Senate Hearing, ADA, Address Insulin Prices for Diabetes Patients

Posted by zedie

The American Diabetes Association (ADA) has published a new white paper addressing the high price of insulin that includes recommendations for health care providers to help minimize patients’ out-of-pocket costs.

Entitled Insulin Access and Affordability Working Group: Conclusions and Recommendations, the paper was published online May 8 in Diabetes Care by the working group, which was chaired by William T. Cefalu, MD, ADA Chief Scientific, Medical, and Mission Officer.

The release of the paper was timed to coincide with a hearing by the US Senate Special Committee on Aging, entitled Insulin Access and Affordability: The Rising Costs of Treatment.

In the paper, Cefalu and colleagues write, “The average list price of insulin has skyrocketed in recent years, nearly tripling between 2002 and 2013. The reasons for this increase are not entirely clear but are due in part to the complexity of drug pricing in general and of insulin pricing in particular.”

About 7.4 million Americans with diabetes take insulin, including all patients with type 1 diabetes and roughly a quarter of those with type 2 diabetes.

The ADA advises that physicians discuss the advantages, disadvantages, and financial implications of the various types of insulin preparations with patients, and prescribe “the lowest-price insulin required to effectively and safely achieve treatment goals,” which may include using human insulin (ie, NPH and Regular rather than analogs) “in appropriately selected patients.”

In addition, ADA advises that healthcare providers be mindful of how the rising price of insulin may adversely affect treatment adherence and “be trained to appropriately prescribe all forms of insulin preparations based on evidence-based medicine.”

Drawing on input from numerous stakeholders, the document also calls for transparency throughout the insulin supply chain and makes additional recommendations aimed at insulin manufacturers, pharmacies, health plans, pharmacy benefit managers (PBMs), advocacy organizations, and patients.

And the ADA says it will soon release a follow-up paper with more specific public policy recommendations on lowering out-of-pocket costs for people with diabetes.

Senate Panel Examines Insulin Pricing, Patients Suffering

Among those testifying before the Senate panel were Cefalu, Jeremy A. Greene, MD, PhD, Professor of Medicine and the History of Medicine at Johns Hopkins University, Baltimore, Maryland, and Paul Grant, whose child has type 1 diabetes.

In her opening remarks, Senate committee chair Susan Collins (R-Maine), who is also the founder (in 1997) and co-chair of the Senate Diabetes Caucus, noted, “The cost of insulin has soared in recent years. In 2013, more was spent on insulin than on all other diabetes medications combined.”

The price for a vial of Humalog increased from $21 in 1996 to $275 in 2017, while out-of-pocket costs rose by 10% for Medicare Part D beneficiaries between 2006 and 2013, Collins said, adding, “While the prescription drug market, and the insulin market specifically, is opaque to virtually everyone involved, one fact is clear: patients are not getting the best deal.”

Indeed, she said, members of Congress have heard stories of people skipping or rationing their insulin doses, seeking insulin from other countries — Canada in particular among Maine residents — or resorting to the black market or crowdfunding from the Internet.

“These measures can result in major risks that can compromise health and even life,” she said.

During his testimony, Cefalu said, “As the leading organization whose mission is to prevent and cure diabetes and to improve the lives of all people affected by diabetes, the ADA believes that no individual in need of insulin should ever go without it due to prohibitive costs.”

Greene, a practicing internist in an inner-city community health center and historian who has written on the topic of insulin pricing, told the Senate panel, “No single issue exposes the tragedy and absurdity of our inability to provide 20th-century cures to patients in the 21st century as does the increasing unaffordability of insulin for Americans living with diabetes today.”

No Generic Insulins, Not Enough Manufacturers to Drive Down Prices

Greene pointed out that there are no generic insulins in the United States, and that all of the currently available preparations, including the recently available “follow-on” insulins (called biosimilars in other countries), come from just three manufacturers, Eli Lilly, Novo Nordisk, and Sanofi, who control 99% of the nearly $27 billion global insulin market by volume.

At the same time, “We know from pharmacoeconomic analysis that you don’t really see true competition driving down drug prices in a significant way until you have four or more manufacturers in the market,” Greene told the Senate panel.

He noted that the two follow-on insulins approved by the US Food and Drug Administration (FDA) are Eli Lilly’s Basaglar, a copycat version of Sanofi’s long-acting insulin glargine, and Admelog, Sanofi Aventis’s copy of Lilly’s short-acting Humalog.

Both of the follow-ons are priced only slightly below the brand names, by about $50 a vial. “It doesn’t bring it down to a reasonable rate,” said Greene.

“Multiple Opaque Transactions Between and Among…Stakeholders”

The ADA document details the complex interactions among the insulin manufacturers, wholesalers, PBMs, pharmacies, health plans, and employers involved in the insulin supply chain, as well as the distribution and payment systems amongst those stakeholders.

“With this system, there is no one agreed-upon price for any insulin formulation. The price ultimately paid by the person with diabetes at the point of sale results from the prices, rebates, and fees negotiated,” Cefalu and colleagues write.

And, they say, the lack of transparency about the process means that “it is unclear how the dollars flow and how much each intermediary profits.”

The paper levels much of the blame at PBMs, the third-party administrators of prescription drug programs for both private and public health plans.

Interactions, including discounts and rebates negotiated between PBMs and both manufacturers and pharmacies are kept confidential, as are formulary decisions, the ADA says, noting “PBMs have substantial market power.”

What Should Be Done to Solve the Pricing Problem, and By Who?

The ADA recommends that list prices for insulins should more closely reflect the net price, and that overall the system relies less on rebates, discounts, and fees based on list price. Rebates, they say, should be used by PBMs and payers to lower costs of insulin at the point of sale for people with diabetes.

Moreover, formularies should include a full range of insulin preparations, including human and analog insulins, in the lowest cost-sharing tier.

At the same time, they say, innovation in developing new insulins should be encouraged and the FDA should streamline the process of bringing more lower-cost insulin products to the US market.

But endocrinologist Kasia Lipska, MD, Yale University, New Haven, Connecticut, whose research on insulin pricing was cited in the ADA white paper, told Medscape Medical News that manufacturers also need to step up.

“The ADA white paper focuses on the lack of transparency in the entire insulin supply chain — this is a valid point — but I think this lets industry off the hook. There should be a stronger call for manufacturers to lower prices to make insulin affordable.”

Greene, in his testimony, echoed the call for transparency but said that Congress is the only entity that can ensure it happens.

“Preserving access to affordable insulin is not a Democratic or Republican issue….Only Congress has the power to follow all the steps from production to consumption and understand where exactly this market is being distorted.”

Senator Collins vowed to do just that. “I want to deconstruct that complicated web of transactions to figure out who is making how much money and why aren’t discounts that are negotiated with manufacturers reaching the patient….It’s astonishing that for a drug approaching a hundred years old and that is serving millions of Americans that we don’t see a proliferation of manufacturers.”

And to Grant, a contract company employee with a high-deductible health plan who testified that the 90-day cost of his 13-year-old son’s insulin jumped from $450 in 2017 to more than $900 in 2018, Collins said, “We want to keep him healthy, but we also don’t want you to go broke in doing so. I’m committed to trying to get to the bottom of this.”

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Alogliptin does not increase risk of cardiovascular death in diabetes patients

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Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, did not increase the risk of cardiovascular (CV)-related death or nonfatal CV events in type 2 diabetes (T2D) patients with recent acute coronary syndrome (ACS) compared with placebo, according to a post-hoc analysis of the EXAMINE* trial presented at the American Diabetes Association’s (ADA) 76^th Scientific Sessions held recently in New Orleans, Louisiana, US.

“Heart failure is a powerful predictor of mortality in patients with both T2D and coronary heart disease,” said principal investigator Professor William White from the Calhoun Cardiology Center at the University of Connecticut School of Medicine in Farmington, Connecticut, US.

“These findings emphasize how critical it is to aggressively make use of evidence-based, secondary preventive therapies… in the clinical management of patients with T2D who are at high risk for cardiovascular disease.”

Researchers found that CV-related death rates were similar between T2D patients treated with alogliptin or a placebo (4.1 versus 4.1 percent, hazard ratio [HR], 0.85, 95 percent confidence interval [CI], 0.66-1.10). [Diabetes Care 2016;doi:org/10.2337/dc16-0303]

There was also no significant difference in sudden cardiac deaths between the alogliptin and placebo arms (2.2 versus 2.7 percent, HR, 0.80, 95 percent CI, 0.57-1.12).

Among all patients, 13.7 percent had at least one nonfatal CV event, with heart attack being the most common CV event (5.9 percent), followed by unstable angina (UA, 3.8 percent), hospitalization for heart failure (HHF, 3.0 percent), and stroke (1.1 percent).

In T2D patients with a nonfatal CV event, those who experienced HHF had the highest increased risk of CV-related death (HR, 4.96; p<0.0001), followed by myocardiac infarction (MI, HR, 3.12; p<0.0001), stroke (HR, 3.08; p=0.011), and UA (HR, 1.66, p=0.164) compared with patients without a nonfatal CV event.

The EXAMINE trial randomized 5,380 T2D patients to alogliptin or placebo within 15-90 days following an ACS, which included any condition with blockage to the heart’s blood supply. Patients were monitored for deaths and nonfatal CV events such as MI, stroke, HHF, and UA during a median follow-up of 18 months.

Alogliptin, like other DPP-4 inhibitors, is designed to delay the inactivation of incretin, a class of hormones that stimulate insulin release from the pancreas and help lower blood glucose levels.

Heart disease is the leading cause of death in T2D patients and accounts for 50 to 80 percent of deaths in diabetic people, according to White.

“So it’s critical we have a clear understanding of the impact these medications have on patients with T2D who are at a high risk for CV diseases such as those involved in EXAMINE,” he said.

Intensive Glycemic Control May Harm Some Diabetes Patients

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One in five elderly and “clinically complex” patients with type 2 diabetes may be receiving unnecessarily intensive glucose-lowering treatment, leading to a dramatically increased risk for severe hypoglycemia, a new study finds.

The findings were published online June 6 in JAMA Internal Medicine by Rozalina G McCoy, MD, assistant professor of medicine at the Mayo Clinic, Rochester, MN, and colleagues.

“It is time that we, as physicians and patients, recognize that high-quality diabetes care should emphasize not only avoiding hyperglycemia but also preventing hypoglycemia,” Dr McCoy told Medscape Medical News.

She added, “We should recognize the harms of intensive treatment and hypoglycemia, particularly when there is little likely benefit of keeping HbA1c low in the setting of limited life expectancy or multiple comorbidities.”

The retrospective database analysis included over 30,000 adults with type 2 diabetes who had HbA1c levels less than 7% without using insulin and had no episodes of severe hypoglycemia or hyperglycemia in the prior 12 months.

Nearly 4000 of the subjects were aged 75 years or older and/or had serious comorbidities. During the 2-year study period, 19% of that “high clinical complexity” group received intensive glucose-lowering therapy. And among those patients, the risk for severe hypoglycemia necessitating medical care was 3%, compared with just 1.7% for the high-complexity patients not receiving intensive treatment.

“Severe hypoglycemia is not rare, even among patients who are not treated with insulin and who have no prior history of severe hypoglycemia,” Dr McCoy commented.

More Research Needed on How to Deescalate Treatment

The findings highlight the lack of clinical guidance on when to stop or “deescalate” treatment in people with chronic conditions, and in fact clinicians are often incentivized not to, say Eve A Kerr, MD, of the Veterans Affairs Center for Clinical Management Research, University of Michigan Medical School, and Timothy P Hofer, MD, professor in the division of general medicine, University of Michigan, Ann Arbor, in an accompanying editorial.
“Balancing the medical profession’s focus on aggressively treating patients who are likely to benefit with an explicit consideration of when to deintensify treatments when they are no longer useful or are potentially harmful, and doing so in a manner that is respectful to the patient-physician relationship and promotes shared decision making, is the next frontier for improving care quality,” Drs Kerr and Hofer write.

Dr McCoy agrees. “The culture of healthcare has been that ‘more is better,’ and doing less is automatically an indicator of low-quality care. We need studies looking at how and when treatment should be deescalated…without causing patient harm.”

Also in the same issue of JAMA Internal Medicine is a short research letter describing a small study by Medha N Munshi, MD, of Joslin Diabetes Center, Boston, Massachusetts and colleagues, in which the insulin regimen in older adults with type 2 diabetes was simplified. This was achieved by switching multiple daily premeal dosing of insulin to once-daily insulin glargine, resulting in decreased hypoglycemia and disease-related distress without compromising glycemic control.

Dr McCoy commented, “It was reassuring to see that their HbA_1c did not rise, which I think is a common fear of physicians and patients when faced with the prospect of deintensifying glucose-lowering therapy.”

Clinical Complexity and Hypoglycemia

In Dr McCoy et al’s study, the researchers obtained 2001–2011 figures for adults with diabetes who had HbA_1c levels below 7% over 2 years from an administrative claims database of more than 100 million individuals enrolled in private and Medicare Advantage plans across the United States.

After exclusion of patients with severe hypoglycemia in the prior 12 months, those prescribed insulin in the prior 120 days, and those with type 1 or gestational diabetes or missing data, a total of 31,542 patients were included.

High clinical complexity, defined as a composite of age 75 years or older or high comorbidity burden defined by the presence of end-stage renal disease, dementia, or three or more serious chronic conditions, was identified in 12.4% of the total (3910 patients).

“Intensive” treatment was defined by the addition of any medication in those with baseline HbA_1c levels of 5.6% or below, the use of two or more drugs at baseline or the addition of one more over the study period in those with initial HbA_1c 5.7% to 6.4%, or the addition of two or more drugs or insulin in those with baseline HbA_1c 6.5% to 6.9%.

Regimens that did not meet intensive-treatment criteria were considered standard treatment.

In all, 8048 patients (25.5%) were treated intensively, including 7317 (26.5%) with low clinical complexity and 731 (18.7%) with high clinical complexity.

Of note, 76% of the intensively treated patients did not have their treatment deescalated after the low HbA_1c test result was obtained. Approximately three-quarters of both the low and high clinical complexity groups continued with their baseline intensive regimen.

The risk-adjusted probability of intensive treatment was 25.7% for patients with low clinical complexity and 20.8% for those with high clinical complexity (P < .001 for the absolute difference).

Patients with high clinical complexity were significantly less likely to be treated intensively than patients with low clinical complexity (odds ratio [OR], 0.76).

The overall unadjusted 2-year incidence of severe hypoglycemia — defined as episodes necessitating an outpatient, inpatient, or emergency visit — was 1.4%.

Severe hypoglycemia was significantly more frequent among patients with high vs low complexity (2.9% vs 1.2%, P < .001).

Among patients with low clinical complexity, the risk-adjusted probability of severe hypoglycemia did not increase with intensive treatment (1.02% with standard treatment vs 1.30% with intensive treatment).

In contrast, among patients with high clinical complexity, the risk-adjusted probability of severe hypoglycemia increased significantly from 1.74% with standard treatment to 3.04% with intensive treatment.

Sulfonylurea and glinide therapy significantly raised the risk of severe hypoglycemia (OR, 2.19). However, the overall results remained consistent in a sensitivity analysis even after researchers excluded patients using these agents, although the numbers were small.

Dr McCoy noted that newer diabetes drugs are “thought not to cause hypoglycemia and therefore used with less caution…yet we now see that these medications too can cause hypoglycemia among clinically complex patients…I think that physicians need to ask all patients receiving pharmacotherapy for diabetes about hypoglycemia, not just if they receive insulin or sulfonylureas.”

Also of note, patients treated by endocrinologists had significantly higher risk of hypoglycemia (OR, 1.65), even after adjustment for the HbA_1c level and medications used.

Reasons for Not Deescalating

In their editorial, Drs Kerr and Hofer summarize four main reasons that treatment deintensification is rare even when clearly indicated.

First, the question is rarely examined in clinical trials, so data are lacking about when to stop most medical services.

Second, physicians and patients may suspect that cost saving is behind recommendations to stop treatments. Third and, “less nobly, physicians may be concerned about their own performance on report cards.”

Finally, the editorialists suggest, lack of time and effective decision-support tools may hinder discussion about stopping or scaling back on established treatments and services.

“When guidelines are silent on the limits of generalization, the default in clinical practice and pharmaceutical marketing is often to generalize to the entire population all treatment benefits in the absence of definitive proof of harm,” they write.

Dr McCoy added another possible factor: “I think we also need to recognize the discomfort that physicians may feel in telling patients that they may not benefit from intensive treatment. I think that we, as physicians, may worry that this comes across as us saying that patients don’t have long to live or do not ‘deserve’ high-quality care.”

And regulatory bodies should not necessarily always equate low HbA_1c with high-quality care, she said, adding, “High-quality care is care that is efficient and safe, so quality metrics should incorporate indices of overtreatment and hypoglycemia in them.”

“If physicians are ‘graded’ and reimbursed on the basis of how low their patients’ HbA_1c is, there is inevitable potential for seeking lower HbA_1c at the expense of potential patient harm.”

One Way to Simplify

The single-arm intervention study by Dr Munshi and colleagues recruited 65 adults with type 2 diabetes who were 65 years or older and had a mean HbA_1c of 7.7%, taking two or more insulin injections a day (mean 3.7) and who had had hypoglycemia in the past 5 days detected by continuous glucose monitoring.

Mealtime insulin was stopped, and all were switched to once-daily insulin glargine, with or without noninsulin agents as needed, over 5 months. Hypoglycemia duration decreased at 5 and 8 months (P < .001) without any change in HbA_1c levels after simplification.

Improvements in HbA_1c occurred in patients with baseline HbA_1clevels 8% to 9% (P < .001) and above 9% (P = .03), whereas there was a small worsening in those with baseline HbA_1c levels below 7% (P = .03), and no change in those with HbA_1c levels between 7% and 8% (P = .80).

Diabetes-related distress scores improved at 5 months and remained low at 8 months (P < .001).

In a short note, journal editor Deborah Grady, MD, of the Veterans Affairs Medical Center, San Francisco, California, points out that the study by Dr Munshi and colleagues is small and uncontrolled and therefore should be considered preliminary.

However, she wrote, “we decided to publish the study because we believe it should inspire larger trials to investigate optimum insulin regimens that minimize hypoglycemia and patient burden.”