Deintensification Discourse: Why are we still hesitant to pump the breaks on diabetes management?

It is well-established that the efficacy of diabetes therapy is frequently limited by clinical inertia, whether it be attributed to the patient, the clinician, or the health care system. The need for more frequent follow-up and education in the management of diabetes mellitus has created an area of opportunity for pharmacists, as we are more available to meet with patients and facilitate the initiation and acceleration of different therapies. Yet, we are often so concerned with adding on antihyperglycemic agents to getting our patients to goal that we often forget to pause and reassess if the patient really needs all of the medication they are prescribed.

In 2012, the American Diabetes Association (ADA) and European Association for the Study of Diabetes dismissed the one-size-fits-all-approach for glycemic targets and released a position statement describing the importance of individualizing treatment strategies, with an emphasis on patient-centered care and shared decision-making in the management of patients with type 2 diabetes.(1) This was based on literature that demonstrated intensive glycemic control (A1c <6–6.5%) may improve surrogate outcomes for microvascular complications and reduce cardiovascular events at the possible expense of all-cause mortality.(2-5) Factors such as disease duration, life expectancy, comorbidities, established vascular complications, patient preferences, available resources and support, along with risk for hypoglycemia and other adverse effects should be taken into consideration when establishing patient-specific glycemic targets.(6) As clinicians, we frequently assess these factors at diagnosis, but do we do the same for our aging patients with long-standing diabetes?

While we may think this isn’t a common problem, multiple studies have demonstrated possible overtreatment in vulnerable populations (7) and poor rates of treatment deintensification among patients with low HbA1c values or those at risk for hypoglycemia.(8, 9) A retrospective cohort study of data from the Veterans Health Administration examined rates of treatment deintensification among patients that were aged 70 years or older on active treatment for diabetes.(8) Of the 23,769 patients with moderately low HbA1c levels (6.0–6.4%) and the 12,917 patients with very low HbA1c levels (<6%), treatment deintensification was initiated in 20.9 and 27.0% of patients, respectively. Another retrospective analysis using OptumInsight data from 2004 through 2010 determined that antihyperglycemic therapy was deintensified in 18.3% of all patients with recently diagnosed type 2 diabetes mellitus.(9) Furthermore, treatment deintensification occurred in only 19.4% of patients with multiple comorbidities and 21.2% of those that met authors’ definition for frailty, regardless of glycemic control at baseline. This demonstrates the need for us as clinicians to step back and think, “does my patient actually need all of this medication?”

The widespread lack of treatment deintensification described by these studies demonstrates the need for further education among health care professionals and stakeholders. Patients that have not yet experienced a hypoglycemic event and are comfortable with their diabetes treatment are often empowered by their glycemic control, and therefore, patient preference serves as a barrier to deintensification. Providers may struggle identifying the need for and prioritizing diabetes treatment deintensification because what appears to be well-controlled diabetes may seem like the smallest obstacle in the road to comprehensive disease management, especially when patients present with a list of more active problems that require immediate attention. So, how can we better recognize the patient-specific transition of well-controlled to overcontrolled diabetes? How often do you assess an A1c goal in a well-controlled patient and consider their risk of hypoglycemia and falls along with their comorbid conditions to incorporate those factors into their treatment plan?

Just as pharmacists have demonstrated value in the implementation and optimization of antihyperglycemic therapy, their role in identifying those that would benefit from treatment deintensification and facilitating that process is equally important. That being said, what are some strategies you have used to identify the need for and to initiate deintensification of therapy in clinical practice?

Authored by Liz Van Dril, PharmD, PGY-1 Resident, Midwestern University

  1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–79.
  2. Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371:1392–406.
  3. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
  4. Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818–28.
  5. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197–206.
  6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–149.
  7. Lipska KJ, Ross JS, Miao Y, et al. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med. 2015;175:356–362.
  8. Sussman JB, Kerr EA, Saini SD, et al. Rates of deintensification of blood pressure and glycemic medication treatment based on levels of control and life expectancy in older patients with diabetes mellitus. JAMA Intern Med. 2015;175:1942–1949.
  9. McAlister FA, Youngson E, Eurich DT. Treatment deintensification is uncommon in adults with type 2 diabetes mellitus: a retrospective cohort study. Circ Cardiovasc Qual Outcomes. 2017;10(4).
  10. National Committee for Quality Assurance. Healthcare effectiveness data and information set: comprehensive diabetes care. http://www.ncqa.org/report-cards/health-plans/state-of-health-care-quality/2016-table-of-contents/diabetes-care (accessed 2017 June 11).

 

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New Year and New Guidelines: Incorporating Cardiovascular Outcome Data

After a long year of being on the look-out for new cardiovascular outcome trial (CVOT) data, the American Diabetes Association (ADA) has released the much anticipated 2017 Standards of Medical Care in Diabetes update. The overall value of the CVOT data has been called into question and clinicians have varied predictions regarding how the ADA may incorporate those findings into their recommendations.  So let’s take a look:

The ADA has incorporated their recommendation regarding the positive outcomes seen with the use of empagliflozin in the EMPA-REG OUTCOME trial and liraglutide in the LEADER trial into the section on the pharmacologic approaches to glycemic treatment in type 2 diabetes mellitus (T2DM). Regretfully, the data was not incorporated into the general treatment algorithm, which continues to focus on patient centered characteristics for the selection of second line agents. Instead, the level B ADA recommendation comes with some caveats. The recommendation outlines the use of empagliflozin and liraglutide in patients with long-standing, poorly controlled T2DM and established atherosclerotic cardiovascular disease (ASCVD) in addition to the existing standards of care. (ref 1)  These guideline updates are on the heels of the new indication approval by the FDA for empagliflozin. This new indication is to reduce the risk of cardiovascular death in adults with T2DM and cardiovascular disease.(ref 2)

While this blanket statement for established ASCVD may by easier for clinicians to apply in practice, it is important to recognize the differences in patient population that were included in both the EMPA-REG OUTCOME and the LEADER trials.(ref 3,4) The LEADER trial exemplified a higher level of external validity, because of the more inclusive study design and expansive definition of high cardiovascular risk. (ref 4) While the EMPA-REG OUTCOME study included patients with only established cardiovascular disease, the LEADER trial also included patients with at least one cardiovascular disease risk factor and aged > 60 years. (ref 3,4) The LEADER trial also considered CKD stage 3 or greater or CHF of NYHA class II or III in their definition of coexisting cardiovascular condition, which only had an inclusion age cut off of 50 years.(ref 4) I feel that in my practice, while established ASCVD is not rare, the positive CVOT data can be applied more widely for liraglutide than for empagliflozin due to the broader inclusion criteria seen in the LEADER study.

How do the differences in study population affect how other clinicians apply this data? I am eager to hear other opinions in the clinical community about how the ADA has classified this data and if it will change your practice. Another clinical discussion starter can also be if this data fulfils the original purpose of CVOT and if they are worth the large cost and limited external  . Lastly, does anyone think that metformin with be over-thrown from the high castle as the backbone of therapy with any of this CVOT data? If you aren’t convinced just yet, what do you think it would take to convince you?

  1. American Diabetes Association (ADA). Standards of medical care in diabetes 2017. Diabetes Care 2017 Jan; 40 (Supplement 1): S64-S74.
  2. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm. [Accessed January 10, 2017]
  3. Zinman B, Wanner C, Lachine JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
  4. Marso SP, Daniels, GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in Type 2 diabetes. N Eng J Med 2016;375(4):311-22

 

Co-Pays and Policy

An recent editorial in New England Journal of Medicine (N Engl J Med 2016; 375:2013-2015) from Dr. Leemore Dafny and others spoke of the U.S. DHHS announced goal of linking at least 50% of Medicare spending to value-based payment models. They noted that “health care providers are now scrambling to reorganize in a way that delivers value while preserving or enhancing ‘commercial success’ […of their health care businesses]…For years, insurers and pharmacy benefits managers have steered consumers toward generic and other ‘high-value’ drugs by categorizing drugs into ‘tiers’ and requiring lower copayments for ‘preferred’ drugs.” High value and preferred decisions are being made by the insurer/PBM based perhaps on criteria other than what a clinical pharmacist might consider high value… The authors note that “under tiering, insurers offer manufacturers favorable tier placement in exchange for better discounts” a clear benefit to the insurer or PBM. “Placement on a preferred-brand tier, with a [low] co-pay, will [arguably] yield higher sales than placement on a non-preferred-brand tier with a typical copayment of more than $50. Insurers can also negotiate lower prices for drugs that have therapeutic substitutes or questionable benefits by threatening to exclude them from their formularies entirely.”  The philosophy espoused by the authors of the article is that this is all good!  However, they note that the pharmaceutical industry “counterattacked” (…interesting choice of emotional vocabulary) “by offering ‘copayment coupons’. These coupons or discount cards — distributed by physicians’ offices, through the mail, and online — enable the manufacturer to pay some or all of a consumer’s copayment for a prescription. By severing the link between cost sharing and the ‘value’ generated by a drug, copayment coupons can undo the perceived beneficial effects of tiering.”  They estimate that “coupons increase the percentage of prescriptions filled with brand-name formulations by more than 60%” (!)

OK, I get it! The tiering process is one way to control costs, and healthcare policymakers like that!  I wanted to present a flip side view from the patient care perspective. It is well known that medication adherence is related in part to the size of co-pay assessments in an attempt at ‘cost sharing’ (1-2) both generally and for those entering the Medicare ‘donut hole’.(3)  The use of ‘high value’ [my definition is not necessarily based on medication cost…] drugs such as those that are still branded, may offer improved outcomes, but they are often made second or third tier by insurers to limit their own costs.   Adherence with a number of new medications, especially those with minimal co-pays suggests that there are adherence benefits to be gleaned from the discount cards or coupons.  Add to that the evidence that some of the older diabetes medications, available with little or no co-pays may have a higher rate of adverse effects. (4-7)

So ask yourself, if your mother or father were diagnosed with type 2 diabetes, would you want early aggressive therapy with agents that may have significantly more benefits (8-9), not to mention the benefit of early glucose control, or would you want them to start older agents (some with potential CV risk) and then stay with them for years in the clinical inertia that plagues diabetes care. I know what the policy makers prefer, and I know what my preference is for making new and better drugs more available regardless of ability to handle the co-pay…How about you?

  1. Effect of prescription copayments on adherence and treatment failure with oral antidiabetic medications. Barron J, Wahl P, Fisher M, Plauschinat C. P.T. 2008 Sep;33(9):532-53
  2. How patient cost-sharing trends affect adherence and outcomes: a literature review.Eaddy MT, Cook CL, O’Day K, Burch SP, Cantrell CR. P T. 2012 Jan;37(1):45-55
  3. Part D coverage gap and adherence to diabetes medications. Gu Q1, Zeng F, Patel BV, Tripoli LC. Am J Manag Care. 2010;16(12):911-8
  4. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Phung OJ1, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Diabet Med. 2013 Oct;30(10):1160-71
  5. Hyperinsulinemia and sulfonylurea use are independently associated with left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus with suboptimal blood glucose control. Inoue T, Maeda Y, Sonoda N, Sasaki S, Kabemura T, Kobayashi K, Inoguchi T. BMJ Open Diabetes Res Care. 2016 Aug 18;4(1):e000223
  6. Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies.Pladevall M, Riera-Guardia N, Margulis AV, Varas-Lorenzo C, Calingaert B, Perez-Gutthann S. BMC Cardiovasc Disord. 2016 Jan 15;16:14
  7. Mortality risk among sulfonylureas: a systematic review and network meta-analysis.Simpson SH, Lee J, Choi S, Vandermeer B, Abdelmoneim AS, Featherstone TR. Lancet Diabetes Endocrinol. 2015 Jan;3(1):43-51
  8. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. N Engl J Med. 2015 Nov 26;373(22):2117-28
  9. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M1, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. N Engl J Med. 2016 Jul 28;375(4):323-34

Treatment of T2DM after metformin: what’s next?

Pharmacologic options for the treatment of type 2 diabetes mellitus have expanded over the past ten years.  Metformin has remained the first-line agent due to a well-established safety and efficacy, low cost, and data demonstrating a reduction in cardiovascular events.1  It is pretty clear from a number of studies that metformin therapy should be maximized, which in some patients may require doses above 2000 mg/day. 2  Second-line treatments include a variety of agents, including basal insulin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones.  Metformin is synergistic with many of the other agents, and should not be discontinued as beneficial effects can be seen even in patients taking insulin as the second line agent. 3 The 2016 treatment recommendations detail the above mentioned medications as all viable options for second-line therapy with no preference to one drug class over the other. 1 While this seems like this might open up treatment options for clinicians, it often in fact, leaves clinicians wondering about the BEST next option for their patients.  All of the options will always have a cost/benefit ratio, and so trying to choose the best agent that minimizes patient out of pocket costs is important.  In that regard, SGLT2s from all the current manufacturers have co-pay cards to minimize the cost (for patients not on Medicare).

The likely reason for no definitive recommendation for a second-line agent is that controversy exists regarding which agents should be used for the treatment of T2DM in those who cannot achieve glycemic control with metformin alone.  The newer agents, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors are effective, exhibit positive/neutral effects on body weight, and pose minimal risk of hypoglycemia in comparison to other available agents to treat hyperglycemia. Trials have been completed, or are ongoing, regarding the cardiovascular effects of these agents.3-9   and in the case of empagloflozin, the results of a recent trial have resulted in the manufacturer seeking a cardiovascular risk reduction, and leading to a debate on whether FDA should grant this request (http://www.ptcommunity.com/news/2016-06-24-000000/fda-panel-vote-whether-empagliflozin-jardiance-cuts-risk-cardiac-death). 5  Thus far, CV outcomes have either been positive or neutral with these agents leading clinicians to head towards those agents even though the cost may be higher.

Recently, the FDA has issued concerns regarding the newest agents, the SGLT2 inhibitors regarding the risk for acute kidney injury and ketoacidosis leaving us scratching our heads again, especially after some data exists that there many actually be reno-protection from this drug class (http://www.dddmag.com/news/2016/01/new-data-shows-sglt2-inhibitors-may-be-effective-preventing-kidney-failure).  Time and studies will tell which may be the best second line agents, but it is always important to consider patient out-of-pocket costs especially since diabetes patients take many different medications for diabetes, hypertension, and dyslipidemia…and more.

 

 

  1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2016;39(Suppl 1)
  2. Hirst JA, Farmer AJ, Ali R, et al. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012;35:446-454.
  3. Holden SE, Jenkins-Jones S, Currie CJ. (2016) Association between insulin monotherapy versus insuln plus metformin and the risk of all-cause mortality and other serious outcomes: a retrospective cohort study. PLoS ONE 11(5):e0153594. Doi:10.137/journal.pone.0153594.
  4. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015 Dec 3;373(23):2247-57.
  5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
  6. Scirica BM, Bhatt DL, Braunwald E, et al; for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
  7. White WB, Cannon CP, Heller SR, et al; for the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
  8. Zannad F, Cannon CP, Cushman WC, et al; for the EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE:  a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076.
  9. Van der Werf F, Armstrong P. Trial evaluating cardiovascular outcomes with sitagliptin in patients with type 2 diabetes: TECOS. Presented at ESC Congress 2015. London, England, UK. Abstract 3147.

 

Paying for diabetes medicines–it’s not just frustrating for patients

Treating diabetes these days is exciting, considering there are many more options for us to choose from, and it seems like new drugs are coming on the market every other day.  While some of these drugs are novel, focusing on a new mechanism of action to combat a complex disease process, other medications seem to provide little advantage over medicines that have been available for some time.

When these new drugs come to market, the pharmaceutical companies tend to offer great rebate programs and/or co-pay savings cards where the patient can get the new medication for as little as zero dollars per month for a period of time, sometimes for 1 to 2 years. However, these programs can’t be used if the patient receives insurance through a government agency, like Medicare or Medicaid. Generally the patient who has Medicaid will have reduced co-pays anyway so this is not really a problem. It’s very problematic or frustrating  when treating patients who have a Medicare part D plan, and are on a fixed income but do not qualify for additional help or low income subsidy. It’s often difficult to use new, novel medications with these patients because of the increased co-pay for them. Even trying to use basal bolus therapy with synthetic rapid-acting insulins plus the longer-acting basals can be quite expensive for patients. Often, it seems the practitioner is faced with trying to use cheaper medications (if they are not already using them) that may not work as well given duration of disease, or may have more side effects, simply because they are more affordable. If Medicare Part D patients may be able to obtain some of these medications throughout the year, it may be a different story once they fall into the gap.  Although the amount the individual patient is responsible for during this period is improving due to reforms, it often is still too expensive. In addition, several articles suggest that increased copays lead to lower adherence. (Cole JA, et al. Pharmacotherapy 2006;26:1157–1164; Schultz JS, et al, Am J Manag Care. 2005;11:306–312; Goldman DP, et al, JAMA 2007;298:61–69)

It’s also frustrating to have to change medicines throughout the year because of the formulary change.  Many practices try to be proactive when prescribing by searching formularies ahead of time.  However, the formulary available may not be the most current, or the formulary may only be available to the individual patient covered by the plan.  Many of my patients don’t quite understand the ins and outs of insurance, let alone understand that I need them to bring in their updated formulary booklet each time they receive one.

I fully support research and development of new entities, the approval and use of new medications when they are beneficial (i.e. empagliflozin and cardiovascular outcomes [N Engl J Med 2015; 373:2117-2128])  as well as the opportunity or availability of insurance.  I understand the need for restrictions regarding insurance coverage, the need for formularies, and the need to improve medication use across the board.  However, I wish the costs of these newer medications were not as high, and that more programs were available for those that need it most—the patients who fall in the gaps.  I also wish the process related to obtaining medications through insurance was less cumbersome and time-consuming.  But for now, I’ll keep working with patients to optimize the medications they do obtain, tolerate, and take as well as helping to improve other non-drug measures such as meal planning and physical activity.  I’ll keep researching formularies online with the hope that coverage is still the same as well as completing prior authorizations when needed, while holding in my frustrations and remaining hopeful for continued progress in our health care system.  Can I just use the best medicine, even if somewhat expensive, in all patients to get the best outcome??