Measure Attainment With CanagliflozinMichael R. Page, PharmD, RPh

A t the 2016 American Diabetes Associ-ation Scientific Sessions, held in New

Orleans, researchers presented data from 6 posters supporting the safety and efficacy of Invokana (canagliflozin) in the treatment of type 2 diabetes (T2D). The posters were among 18 presentations related to canagli-flozin that took place during the meeting.

These studies assessed the effica-cy of canagliflozin, a sodium glucose co-transporter-2 inhibitor, and the di-peptidyl peptidase-4 (DPP-4) inhibitor sitagliptin—both in combination and individually—and reported favorable re-sults on adherence and persistence out-come measures, rates of target metabolic parameter attainment, and delayed insu-lin initiation. Importantly, these results included not only clinical trial data, but also real-world efficacy assessments.

Comparing Canagliflozin to Sitagliptin in Different Settings In this study, researchers presented the glycated hemoglobin (A1C)- lowering efficacy of canagliflozin 100 mg and 300 mg versus sitagliptin 100 mg across 2 ran-

domized controlled trials in patients with T2D, and confirmed these results in a re-al-world setting through a retrospective analysis of claims data.1

In the original pivotal clinical trials for canagliflozin, patients with a baseline A1C of approximately 8% receiving cana-gliflozin 100 mg experienced reductions comparable to those of sitagliptin 100 mg. However, the A1C-lowering efficacy with canagliflozin 300 mg was greater than that observed with sitagliptin 100 mg.

In the real-world, retrospective, case-control cohort study, using propen-sity score matching, investigators com-pared patients receiving canagliflozin with similar patients receiving DDP-4 inhibitors. Approximately two-thirds of patients (65%) received canagliflozin 100 mg, with the remaining patients receiving canagliflozin 300 mg.

Patients experienced significantly greater reductions in A1C, with canagli-flozin therapy resulting in an A1C reduc-tion of 1.07 percentage points versus 0.79 percentage points with a DPP-4 inhibitor (P = .004). Although these results were

obtained in patients with higher baseline A1C (approximately 9% versus 8% in the pivotal trials), these results confirm the superiority of canagliflozin versus DPP-4 inhibitors in the real-world setting.

A1C Outcomes, Canagliflozin vs Sitagliptin in a US Health Plan2 Additional real-world evidence gleaned using data from a large insurance claims database also confirmed the superiority of canagliflozin over sitagliptin. In this study, researchers evaluated changes in A1C among patients 18 years or older who had enrolled in the health plan prior to the index date of April 1, 2013, and con-tinued enrollment in their health plan through 9 months of follow-up.

Using propensity score matching, re-searchers paired 1472 patients receiving canagliflozin with an equal number of patients receiving sitagliptin. This statis-tical method enabled researchers to com-pensate for differences in the population of patients using sitagliptin, who tended to be older, female, and more likely to have comorbidities than patients receiv-

2016 ADA SCIENTIFIC SESSIONS

8www.ajmc.com/compendium/diabetes

ing canagliflozin. After matching patients by clinical characteristics, the populations assessed had comparable characteristics.

Over the study period, patients receiv-ing canagliflozin experienced significantly (P = .004) greater reductions in A1C (0.93 percentage points) versus patients receiv-ing sitagliptin (0.57 percentage points). These results were more pronounced in patients with a baseline A1C of 7% or great-er, with the A1C reduction with canagli-flozin averaging 1.08 percentage points ver-sus 0.71 percentage points with sitagliptin (P = .01). Through this real-world study, re-searchers further reinforced the real-world superiority of canagliflozin over sitagliptin therapy in terms of A1C reduction.

Does Canagliflozin Help Post-pone the Start of Insulin?3 As demonstrated in a study conducted in simulated patients in the United Kingdom, the superior A1C-reduction efficacy with canagliflozin may postpone the need for insulin therapy versus patients receiving sitagliptin in addition to 1 or 2 other medi-cations. Researchers used economic mod-eling techniques to estimate the time to insulin initiation over 40 years of follow-up.

In this simulation, and consistent with the package insert for canagliflozin, re-searchers modeled the effect of initiating therapy at the 100-mg daily dose and esca-lating to the 300-mg daily dose in patients requiring additional glycemic control. An A1C exceeding 7.5%, or a decline in kidney function parameters to values inconsis-tent with use of canagliflozin, defined the threshold for initiation of insulin therapy.

Compared with sitagliptin, use of cana-gliflozin delayed insulin therapy by 0.9 years in patients receiving 1 other medica-tion (5.7 years vs 4.8 years) and by 1.2 years in patients receiving 2 other antidiabetic agents (5.1 years vs 3.9 years). Researchers noted that delays in insulin therapy initi-ation may also modestly reduce the risk of patients experiencing severe hypoglycemic events. These results underline the clin-ical relevance of the superior efficacy of canagliflozin over sitagliptin in simulated long-term outcomes for patients with T2D.

Likelihood of Achieving Goal With Add-on Therapy4 In addition to offering improved A1C reduction efficacy versus DPP-4 inhib-itors, which may delay the need for in-sulin therapy, canagliflozin has blood pressure-lowering effects that may help patients with T2D reach goal levels con-sistent with quality-of-care measures that are used to grade physician performance. Researchers performed a 26-week ran-domized, double-blind study in 213 pa-tients transitioning from dual therapy to triple oral therapy.

In patients who did not achieve ade-quate control with metformin/sitagliptin, researchers randomized patients to re-ceive canagliflozin or placebo. Treatment with canagliflozin started at the 100-mg daily dose and was escalated to 300 mg

daily after 6 weeks provided patients had kidney function parameters consistent with use of the higher dose, fasting blood glucose levels of 100 mg/dL or greater, and no signs of adverse events related to vol-ume depletion in the 2 weeks after initi-ating the increased dose of canagliflozin. The majority of patients (85.4%) success-fully transitioned to the 300-mg dose over an average titration period of 6.2 weeks.

In terms of quality measure attain-ment, patients receiving canagliflozin were more likely to reach an A1c <7.0%, with nearly one-third (32.3%) attaining this threshold versus 12.2% of patients receiving placebo (P = .001). Similarly, patients receiving canagliflozin attained an A1c <8.0% in more than two-thirds (70.8%) of patients versus just over one-third (39.0%) of patients receiving placebo (P <.001). Attainment of a blood pressure target <140/90 mm Hg was also signifi-

cantly more likely with canagliflozin than placebo (86.5% vs 78.3%; P = .017), and a more stringent goal level of <130/80 mm Hg was also more often achieved with canagliflozin (54.2% vs 32.5%; P = .001). These results indicate improved attain-ment of quality measures with canagli-flozin as part of a 3-drug combination.

Medication Adherence and Real-World Control5 In addition to efficacy results and quali-ty measure results with canagliflozin, re-al-world adherence data are important to validate the acceptability of long-term use in patients with T2D.

In a study of treatment adherence, researchers evaluated medical claims of patients who initiated canagliflozin in April of 2013. Patients were required to have continuous insurance enrollment in the 12 months before and after initiat-ing therapy. Exclusion criteria included a diagnosis of type 1 diabetes, pregnancy, gestational diabetes, or steroid-induced diabetes. Adherence measures evaluated included proportion of days covered (PDC) and medication possession ratio (MPR).

Over 12 months of follow-up, 881 pa-tients with a mean age of 55 years expe-rienced an average A1C decline of 0.8 percentage points while using a mean of 2.3 (median 2.0) other antidiabetic thera-pies. For patients receiving canagliflozin, PDC averaged 71% and MPR averaged 76%. Corresponding median PDC and MPR values were higher, at 83% and 88%, respectively. In patients receiving canagli-flozin, good medication adherence (as de-fined by MPR and PDC measures ≥80%) was achieved in the majority of patients.

Do Patients Stay on Therapy?6 In addition to adherence, persistence with antidiabetic therapy is an important predictor of outcomes. In an analysis of persistence, researchers assessed patients receiving antidiabetic therapies from Feb-ruary 2014 to October 2014. Persistence was assessed in patients receiving canaglifloz-in, dapagliflozin, DPP-4 inhibitors and the glucagon-like peptide-1 (GLP-1) receptor

These studies assessed both the efficacy of canagliflozin, a sodium glucose co-transporter-2 inhibitor and the dipeptidyl peptidase-4 inhibitor sitagliptin both in combination and individually.

9

agonists. Of 38,083 patients receiving any of these therapies and meeting inclusion criteria, two-thirds (67%) of patients receiv-ing canagliflozin remained persistent at 9 months compared with 46% of patients receiving dapagliflozin, 47% to 53% of pa-tients receiving DPP-4 inhibitors, and 26% to 50% of patients receiving GLP-1 agonists. These results indicate that canagliflozin is more likely to be used consistently than other antidiabetic therapies.

ConclusionsRegarding these studies, Paul Burton, MD, PhD, vice president of medical affairs at Janssen stated, “These real-world findings provide valuable information for physi-cians in identifying therapeutic options

with the best potential for success, which is especially important since up to half of pa-tients with T2D are not at treatment goals.” Burton continued, “These findings show that the use of Invokana in people with T2D lead to reduced A1C levels and, for many, achievement of treatment goals.”7

References1. Canovatchel W, Thayer S, Chow W, Qiu R, Davies MJ. Efficacy of canagliflozin (CANA) vs. dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with type 2 diabetes mellitus (T2DM): results from random-ized, controlled trials (RCTs) and a real-world (RW) study. Diabetes. 2016;65(suppl 1):1194-P.

2. Thayer SW, Aguilar R, Chow W. HbA1C out-comes in patients treated with canagliflozin vs sitagliptin in a US health plan. Diabetes. 2016; 65(suppl 1):1224-P.

3. Schroeder M, Chan E, Willis M, et al. Time until insulin initiation for canagliflozin (CANA) vs

sitagliptin (SITA) in dual therapy and triple therapy for type 2 diabetes mellitus (T2DM) in the UK. Diabetes. 2016;65(suppl 1):1248-P.

4. Seufert J. Target achievement and quality measure (QM) attainment with titrated canagliflozin (CANA) in patients with type 2 diabetes mellitus (T2DM) as add-on to metformin (MET) + sitagliptin (SITA). Diabetes. 2016;65(suppl 1):1174-P.

5. Jain R. Real-world (RW) glycemic control and medication adherence among patients with type 2 diabetes mellitus (T2DM) initiated on canagliflozin. Diabetes. 2016; 65(suppl 1):1161-P.

6. Cai J. Comparative persistence with antihy-perglycemic agents used to treat type 2 diabetes mellitus in the real world. Diabetes. 2016; 65(suppl 1):1155-P.

7. Janssen presents new data showing INVOKANA (canagliflozin) is associated with greater blood glucose control and treatment adherence compared to DPP-4 inhibitors [press release]. Raritan, NJ: Janssen Pharmaceuticals; June 11, 2016. https://janssen.com/us/sites/www_janssen_com_usa/files/ada_data_press_release_final_embargoed_ 6-11-16_11am_est.pdf. Accessed June 11, 2016.  ●

Intensive Diabetes Management Adds Years to Life, Study FindsMary Caffrey

A ggressive treatment of type 2 diabe-tes (T2D) before complications set

in can keep them at bay and add years to a person’s life, according to the results of a study published in the journal Diabetologia.

The study followed 160 Danish people with T2D and microalbuminuria for 21 years. The participants were an average age of 55 when the study began. At the start of the study, they were randomly di-vided into 2 groups for either convention-al treatment or an intensive, multi-part treatment that included behavioral and pharmacological approaches. Treatment lasted for an average of 7.8 years.

After that, the participants were observed in a follow-up period. By the

end of the study, 38 patients in the in-tensive treatment group and 55 in the conventional treatment group had died; researchers found that those in the in-tensive therapy group lived 7.9 years lon-ger. They also had less heart and kidney disease, as well as less blindness. In fact, the mean time to the first cardiovascu-lar event after randomization was 8.1 years for those receiving the intensive therapy. Both groups had the same risk of neuropathy, however. In addition, the patients in the conventional treatment group experienced twice as many cardio-vascular events per person overall.

The authors note that recent chang-es to clinical guidelines recognize the

benefits of early aggressive treatment of T2D before the additional loss of beta cell function. Aggressive use of therapy early on has benefits even after treatment ends, they note, as “effects in these trials has been termed ‘metabolic memory’ or ‘legacy effect.’ In these trials, intensified intervention according to protocol was stopped at the end of the trial and the subsequent risk factor was relaxed or not reported.”

Reference1. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and micro-albuminuria: 21 years follow-up on the Steno-2 randomized trial. Diabetologia. 2016;59(11):2298-2307. doi:10.1007/s00125-016-4065-6.  ●

Military’s Problem With Obesity Getting Worse, Report FindsMary Caffrey

A recent report shows the nation’s obesity crisis now extends to the

men and women who defend it, with 7.8% of our total military force now classified as obese. The figure is based

on data released by the Department of Defense, which appeared September 11, 2016, in the Military Times.

The portion of the force deemed obese is the percentage with a body mass index

(BMI) at or above 30 kg/m2. As a group, military members are still far less obese than America’s overall adult population, however: more than one-third (36.5%) of the general public is obese, according to

10www.ajmc.com/compendium/diabetes

the CDC. However, the rate of the military force that is obese has climbed steadily since 2001, when it was just 1.6%.

Data show the obesity rate varies by job type. There is less obesity among combat troops (6.7%) than among healthcare work-ers (9.8%). Obesity is also more prevalent among women (10.3%), minority members, and older service members.

But the report also found that the gen-der gap is shrinking. Quoting a report from a nonprofit group of 600 retired military officers, the report found obesity and poor fitness are top reasons that most American teenagers are not eligible for military service.

Sources in the Military Times report offered a number of explanations for the obesity trend, from American youth being less active to the nature of military life itself

since September 11, 2001. Wars in Iraq and Afghanistan have made operations less fo-cused on fitness drills and more on walking over rough terrain, which some experts said build muscle but don’t help service mem-bers stay lean. The quality of food offered in the chow halls was blamed, too.

Others noted that the fact that service members remain far less obese than the general population is a good sign. In 2001, when the US Surgeon General issued a “Call to Action” to combat obesity, only 21 states had rates at 20% or higher and no state was above 30%. Today, the most recent CDC data show no state has a rate below 20%. In addition, many of the Deep South states, where the military tradition is the strongest, have some of highest adult obesity rates.

Inside and outside the military, use of BMI to evaluate fitness has been heav-ily criticized. At best, critics say, it is a screening tool that demands follow-up to further evaluate a person’s overall health and fitness. People of Asian descent, in particular, have been shown to have un-healthy levels of body fat at much lower BMI levels and some world-class athletes can be very healthy at a high BMI.

According to the report, current poli-cy requires service members to maintain body fat levels below 28% for men and 36% for women. Failure to do so can im-pact future promotions and result in early separation from the service. The military plans a new system for evaluating health and fitness in service members that will be published later this year.  ●

Sleep Disorders Linked to Heart Disease Risk in AHA StatementMary Caffrey

R ecent evidence has linked irregular sleep with obesity and diabetes, and

studies find that sleeping too much can be just as bad for cardiovascular (CV) health as sleeping too little.

On September 19, 2016, the American Heart Association (AHA) issued its first statement on the topic of sleep disorders, which have joined poor diet and lack of ex-ercise as lifestyle red flags that indicate the likelihood of chronic disease. The state-ment appeared in Circulation, the official journal of the AHA.

The authors, led by Marie-Pierre St.-Onge, PhD, recognize that until recently, lack of sleep was not recognized as a con-tributor to chronic disease. “An increasing number of Americans choose to curtail sleep in favor of other social, leisure, or work-related activities. This has resulted in a decline in average sleep duration over time,” they wrote.

About 50 to 70 million US adults do not get enough sleep or suffer from a sleep disorder, according to the Nation-al Heart, Lung, and Blood Institute, part of the National Institutes of Health. The

share of Americans who report sleeping fewer than 7 hours a night is increasing; up from 21.6% in 1977 to 29.1% in 2009.

Increases in night shifts and Americans working more than 1 job to make ends meet have contributed to this phenomenon, and a paper by authors at the Harvard School of Public Health found a decade of shift work was associated with a 40% increase in the likelihood of developing diabetes. A separate study among women found that any shift work was associated with a 9% increase in developing the disease. Anoth-er study published earlier this year found that men, in particular, responded poorly to less than optimal hours of sleep.

“We know that short sleep, usually de-fined as under 7 hours per night; overly long sleep, usually defined as more than 9 hours per night; and sleep disorders may increase some cardiovascular risk factors, but we don’t know if improving sleep quality re-duces those risk factors,” said St.-Onge, an associate professor of nutritional medicine at Columbia University in New York City.

Because more work is needed in this area, the AHA statement does not recom-

mend a precise amount of sleep for CV wellness. But the statement does detail what is known about the connections be-tween irregular sleep and risk factors that include obesity, type 2 diabetes, heart dis-ease, high blood pressure, arrhythmias, atherosclerosis, and unhealthy levels of triglycerides and cholesterol.

“Since the scientific evidence doesn’t show a specific dose/response relationship between sleep duration and cardiovascular wellness, the American Heart Association cannot offer specific advice on how much sleep is needed to protect people from car-diovascular disease,” St.-Onge said.

Most research thus far has involved the connections between sleep and its effects on diabetes and obesity. “Those are the 2 main conditions in which there are interventions studies that show that risk factors are in-creased when sleep is altered,” she said.

Although studies show that sleep pat-terns affect food intake, more work is needed on measuring the impact on actual weight. Studies of longer duration might also show whether varying sleep affects cholesterol, triglycerides, and inflammatory markers.

11

Better evidence is needed to make stronger links between poor sleep and diabetes, rising blood pressure, and CV disease, she said.

Most research in this area has been ob-servational; links have been established, but a cause-and-effect relationship has not been shown. Healthcare providers are still encour-aged to ask patients about sleep problems, such as snoring. And the need for good sleep must be emphasized by physicians—going

without sleep should not be glamorized as a sign of toughness or a better work ethic.

“Patients need to be aware that ad-equate sleep is important, just as being physically active and eating a balanced diet rich in fruits, vegetables, whole grains, lean meat, and fish are important for car-diovascular health,” St-Onge said. “Sleep is another type of ammunition that we can tailor to improve health.”

Reference1. St-Onge MP, Grandner MA, Brown D, et al; American Heart Association Obesity, Behavior Change, Diabetes, and Nutrition Committees of the Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Stroke Council. Sleep duration and quality: impact on lifestyle behaviors and cardiometabolic health: a scientific statement from the American Heart Association [published online September 19 2016]. Circulation. 2016; pii:CIR.0000000000000444. ●

Minorities, Southerners in Medicare Less Likely to Take High Blood Pressure MedicationMary Caffrey

O ne of the more frustrating challeng-es in healthcare is nonadherence—

patients who see the doctor but don’t take their medication as prescribed. For a vari-ety of reasons, nonadherence rates are high among patients being treated for hyperten-sion. But rates are not uniform, according to a recent CDC report.

Nonadherence among those being treated for hypertension is troubling, since cardiovascular disease is the leading cause of death in the United States; hypertension affects 70% of those age 65 and older, accord-ing to the report, released September 13, 2016. The data, based on claims from Medicare Part D, found that 26.3% of patients pre-scribed medication were nonadherent in 2014, which means these patients were not taking their drugs at least 80% of the time.

The study found wide disparities among groups: whites had nonadherence rates of 24.3%; Asians and Pacific Islanders, 26.3%; Hispanics, 33.8%; African Americans, 35.7%; and Native Americans, 38.8%. Being poor in-creased nonadherence, with the rate at 32.1% among those with a low-income subsidy and 25.4% among those with no subsidy.

Geography also played a role. Coun-ties with the highest nonadherence rates were clustered in the southeastern United States, but there were also clusters in New Mexico, Arizona, northern Alaska, and the District of Columbia, which had a rate

of 33.7%. The lowest rates of nonadher-ence were seen in North Dakota (18.7%), followed by Wisconsin (18.8) and Minne-sota (18.9%). This geographic divide was noted by the study’s authors, who made several recommendations:

• For adults with multiple chronic conditions, decrease pill counts by increasing the use of fixed-dose com-bination therapies. The study found these therapies were underused by most groups in the study.

• Limit the number of pharmacy visits by increasing the days of supply in each fill from 30 to 90 days

• Synchronize fills for all medica-tions. This strategy was the subject of a study in The American Journal of Managed Care;

• Use reminder devices and aids to encourage patients to stay on their medication schedule.

The authors recognized that the amount of co-payments could be a fac-tor, and CMS has taken steps to start phasing out the “donut hole,” which has been shown to cause some beneficiaries to stop taking medications as prescribed once they hit the coverage gap limit.

The study had several limitations: it may have overestimated those patients who switched therapies based on a doc-tor’s recommendations, but it could have underestimated those who are prescribed therapy but do not initiate treatment. There are also some patients who buy low-cost generics outside the prescription drug plan and would not show up in the data.

Still, this was the first study to examine geographic variation in antihypertension nonadherence down to the county level, the authors noted.

“Strategies to improve adherence range from individual patient engage-ment and intervention to systematic health systems changes, and coordinated approaches are important to improving adherence and the cardiovascular health of this population,” the authors wrote.

ReferenceRitchey M, Chang A, Powers C, et al. Vital signs: disparities in antihypertensive medication nonadherence among Medicare Part D beneficia-ries—United States, 2014. MMWR Morb Mortal Wkly Rep. 2016;65(36):967-976. doi:10.15585/mmwr.mm6536e1. ●

Nonadherence among those being treated for hypertension is troubling, since cardiovascular disease is the leading cause of death in the United States; hypertension affects 70% of those aged 65 and older.