Prediabetes and diabetes prevention: Are we doing enough? What could we be doing differently?

Time and time again, as I work with prediabetes patients in clinic, I see many individuals come in feeling defeated.  At our last visit, my patient was really ready to “get serious” about watching portions, making healthy food choices, and getting in the recommended physical activity of moderate aerobic exercise for 150 minutes per week.  My patient did well for a week or two, and then life happened.  They had a sick child, work asked for some overtime, and there were multiple family gatherings that revolved around food (think holidays).  And my patient “fell off the bandwagon” so to speak.  After a couple of days of dietary indiscretion, and not making it to the gym, they thought, “to heck with it” and binged on comfort foods while watching T.V. as a method of stress reduction.  They gained a few more pounds.  Guilt crept in, and that turned into missing a follow-up appointment with me, because they were embarrassed that I would think poorly about the lack of effort.

What I described is too often a reality, and becomes a dangerous cycle for patients.  A cycle that leads to depression, which can lead to giving up the treatment plan, then worsening glycemic control, a feeling of overwhelm or lack of control, and then finally, despair—once prediabetes becomes Type 2 diabetes.

We know from the Diabetes Prevention Program (DPP) that intensive lifestyle modifications are effective, and the efforts needed don’t seem too difficult to those of us who are already doing them on a habitual basis.1 But for many with prediabetes, the modifications needed are a complete overhaul from what they are already doing.  For example, you can’t easily go from two double cheeseburgers with fries and regular soda for lunch on the run, to an expectation of eating a large plate of green leafy vegetables with a 3 oz. portion of protein and 30-45 grams of carbohydrate on the side.  It sets a person up for failure. Change takes discipline, but also, time and planning.  You start with subtracting one cheeseburger, lots of encouragement, and maybe a 10 minute walk around the block.  Add in a behavioral health session or two to rid the mind of focusing on failure, and what is not possible, and instead think about what is possible.

Diabetes Prevention Program outcomes, which included a 58% reduction in 3-year diabetes incidence and 34% reduction in 10-year diabetes incidence were achieved in the intensive lifestyle group, but not without significant efforts on the part of both participants and the clinicians and educators working with them.1,2  Lifestyle measures included a healthy, low calorie, low-fat diet (flexible, individualized, and culturally sensitive) and the 150 minutes of physical activity per week described.  Participants in this group had an incredible amount of support to achieve this:  1) A 16-lesson curriculum covering diet, exercise, and behavior modification designed to help achieve goals, 2) one-to-one meetings for 16 sessions occurring over 24 weeks, 3)subsequent individual sessions (at least every other month), AND 4) group sessions with case managers to reinforce behavioral changes.  This all occurred in the first year.  There was support that followed that as well.  Participants got frequent reminders of what they needed to do, frequent encouragement, and mild “nagging” if they didn’t show up to exercise (“we missed seeing you today, Mr. Smith”).  Don’t forget that study participants get financial compensation as well.  Could our patients do better with a free gym membership, cooking lessons, constant encouragement from prediabetes “cheerleaders” and financial rewards?  Probably!  Also, we cannot discount the concept that study participants tend to be more motivated in general than those who don’t have the time or interest in participating in a study.

Why do people still progress on to developing type 2 diabetes, despite some attempt at lifestyle measures?  There could be a strong family history of rapid progression of disease.  The ability to replicate the DPP in a real-world setting is very challenging.  Positive outcomes in the intensive lifestyle group outcomes were more commonly seen in patients with impaired glucose tolerance (IGT), so the measures may not have fully addressed impaired fasting glucose (IFG).1  Women with a history of gestational diabetes mellitus (GDM) faired equally well with metformin as with lifestyle interventions, as did patients in the largest BMI group (≥35 kg/m2).1,3, 4 There may be other pathophysiologic reasons that are not fully addressed with lifestyle measures alone.  A progressive disease, by nature, often requires add-on therapies.  We also know that when prediabetes is identified by use of A1C criteria, we are only getting part of the picture.  A1C is still not an ideal diagnostic measure, and there can be lower sensitivity when using the A1C for diagnostic purposes—especially at the lower end of the A1C range.5   A1C can be affected by a number of factors that influence hemoglobin glycation. 5 In addition, The American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE), often partnered with the American College of Endocrinology (ACE), are not consistent in defining diagnostic cut points for A1C as it relates to prediabetes.5,6.  Lastly, there are the individual reasons already stated previously—life gets busy!  There may be a multitude of other reasons; but we know that translation of DPP to real world settings can be less than ideal and outcomes are not always identical.  For example, a systematic review and meta-analysis which included 22 translational diabetes prevention programs showed that the mean level of weight loss was approximately one-half to one-third of the levels reported in the DPP.7

We also need to remember that Diabetes Prevention Program outcomes did include positive results for metformin—just to a lesser degree than for the intensive lifestyle group.  Metformin at a dose of 850 mg twice daily resulted in a 31% reduction in progression from prediabetes to Type 2 diabetes within the almost 3 year follow-up period, and resulted in an 18% reduction in the 10-year follow up period.1,2  The metformin group in the DPP did not receive any lifestyle intervention, but were provided with “standard” care or counseling that could be more similar to what is received in many typical primary care settings.  I often wonder, how powerful would it have been to have had a group studied with the combination of intensive lifestyle AND metformin?  Nonetheless, the data with metformin alone doesn’t look too shabby!  In the words of the simple-minded Peter Griffin, “why are we NOT funding this??”8

Lifestyle interventions were considered more cost effective than metformin in the DPP; however, metformin was not available as a generic formulation at the time.With the availability of $4 per month immediate-release metformin at many pharmacies across the nation, it almost seems like a no brainer for a prediabetes patient without contraindication.  Metformin therapy for diabetes prevention is now a grade A level recommendation in the American Diabetes Association Standards of Medicare Care for 2018; especially for those with BMI ≥35 kg/m2, those aged <60 years, and women with prior GDM—all the groups that benefitted the most in the DPP.10

For patients that cannot tolerate an inexpensive immediate-release metformin at a dose of 850 mg twice daily; generic extended release formulations are a slightly more expensive, but a reasonable alternative that often results in less GI intolerance.11-15  The least costly formulations are available as 500 mg tablets.  I start with 500 mg of the extended release daily, and titrate to at least 1500 mg daily (typically, 500 mg in the morning and 1000 mg in the evening), and increase up to 2000 mg daily, in divided doses.  For previous cases of GI intolerance, I have better luck avoiding future intolerance when I recommend that the extended release formulation be administered twice daily, instead of opting for once daily.  If adherence issues surface, once daily administration can be tried.

For patients who still cannot take metformin, there are multiple other good pharmacotherapeutic options for prediabetes, although often at a higher cost.  Most patients would not prefer to use basal insulin for diabetes prevention; however the work and theories set forth by Dr. Ralph DeFronzo and subsequent research certainly support its use, consistent with the concept of beta cell defect occurring early in disease. 16,17,18  We know from this research that there appears to be a period of glucose intolerance and pathophysiologic changes that long precede the development of diabetes.16,17  The other treatment modalities described in the table below are supported by good outcomes and share a physiologic basis for use (see the hyperlink for the actions targeted).17  Consider these alternatives to metformin in select patients, as appropriate.

Diabetes Prevention Pharmacotherapy Table 1.18.18

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5317235/figure/F3/

In summary, I would never advocate for eliminating completely lifestyle measures in prediabetes or diabetes; these should always be encouraged.  But I’m more of a realist than an idealist.  And I think that we could be more aggressive in employing all types of diabetes prevention strategies, especially pharmacotherapy, than what appears to be the current standard of practice in many clinical settings in the United States.  Pharmacists can be pivotal in educating others and employing strategies toward type 2 diabetes prevention.

References:

  1. Diabetes Prevention Program Research Group, Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
  2. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study [Erratum in Lancet. 2009;374:2054]. Lancet. 2009;374:1677-86.
  3. Ratner RE, Christophi CA, Metzger BE, et al.; Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008;93:4774–4779.
  4. Aroda VR, Christophi CA, Edelstein SL, et al.; Diabetes Prevention Program Research Group.  The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program Outcomes.  Study 10-year follow-up. J Clin Endocrinol Metab 2015;100:1646–1653.
  5. American Diabetes Association. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes 2018.  Diabetes Care 2018;41(Suppl. 1):S13–S27.
  6. American Association of Clinical Endocrinologists and American College of Endocrinology. Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan—2015.  Endocr Pract. 2015;21(Suppl 1).
  7. Dunkley AJ, Bodicoat DH, Greaves CJ, et al. Diabetes prevention in the real world: effectiveness of pragmatic lifestyle interventions of the prevention of type 2 diabetes and of the impact of adherence to guideline recommendations.  A systematic review and meta-analysis.  Diabetes Care 2014;37:922-933.
  8. Fox TV: Family Guy. McStroke: Season 6, Episode 9.  Full episode first aired on January 13, 2008.  Short clip: https://www.youtube.com/watch?v=TRtlkcQ6brE.  Accessed 1/17/18.
  9. Within-Trial Cost-Effectiveness of Lifestyle Intervention or Metformin for the Primary Prevention of Type 2 Diabetes. Diabetes Prevention Program Research Group.  Diabetes Care 2003;26:2518-2523.
  10. American Diabetes Association.  Prevention or delay of type 2 diabetes: Standards of Medical Care in Diabetes 2018. Diabetes Care 2018;41(Suppl.1):S51–S54.
  11. Fujioka K, Pans M, Joyal S. Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation.  Clin Ther. 2003;25(2)515-29.
  12. Blonde L, Dailey GE, Jabbour S, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study.  Curr Med Res Opin. 2004;20(4)565-72.
  13. Feher MD, Al-Mrayat M, Brake J, Leong KS. Tolerability of prolonged-release metformin (Glucophage) in individuals resistant to standard metformin—results from four UK Centeres.  Brit J Diabetes Vasc Dis. 2007; 225-228.
  14. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study.  Diabetes Obes Metab. 2009;11:338-342.
  15. Levy J, Cobas RA, Gomes MB. Assessment of efficacy and tolerability of once-daily extended-release metformin in patients with type 2 diabetes mellitus.  Diabetol Metab Syndr. 2010;2:16.
  16. DeFronzo R. From the triumvarariate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
  17. Schwartz SS, Epstein S, Corkey B, Grant SFA, Gavin III JR, Aguilar RB. The time is right for a new classification system for diabetes: rationale and implications of the β-cell-centric classification schema.  Diabetes Care 2016;39:179-186.
  18. Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-28.
  19. STOP-NIDDM Trial Research Group, Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-7.
  20. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364:1104-15.
  21. DREAM (Diabetes REduction Assessment with rampipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial [Erratum in: Lancet. 2006:368:1770]. Lancet. 2006;368:1096-105.
  22. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308
  23. Le Roux C, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomized, double-blind trial.  Lancet. 2017;368:1096-105.
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How Sweet it Ain’t

Ah, it’s that time of year again. Turkeys getting stuffed, people getting stuffed and “leave room for dessert.” We love our sweets, and over time our sweet tooth has increased to where the average American eats 15-20 grams of sugar a day, primarily as sweet snacks or sugar sweetened beverages (Carbonated Soft Drinks -CSDs). (1) When we were young we worried about getting cavities, as we got older we worried about getting fat, but we still increased our sugar intake as we aged, and overall as our society aged. Over the years, children and adolescents increased their consumption of sugar sweetened beverages as more of them became available and more readily available in the ubiquitous ‘soda machines’. (2) Of course, ‘sugars’ are of different types, and how the body metabolizes the sugar in fruit and milk differs from how it metabolizes the refined sugar added to processed foods. For the sake of this discussion, ‘sugar’ (sucrose) is refined from sugar cane (to remove the molasses) or a sugar-like sweetener (High Fructose Corn Syrup -HFCS)produced as starch in corn is digested with heat and enzymes to make corn syrup. This process is very involved, requires heat, acid, multiple enzymes and a small amount of mercuric chloride. (3) The sweet syrup still contains some undigested oligosaccharides as well as 5-hydroxymethyl-2-furfural (HMF) which is a known toxin. HMF contents in both sucrose and HFCS are very high (406.6-2121.3 mg/kg for corn syrup and 109.2-893.1 mg/kg for cane syrup), which arouses concern about food safety of these products. (4) In addition, analysis of carbonated soft drinks (CSD) has shown significant degradation products of sugar components, namely -dicarbonyl compounds (5) which most of us associate with diabetes. There is clear evidence that dicarbonyl stress is a contributing mediator of obesity and vascular complications of diabetes. (6,7) While sucrose contains glucose and fructose, it seems that spiking additional fructose (as in HFCS) may not be a good idea since it has been associated with fatty liver and other biochemical changes. (8) We also know, that in many common CSDs there is even more fructose than you might believe from the use of HFCS as a sweetener (as high as 65%). (9) So now we know that the ‘sweetness’ we seek, may have some downsides, but is this new? It turns out that some of the issues uncovered with sugar experiments in rodents were somehow never fully completed in experiments or published. A recent article in JAMA Internal Medicine exposes a 1960s study, which suggests a link between a high-sugar diet and high blood cholesterol levels and cancer in rats, was sponsored by the sugar industry, and when initial findings were presented to the sponsor, the funding disappeared. (10). A more recent article from the same authors suggested that the Sugar Research Foundation sponsored a research program that successfully cast doubt about the health hazards of a high-sugar diet and rather promoted fat “as the dietary culprit” in health concerns such as heart disease. (11) So, there you have it! That is part of the reason the new dietary guidelines call for reducing sugar intake roughly in half. (12) Coca-Cola anyone?

References:

1) SUGAR INTAKE STATISTICS: (FIGURES 2-9 AND 2-10 FROM GUIDELINES)
https://health.gov/dietaryguidelines/2015/guidelines/chapter-2/a-closer-look-at-current-intakes-and-recommended-shifts/#figure-2-9

2) Sugar sweetened Beverage Consumption Among U.S. Youth 2011-2014. Rosinger A, Herrick K, Gahche J, Park S. National Center for Health Statistics Data Brief No. 271, January 2017

3) High Fructose Corn Syrup
https://en.wikipedia.org/wiki/High-fructose_corn_syrup

4) In house validation fro direct determination of 5-hydrosymethyl-2-furfural in corn and cane syrups samples by HPLC-UV. deAndrade JK, Komatsu E, Perreault H, Torres YR, daRosa MR, Felsner ML. Food Chem. 2016;190:481-486

5) Analysis of sugar degradation products with -dicarbonyl structure in carbonated soft drinks by UHPLC-DAD-MS/MS. Gensberger S, Glomb MA, Pischetsrieder M. J. Agri. Food Chem. 2013;61:10238-10245

6) Post-Glucose Load Plasma α-Dicarbonyl Concentrations Are Increased in Individuals With Impaired Glucose Metabolism and Type 2 Diabetes: The CODAM Study. Maessen DE, Hanssen NM, Scheijen JL, van der Kallen CJ, van Greevenbroek MM, Stehouwer CD, Schalkwijk CG. Diabetes Care. 2015;38:913-20

7) Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Rabbani N, Xue M, Thornalley PJ. Glycoconj J. 2016;33:513-25.

8) Added fructose as a principal driver of non-alcoholic fatty liver disease: a public health crisis. DiNicolantonio JJ, Subramonian AM, O’Keefe JA. Open Heart. 2017; 4(2): e000631

9) Sugar Context of Popular Sweetened Beverages Based on Objective Laboratory Analysis: Focus on Fructose Content. Ventura EE, Davis JN, Goran MI. Obesity 2010;19:868-874

10)Sugar Industry and Coronary Heart Disease research: A historical analysis of internal industry documents. Kearns CE, Schmidt LA, Glantz SA. JAMA Intern. Med. 2016;176:1680-1685

11) Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents. Kearns CE, Appolonio D, Glantz SA. PLoS Biol. 2017;15:e2003460

12) Dietary Guidelines for Americans: 2015-2020
https://health.gov/dietaryguidelines/2015/guidelines/ (Accessed 11/25/17)

Autoimmune Protocol Diet – the Secret Cure to Hashimoto’s Thyroiditis?

Within the past 5 years the autoimmune protocol diet (AIP, and sometimes referred to as the autoimmune paleo diet) has been hyped as the key to reversing the symptoms of autoimmune disorders, including hypothyroidism from autoimmune thyroiditis (AIT) a.k.a.Hashimoto’s Thyroiditis. The idea behind this diet is that it reduces the role of the intestine and inflammation, making intestinal inflammation a less likely cause of autoimmune symptoms. The AIP diet itself is much like a paleo diet in that it focuses on protein-rich foods. Like a paleo diet, the AIP recommends no grain or milk products and limits the amount of fruits (to limit fructose intake). Where the AIP differs from the paleo diet is that it also eliminates nuts, legumes and seeds.

But you may ask, what is the science? Well, that’s a good question.

The main theory surrounding the AIP diet and reducing HT symptoms is based on the association between celiac disease (CD) and autoimmune thyroiditis (AIT). Both are autoimmune disorders. It seems logical that if someone has auto-antibodies that are attacking one area of the body, they might be prone to have auto-antibodies attacking another area of the body. In fact, one review article cited ten articles that identified populations with AIT that were subsequently screened for CD. The rate of CD in these AIT populations ranged from 2% to 7.8%.1 This is much higher than the estimated general prevalence of CD which is approximately 1 in 133 people (around 0.7%).2

One study may shed light on how a gluten-free diet could help correct a thyroid disorder. An Italian study enrolled 241 adult patients with a new diagnosis of CD, and matched them to 212 control subjects (matched for age, sex, and ethnic origin).3 Investigators then drew thyroid assays (serum TSH, fT3, fT4, thyroid microsome antibodies [TM-Ab] and thyroperoxidase antibodies [TPO-Ab]) to ascertain thyroid function status. In total, 30.3% of the CD patients had a thyroid disorder, compared to 11.3% of controls (p<0.0005). When sex was taken into consideration, this difference was only significant for females (P<0.0005). Of the 73 patients with CD and a thyroid disorder, 31 were found to have hypothyroidism (10 were able to be identified as autoimmune in nature), 3 had hyperthyroidism, and 39 were euthyroid but with AIT detected. In the 24 subjects in the control group with a thyroid disorder, 9 had hypothyroidism (4 were autoimmune in nature), 7 hyperthyroid, and 8 euthyroid but with AIT detected. In a continuation of this study, 128 of the original 241 subjects with CD were instructed to maintain a gluten free diet. The results are highlighted in the table below. The interesting thing about the results is that a gluten-free diet resulted in half of the patients with autoimmune hypothyroidism and about A few things to note about this study as we apply it to all patients with HT. First and foremost, this was a study in patients with celiac disease. This study has not been replicated in a randomized controlled trial in the general population with thyroid disease (although many anecdotal successes exist on the internet). Furthermore, reversion to a euthyroid state was seen in patients with both autoimmune and non-autoimmune thyroiditis. If a gluten-free diet were to decrease autoimmune antibodies, one might expect to see the reversion to a euthyroid state in only the patients with auto-immune hypothyroidism. Finally, it should be noted that the two patients who remained with overt disease were still treated with pharmacotherapy.

 

Thyroid Function Patients Assessed (n) Outcome after Diet Trial (n)
Hypothyroid, autoimmune Overt (1)* Subclinical hypothyroidism (1)
Subclinical (5) Euthyroid (3)
Unchanged (2)
Hypothyroid, non-autoimmune Subclinical (14) Euthyroid (11)

Unchanged (3)

Hyperthyroidism Overt (1)* Subclinical hyperthyroidism (1)
Euthyroid with AIT detected (16) Normalization (3)

Unchanged (9)

Subclinical hypothyroidism (3)

Subclinical hyperthyroidism (1)

Normal (no thyroid disease detected during screen) (91) Non-autoimmune hypothyroidism (2)

Subclinical hyperthyroidism (1)

Euthyroid with AIT detected (2)

Normal (86)

Adapted from Sategna-Guidetti, et al.
*patients with over thyroid disease were also treated with drug therapy

A second study looked at TSH levels in subjects with hypothyroidism (HT) and lactose intolerance.4 The results showed that when these subjects adhered to a strict lactose-free diet, their TSH decreased (from 2.06 ± 1.02 IU/mL to 1.51 ± 1.1 IU/mL in euthyroid subjects and 5.45 ± 0.74 IU/mL to 2.25 ± 1.88 IU/mL in subclinical subjects). It should be noted that this same diet in subjects with HT but without lactose intolerance did not produce a similar decrease in TSH.4 This study was limited in the length of time of the lactose-free intervention was given.

Where should we go from here? We certainly need more randomized controlled trials on how diet can influence thyroid disease. The above mentioned articles were the only ones found with definitive evidence. There is a plethora of information on the internet regarding the AIP for HT, but these are anecdotal, and weak on evidence. Patients interested in an AIP diet for HT should be warned that it is an intense diet and can be difficult and frustrating to keep up with, and those with overt disease should be maintained on pharmacotherapy during their diet trial.

References

  1. Chin CL, Jones K, Kingham JGC. Celiac disease and autoimmune thyroid disease. Clin Med Res. 2007;5:184-92.
  2. Barker JM, Liu E. Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions. Adv Pediatr. 208;55:349-55.
  3. Sategna-Guidetti C, Volta U, Ciacci C, et al. Prevalence of thyroid disorders in untreated adult celiac disease patients and effect of gluten withdrawal: an Italian multicenter study. Am J Castroenterol. 2001;96:751-7.
  4. Asik M, Gunes F, Binnetoglu E, et al. Decrease in TSH levels after lactose restriction in Hashimoto’s thyroiditis patients with lactose intolerance. Endocrine. 2013;46:279-84.

Single Payer Healthcare: Case study in running out of The People’s money

Currently there is significant and contentious debate about providing and paying for healthcare in America. In 2010, the Affordable Care Act (ACA) was passed by Congress and included a dozen different new taxes, a specific cadre of policy designs, and mandates for employer participation as well as mandates for individuals to carry insurance. Penalties went along with the mandates, of course. A full discussion of the ACA is beyond the scope of this blog, but suffice it to say that a major issue was how to pay for the expansion of healthcare services. Insurance companies signed up to provide healthcare policies to many individuals, Medicaid rolls were expanded in many states, and a unique provision was made to ‘bail out’ insurance companies if they sustained significant losses.

In short, with its continued funding of Medicare, and its role in partially funding Medicaid and [through bailouts] insurance companies, the extensive role of the federal government makes the United States almost a ‘pseudo’ single payer system with many of the provisions found in other single payer systems (SPSs).

While various factions continue to argue about the future of the ACA, and whether or not it was designed to devolve into a SPS, it would be prudent to look at well-established SPSs to see if there are lessons to be learned. The National Health Service (NHS) in the United Kingdom is a classic and longstanding example of a SPS. The NHS has separate bodies to handle the separate countries in the system. England, Wales, Ireland and Scotland each have separate, very complex organizational systems (1).

From the development of the NHS until now, the evolution of the system in England has devolved to decision-making bodies called Clinical Commissioning Groups, which are regional groups of general practitioners, nurses and consultants that plan and commission the best services for their local patients and population, and collectively have a fiduciary responsibility to the NHS in doing so. (1,2). Over the years, the National Institute for Health and Care Excellence (NICE) has evaluated new therapies and technologies to see if they are worthy to be reimbursed by the NHS. (3)

NICE is not known for readily adopting new medications and technologies. It withdrew NHS funding for newer and more expensive modalities that could potentially impact over 20,000 cancer patients, and more recently rationed treatments for Hepatitis C treatments (4,5,6,7)

No coverage for some products or rationing of others is just the tip of the iceberg in England. Surgery for cataracts is not permitted until the patient is nearly blind (x), knee and hip replacements are denied until “pain is so severe that it interferes with your quality of life and sleep….everyday tasks, such as shopping or getting out of the bath, are difficult or impossible.”(8, 9) And most recently, the “most severe [rationing] ever” by NHS, already adopted by several Clinical Commissioning Groups, is the ban of obese patients and smokers from ‘routine’ surgery. (10)

In addition to these specific issues, there is a movement within the NHS/NICE system to establish a new (lower) financial cap for costs per Quality Adjusted Life Year (QALY) as well as a potentially not approving any treatment that will cost the system more than 20 million pounds during the first three years. (10)

Rationing is the unseemly underbelly of Single Payer healthcare, and when discussed in abstract terms tends to lose its true meaning for the individual. If it is your mothers pain awaiting a new hip, your grandmothers inability to read her romance novels, or even your fathers heart attack while awaiting surgery because he is overweight or some other of the myriad possibilities these very real possibilities need to be discussed openly in light of what is going on with the NHS .

Despite these measures, the NHS is still several billions of dollars in the hole. Clearly these draconian measures are an attempt at slowing the rising healthcare debt, yet they haven’t cut any of the huge bureaucracy that adds to these costs. (12) Think the US government can do a better job? I have a bridge I’d like to sell you…

1. The organisation of the NHS in the UK: comparing structures in the four countries. Doheny S., National Assembly for Wales – Research Service. May 2015. http://www.assemblywales.org/research

2. The NHS in England
http://www.nhs.uk/NHSEngland/thenhs/about/Pages/nhsstructure.aspx

3. NHS Commissioning https://www.england.nhs.uk/commissioning/

4. National Institute for Health and Care Excellence https://www.nice.org.uk

5. Betrayal of 20,000 cancer patients: Rationing body rejects ten drugs (allowed in Europe) that could have extended lives
http://www.dailymail.co.uk/health/article-1257944/NICE-rejects-cancer-drugs-extended-patients-lives.html

6. 25 cancer drugs to be denied on NHS http://www.telegraph.co.uk/news/politics/11340860/25-cancer-drugs-to-be-denied-on-NHS.html

7. NHS ‘abandoning’ thousands by rationing hepatitis C drugs https://www.theguardian.com/society/2016/jul/28/nhs-abandoning-thousands-by-rationing-hepatitis-c-drugs

8. Thousands of elderly are losing their sight as NHS rations cataract surgery
http://www.dailymail.co.uk/news/article-2363857/Thousands-elderly-losing-sight-NHS-rations-cataract-surgery.html

9. Pain-level rationing of hip and knee surgery due to cash crisis, admits NHS
https://www.theguardian.com/society/2017/jan/26/royal-college-surgeons-slam-plans-hip-knee-replacements-ccgs

10. Obese patients and smokers banned from routine surgery in ‘most severe ever’ rationing in the NHS
http://www.telegraph.co.uk/news/2016/09/02/obese-patients-and-smokers-banned-from-all-routine-operations-by/

11. Daniel Zeichner MP: Proposed changes to NICE & NHS England must not be implemented without a real debate
https://www.politicshome.com/news/uk/health-and-care/pharmaceuticals/opinion/house-commons/84774/daniel-zeichner-mp-proposed

12. Perspectives on the European Health Care Systems: Some Lessons for America http://www.heritage.org/health-care-reform/report/perspectives-the-european-health-care-systems-some-lessons-america

The Rodney Dangerfield of Cardiovascular Risk Factors in Diabetes

Some of you may remember the great comedian Rodney Dangerfield who passed away in 2004. While some may remember his roles in Caddy Shack or Back to School (my favorite), he was best known for his catchphrase “I don’t get no respect” which was the basis for many comedy monologues.

When we speak of cardiovascular risk in diabetes, we invoke cholesterol, chronic hyperglycemia, reactive oxygen species (ROS), AGE’s, the presence of kidney disease and perhaps others. But almost no one talks about, measures, or attempts to treat one risk factor that is well recognized and treatable (or at least the effects of it seem to be). Have you guessed it yet?

Haptoglobin (Hp) was first described in 1938. It is an α2-sialoglycoprotein coming mainly from hepatocytes in response to the secretion of cytokines such as IL-6, IL-1 and TNF. Haptoglobin is a tetrameric protein that structurally resembles immunoglobulins because it has two light chains (α) and two heavy chains (β) covalently bound to each other by disulfide bridges (S-S). Its main function is to rapidly bind free hemoglobin from intravascular hemolysis to keep it from oxidatively damaging the vascular endothelium. Although present in all vertebrates, in humans Hp is characterized by molecular heterogeneity caused by genetic polymorphism. In the 1940s and 1950s structural heterogeneity was establish when alleles of different structures and lengths were identified, categorized as Hp 1-1, Hp 2-1, and Hp2-2. While these variants can be found in patients without diabetes, much of the work on their role as risk factors has been done in the context of diabetes (both type 1 and type 2). Biologic functions of Hp include prevention of renal damage from intravascular hemolysis, protection against ‘toxic radicals’, and sparing of nitric oxide when unbound to hemoglobin. It has also been found to have a variety of different effects comprising an immune-modulating action. All of these effects seem to differ with the haptoglobin phenotype, and in general a protective role is seen in patients with the Hp 1-1 variant, and a lack of protective effect or more pathological role is seen with the Hp 2-2 variant. Approximately 40% of patients with diabetes carry the Haptoglobin 2-2 gene variant (1)

Increased oxidative stress in diabetic patients results from oxidation of glucose and the modification of low-density lipoproteins (LDL). These changes may stimulate the production of inflammatory cytokines that have been implicated in the morphological and pathological changes found in macrovascular and microvascular complications, and different degrees of susceptibility to the development of vascular problems have been observed in studies of the antioxidant properties of Hp. In diabetic patients, those with Hp 1-1 show better protection against complications than Hp 2-1 and Hp 2-2 individuals. The Hp 2-2 phenotype has been found more frequently in people developing type 2 diabetes (2). Hp 2-2 has been shown to be a major risk factor in diabetic vascular disease (3), an increased risk of Coronary Heart Disease (4) an increased cardiovascular mortality in type 1 diabetes (5), an increased risk of renal function decline (6), an increased risk of death following stroke (7), retinopathy (8) and many other risks of complications in people with diabetes.

Also, as many of you know, both type 1 and type 2 diabetes are associated with the so called ‘leaky gut’. In type 1 diabetes various antigens are presented to the maturing gut which can stimulate the development of activated T-cells which, over time, destroy pancreatic beta cells. In type 2 diabetes, the ‘leaky gut’ allows lipopolysaccharides into the circulation, releasing cytokines and adipokines causing inflammation, insulin resistance and eventually diabetes with loss of beta cell mass due to glucose and lipid toxicity. A major factor associated with ‘leaky gut’ is zonulin, discovered in 2000 by Fasano. Zonulin is pre-haptoglobin-2. (9) It is fascinating that the haptoglobin 2 allele (especially in those individuals who are homozygous [hp 2-2] would confer risk of diabetes, and risk within diabetes likely due to its role in gut permeability and ongoing inflammation…

The risk associated with the presence of the Hp 2-2 genotype can be mitigated with vitamin E treatment to a striking degree. While vitamin E has not been shown to affect surrogates of risk in individuals with Hp 1-1, its effect is clear for those with Hp 2-2. The summary abstract below speaks for itself:

Clinical trial data from the HOPE, ICARE, and WHS studies is presented showing a pharmacogenomic interaction between the Hp genotype and vitamin E on the development of CVD. Specifically, in individuals with diabetes and the Hp2-2 genotype, vitamin E has been shown to be associated with an approximately 35% reduction in CVD. Cardioprotection by vitamin E in individuals with the Hp2-2 genotype appears to be mediated in part by an improvement in HDL functionality as demonstrated in three independent trials in both type 1 diabetes and type 2 diabetes. (10)

Despite this positive review, and others like it, over 300 articles in PubMed regarding haptoglobin in diabetes, and several presentations at ADA Annual meetings, the current ADA Standards of Medical Care don’t even mention haptoglobin.(11) It truly is the ‘Rodney Dangerfield of risk factors in diabetes’!

So my question to all of you is: With the clear role of haptoglobin genotype 2-2 in the risk of micro and macrovascular complications AND with the clear indication that treatment with Vitamin E can substantially reduce that risk…when was the last time you suggested obtaining a haptoglobin genotype for your patient with diabetes?

1) Changing the Face of Diabetic Care with Haptoglobin Genotype Selection and Vitamin E Nina S. Levy, Ph.D. and Andrew P. Levy, M.D., Ph.D. Rambam Maimonides Med J. 2011 Apr; 2(2): e0047

2) Shi X, et al. Haptoglobin 2-2 Genotype Is Associated with Increased Risk of Type 2 Diabetes Mellitus in Northern Chinese. Genetic Testing and Molecular Biomarkers 2012;16:563-568

3) Asleh R. and Levy AP. In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. Vascular Health and Risk Management 2005;1:19–28

4) Cahill LE, et al. The Risk of Coronary Heart Disease Associated With Glycosylated Hemoglobin of 6.5% or Greater Is Pronounced in the Haptoglobin 2-2 Genotype. Journal of the American College of Cardiology 2015;66:1791-9

5) Costacou T. and Orchard TJ. The Haptoglobin genotype predicts cardio-renal mortality in type 1 diabetes. J. Diabetes Complications. 2016;30:221-6

6) Costacou, T, et al. Haptoglobin Genotype and Renal Function Decline in Type 1 Diabetes. Diabetes 58:2904–2909, 2009

7) Ijas P, et al. Haptoglobin Hp2 Variant Promotes Premature Cardiovascular Death in Stroke Survivors. Stroke. 2017;48:1463-1469

8) Mukund R, et al. Haptoglobin2-2 phenotype is an additional risk factor of retinopathy in type 2 diabetes mellitus. Indian Journal of Human Genetic. 2013 Apr-Jun; 19(2): 154–8.

9) Fasano A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation. The American Journal of Pathology 2008;173:1243-1252

10) Hochberg I, et al. Interaction Between the Haptoglobin Genotype and Vitamin E on Cardiovascular Disease in Diabetes. Current Diabetes Reports 2017_online Jun 17

11) American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2017; 40: Supplement 1

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).

 

A pharmacy business model that’s bad for pharmacy and bad for some patients

We’ve all heard about and experienced the impact of high medication costs in recent years (http://www.endocrinologyadvisor.com/diabetes/insulin-prices-rising/article/640087/). While the ACA has increased the number of people who can obtain insurance, it has done nothing to help patients actually afford their medications. While there is no one person to blame, there is one piece of the puzzle that has a domino effect on medication costs.  The Pharmacy Benefit Manager (PBM) is a 4thparty in the mix of insurance that directly manages the prescription benefit for insurance companies.  It is the PBM who negotiates with manufacturers, insurance companies, and pharmacies. It is the PBM that offers different ‘formularies’ to health plans, in many cases disenfranchising patients who may need medications not on the ‘formulary’. A perfect example is the insulin marketplace.  (http://www.nbcnews.com/business/consumer/desperate-families-driven-black-market-insulin-n730026)  Here is a good visual and explanation of how PBM’s work: )  I think they have created a perfect storm of healthcare inefficiency that costs patients access to medications and increases the overall cost of healthcare. Why?  I could list a bunch of reasons, but what do you think?