Answering the (Diabetes) Distress Signal

Brian Terrell, Pharm.D., BCACP

Hello PRN! The world looks a little different than the last time that I had the pleasure to talk to you all through this medium. I sincerely hope that each of you and the ones you care about are safe and have the resources that you need.

Speaking of resources, while it has been on the upswing in popularity in recent years, I think it is safe to say that mindfulness is having a moment, and rightly so. I am usually quite eager to talk to the group about the newest drug or the newest outcomes trial, but this month it felt appropriate to deviate from that (but don’t worry, I will still report some statistics). With so many individuals facing challenges on a spectrum of causality and severity that are far beyond my ability to discuss here, I wanted to take this opportunity to review how mindfulness skills may be utilized in diabetes management.

First, a brief reminder that patients with diabetes may be dealing with different stressors and conditions than other individuals. We even have a term for it, diabetes distress, referred to by the American Diabetes Association (ADA) as “significant negative psychological reactions related to emotional burdens and worries specific to an individual’s experience in having to manage a severe, complicated and demanding chronic disease such as diabetes”.1 The organization recommends that providers should screen for this condition as well as depression, anxiety, disordered eating and cognitive capacities at initial visits, periodically and any time there is a significant change in life situation, disease or treatment.1 Psychological comorbidities and diabetes distress are common in this population and warrant attention from providers.2

Food insecurity, housing instability and financial barriers are already common in patients with diabetes, and these social determinants of health are moving in an unpredictable direction in the current global state of affairs.1,3-4 Understandably, these changes may be increasing challenges and stress for patients with diabetes.5 While mindfulness cannot directly correct any of these issues, it may be able to assist with dealing with the emotional/psychological stress created in their wake.

If mindfulness is a new term for you, one of the most applicable definitions that I have found is “the quality of being present and fully engaged with whatever we’re doing at the moment – free from distraction or judgment, and aware of our thoughts and feelings without getting caught up in them”.6 Typically breathing techniques and meditation exercises are used to pay attention in a nonjudgmental way to the present moment.8 There are many different types of mindfulness practices available and they can be done individually, in groups and across many settings.7-9 Training the mind in this way has many effects including metacognition, relaxation, cognitive flexibility and uncoupling of maladaptive cognitive patterns from painful physical sensations.9 The mechanism is thought to work at least in part through autonomic modulation and has evidence that physiologically it can impact the immune, nervous and endocrine systems.9 This practice has been investigated in many conditions including anxiety, depression, stress, cancer-related syndromes, fibromyalgia and other chronic pain, insomnia, psoriasis, irritable bowl syndrome, smoking cessation and many others.9

Two recent systematic reviews and meta-analyses evaluated mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) and their impact on a few different variables in patients with diabetes. MBCT is more tailored specifically to depression where MBSR is more broadly applicable.10 An example of a formal MBSR program from the Center for Mindfulness at UMass Memorial Medical Center can be found in the link in the respective reference below.10 The example is an eight week program, either in person or online, and includes many activities including guided instruction in mindfulness meditation practices, gentle stretching and mindful yoga, group dialogue and discussions aimed at enhancing awareness in everyday life and daily home assignments.10

Ni and colleagues investigated the effectiveness of diabetes-specific versions of these two types of interventions on depression, quality of life and HbA1c in this population. The review included nine studies from eleven articles of randomized controlled trials in patients with both type 1 and type 2 diabetes.7 This analysis demonstrated a significant effect favoring these interventions for reducing depression (standard mean difference -0.84, 95% CI -1.16 to -0.51; p < 0.001), improving the mental health composite score of quality of life (mean difference 7.06; 95% CI 5.09 to 9.03; p < 0.00001) and decreasing HbA1c (mean difference -0.28; 95% CI -0.47 to -0.09; p =0.004).7 Of these outcomes, significant heterogeneity was only reported for depression (I2 =72%; p = 0.0007).7 The authors caution that the limitations of their investigation include the small number of trials, a non-optimal quality of the included studies and some heterogeneity in design and interventions delivered between studies.7

The other investigation I wanted to briefly review by Guo and colleagues specifically focused on the factors that influence the effect of mindfulness-based interventions on diabetes distress. Ten articles including eight studies were included and subgroup analyses were performed to reveal the factors that impact the effect of this type of intervention.8 The specific interventions included in this analysis included MBSR, MBCT and added dialectical behavior therapy (DBT) as well as mindfulness-based self-compassion.8 The authors identified a statistically significant decrease in diabetes distress in those with elevated baseline diabetes distress (effect size -0.48, 95% CI -0.81 to -0.15, Z =2.82, p =0.005), when MBSR was the intervention (effect size -0.58, 95% CI -0.86 to -0.30, Z= 4.03, P<0.0001), when the intervention was delivered in a group format (effect size -0.36, 95% CI -0.68 to -0.04, Z =2.20, P= 0.03), when there was a home practice assignment (effect size -0.42, 95% CI -0.84 to -0.00, Z =1.95, p=0.05) and when the evaluation was completed at a six month follow up (effect size -0.56, 95% CI -0.94 to -0.18, Z =2.91, p = 0.004).8 The authors identify that their findings should only be suggestive based on limitations of population size and methodology.8

As pharmacists, we may not need to be experts in this discipline or ever even be asked to deliver this type of intervention; but being aware of it for patients, as one of the most accessible healthcare providers, is increasingly pertinent. While formal MBSR programs may potentially be time or cost prohibitive, there are many apps and resources available that offer low cost or free instruction to help individuals explore mindfulness. It should be noted that those with untreated psychosis or mania and active substance abuse may have a relative contraindication to this practice, and those with psychiatric disorders should consult with a mental health professional before they begin this type of training.9 In that same thread, as healthcare providers, we should be aware of when a patient needs a higher level of care, and mental health is no exception to that rule. The ADA provides guidance for practitioners that we should consider referral to a mental health specialist whenever self-care remains impaired after diabetes education for diabetes distress, there is a positive screen on a depression screening tool, there is presence of symptoms of disordered eating, intentional misuse of insulin or oral medications to achieve weight loss is identified, there is a positive screen for anxiety or fear of hypoglycemia, there is suspicion of a serious mental illness, there are repeated hospitalizations for DKA or a positive screen for cognitive impairment.1

In conclusion, the above investigations have demonstrated that there is likely a benefit for patients with diabetes related stress to consider mindfulness as a tool in their arsenal. In the absence of one of the contraindications, precautions or referral indicators listed above, the benefits that may be seen from recommending this practice likely outweigh the risk and may be considered a useful adjunctive therapy for our patients. Beyond that, I think all of us are dealing with challenges that could potentially be helped with this practice. I know that it has helped me tremendously. To avoid any perceived bias, I have opted not to list any particular app or product in the post itself, but I would encourage you to share any that you have found useful either for yourself or for your patients in the comments.

  1. American Diabetes Association. 5. Facilitating behavior change and well-being to improve health outcomes: Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020; 43(Suppl. 1):S48–S65.
  2. Young-Hyman D, de Groot M, Hill-Briggs F, Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: A position statement of the American Diabetes Association. Diabetes Care. 2016;39(12):2126-2140.
  3. Wolfson JA, Leung CW. Food insecurity and COVID-19: Disparities in early effects for US adults. Nutrients. 2020;12(6).
  4. Horsley S. May surprise: U.S. adds 2.5 million jobs as unemployment dips to 13.3%. NPR. June, 5, 2020. Accessed June 9, 2020. https://www.npr.org/sections/coronavirus-live-updates/2020/06/05/869821293/as-america-struggles-to-return-to-work-staggering-unemployment-numbers-loom .
  5. Peters A, Sherr J, Feldman H. Caring for your patients with diabetes who recently have been unemployed due to COVID-19. ADA COVID-19 Webinar Series. May 18, 2020. Accessed June 9, 2020. https://professional.diabetes.org/content-page/caring-your-patients-diabetes-who-recently-have-been-unemployed-due-covid-19.
  6. What is mindfulness? Accessed June 9th, 2020. https://www.headspace.com/mindfulness.
  7. Ni Y, Ma L, Li J. Effects of mindfulness-based stress reduction and mindfulness-based cognitive therapy in people with diabetes: A systematic review and meta-analysis. J Nurs Scholarsh. 2020; 0:0, 1-10.
  8. Guo J, Wang H, Luo J, et al. Factors influencing the effect of mindfulness-based interventions on diabetes distress: a meta-analysis. BMJ Open Diabetes Res Care. 2019;7(1):e000757.
  9. Mehta D. Meditation. In: Papadakis MA, McPhee SJ, Rabow MW. eds. Current Medical Diagnosis and Treatment 2020 New York, NY: McGraw-Hill; http://accessmedicine.mhmedical.com.ezproxy.ttuhsc.edu/content.aspx?bookid=2683&sectionid=223881732.  Accessed June 10, 2020.
  10. UMass Memorial Medical Center. MBSR 8 week in-person program. Accessed June 10, 2020. https://www.umassmemorialhealthcare.org/umass-memorial-medical-center/mbsr-8-week-person-program.

 

Insulin is not ‘Optional’ for People with Type 1 Diabetes!

We know that there is a genetic component to both type 1 and type 2 diabetes and most of these genetic mutations that cause diabetes are foremost inherited.1 In the most simple and basic thinking, these patients, through no fault of their own, will require specialized healthcare for their entire life, but as the system is set up now, the burden of this falls solely on the patients’ shoulders. End Stage Renal Disease (ESRD) and Amyotropic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease) are functionally the only 2 diseases recognized for disability eligibility and therefore Medicare coverage.2

Those with ESRD are generally eligible for Medicare coverage after 3 months of dialysis or after a kidney transplant and that coverage lasts for approximately 36 months after transplant to allow for that patient to rehabilitate and re-enter the workforce.2 Those diagnosed with ALS are immediately eligible for Medicare benefits once they are approved for disability benefits, understandably given the course trajectory of that particular disease.2 My real question is, why isn’t Type 1 Diabetes also a covered chronic disease eligible for disability benefits and then also Medicare benefits? And why do type 1 diabetes patients have to pay for their insulin, a medication that literally keeps them alive?

Since 2008, the Americans with Disabilities Act (ADA) ensures that employers treat type 1 diabetes employees fairly and equally to their other coworkers. So, diabetes does have a disability designation, but only in the sense that patients can secure this law’s protections. In other words, employers cannot discriminate against a patient with diabetes and should hire them if they are the most qualified applicant, should not limit their job responsibilities or promotions, and should not fire them for reasons that link back to the diabetes. Additionally, employers must accommodate the employees need for scheduled meal and snack breaks, and provide a private location where the patient can check their blood sugar and inject their insulin.3

There is a narrow provision that allows eligibility for Social Security disability (SSDI/SSD) benefits or Supplemental Security Income (SSI) benefits. However, to qualify for disability benefits, the damage caused by diabetes must severely limit what the patient can do, or the patient must have complications that fulfill the requirements of one of the SSD listings.3 And if the patients’ diabetes is uncontrolled because they don’t follow their doctor’s prescribed treatment, they would not be eligible for disability. And herein lies the paradox.

To further demonstrate this irony, the following is a listing that people with complications from diabetes that would allow for SSDI/SSD eligibility and SSI benefits.3

  • Poorly healing skin and bacterial infections (Listing 8.04)
  • Diabetic nephropathy (Listing 6.06)
  • Diabetic peripheral neuropathies (Listing 11.14)
  • Diabetic retinopathy (Listing 2.00)
  • Cardiovascular problems (Listings 4.02, 4.04, 4.05, 4.12)
  • Amputation of an extremity(Listing 1.05)

Because SSD listings require that these complications be fairly severe to meet the requirements for disability, Social Security finds that most people who apply for disability by reason of diabetes do not meet one of these listing above.3

To further demonstrate this inconsistency, let’s consider a college student with type 1 diabetes. In the academic setting, they are ENCOURAGED to register as having a disability so they have access to reasonable accommodations when needed. For example, the ability to have food/drink at an exam for a hypoglycemic episode or the ability to easily delay an exam if a hypo/hyperglycemic episode occurs close to exam time. Additionally, this puts the students on the radar of that college or universities health services in case of an on-campus emergency. However, once they graduate, we (as a collective society) do not think they should have this ‘disability designation’.

This is mostly a perception problem. While it’s true that people with type 1 diabetes need insulin to live, they are capable of controlling their disease just enough to stay under the radar. Insulin is expensive, there is no doubting that, but it’s not as expensive as immune-based therapies or other specialized medications.

I have been a pharmacist for nearly 19 years and a Certified Diabetes Educator (CDE) for nearly 6 years and I have often wondered why patients with type 1 diabetes are forced to endure financial hardships to obtain their lifesaving insulin. Analogous to a patient with ESRD, if they do not receive dialysis they will die; a patient with type 1 diabetes who does not receive their insulin, will also die. Insulin is just one piece of the puzzle, supplies and technology is another story entirely. I am sure you, like me, have countless patients who can not afford their insulin and insulin supplies. And their management and control, and then long-term outcomes are sacrificed. Political perspectives aside, healthcare needs a system whereby medications like insulin for type 1 diabetes, anti-epileptic medications for epilepsy and steroids for Addison’s disease etc. would be available for little or no cost!

For patients struggling with insulin costs, the link below is from August 2018 post entitled “Patient’s Dilemma…Picking Insulin Prescription from Pharmacy vs Purchasing School Supplies for Kids” where it lists a number of helpful resources for patients with no or little prescription coverage.

https://wordpress.com/read/blogs/102868129/posts/220

References:

1. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020. 2020;43(Supplement 1):S14-S31.

2. Center for Medicare Advocacy. Medicare for people under 65.  https://www.medicareadvocacy.org/under-65-project/. Accessed April 24, 2020.

3. Laurence, BK. Social Security Disability for Diabetes (Type I Or Type II). https://www.disabilitysecrets.com/social-security-disability-diabetes.html. Accessed April 24, 2020.

Food for Thought: Should Food Be Prescribed?

According to the Centers for Disease Controls (CDC) National Diabetes Statistics Report, 10.5% of Americans have been diagnosed or are thought to have undiagnosed diabetes in 2019.1 In 2018, 1.5 million children under the age of 18 years old were diagnosed with diabetes. In 2017, the CDC’s report on hyperlipidemia in the U.S revealed that 33% of Americans have hyperlipidemia.2 In 2018, 42.4 % of Americans were obese with 9.2% being severely obese.4 All of these conditions are risk factors for the number one leading cause of death in the United States, cardiovascular disease (CVD).4 One characteristic that all of these disease states have in common is their first line intervention for prevention or treatment using an overall healthy diet and physical activity.5,6,7  Edward, Vasanti, and Hu with Harvard’s Department of Nutrition, Epidemiology, and Medicine summarize the current research evaluating the associations between food and CVD prevention.8 They discuss the importance of a diet with caloric balance, high fruits and vegetables, more whole grains and less refined grains, adequate amounts of unsaturated fats (omega-3 fatty acids), high fiber foods, and little to no processed meats and added sugars. But while nutrition research has been a growing area in the past 10 years, there are many factors that influence our patients’ detrimental food choices. This includes their knowledge of what healthy food is, availability of fresh foods, social and cultural factors, time scarcity, marketing of foods, and cost. In the Food Labeling Survey completed by the International Food Information Council Foundation and the American Heart Association, the second major influence on purchasing a particular food product relied on the price, which had more of an influence on younger consumers and those with low income or on food assistance programs.9

While we identify as the medication experts, we also acknowledge that medications are not the only form of treatment. As healthcare providers treating diabetes, hyperlipidemia, and many other chronic conditions associated with poor nutrition, we have these conversations with our patients often. Many of our patients, particularly those who are underserved or low-income, have an incredibly hard time justifying eating healthier food or simply cannot afford it.  As pharmacists, we vowed to use our knowledge, experience, and skills to the best of our ability to assure optimal outcomes for our patients. But what if the tool to providing “optimal outcomes to our patients” isn’t even in our toolbox?

In 2010, the Wholesome Wave created Wholesome Rx, a fruit and vegetable prescription program. Primary care providers prescribe “prescriptions” or vouchers for $1 per person per day for each household to buy fresh fruits and vegetables from local markets or grocery stores. While Jason Martinez, a clinical pharmacist in Logan County Ohio, spoke of this program just recently in an ASHP article last year, many similar programs have been initiated and the results are coming forward.10

Bryce and Colleagues evaluated the impact of a 13-week Fresh Prescription program in 2015 on the A1c of low-income patients with uncontrolled diabetes. At the end of the study, they saw a statistically significant decrease in A1c of about 1% after the program was complete compared to before the program started.11 They did not, however, see any difference in weight or blood pressure.

In New York, Cavanagh and Colleagues evaluated the health outcomes of their Veggie Rx program, a fruit and vegetable prescription program focused towards those diagnosed with obesity, diabetes, or hypertension.12 Their program was a 13-week based program that could be renewed for another quarter if all coupons were redeemed. The coupons were utilized at “Veggie Mobile”, a traveling produce market. After the initial 13 week period, they found a statistically significant decrease in a BMI of 0.74kg/m2 compared to the control group who gained 0.35 kg/m2.

Jason Martinez PharmD explains that with their partnership with Wholesome Rx vouchers and the nutrition classes their patients attend, he has seen notable drops in A1c in his patients over only 3 months.

While Boards of Pharmacy across the country are fighting for the right to prescribe non-diagnostic medications or treatments based on point-of-care testing, shouldn’t we also be fighting for the right to ensure all of our patients have access to the number one “treatment” for preventing or slowing the progression of the preventable?

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: 2020. Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2020.
  2. America’s Health Rankings. Annual Report – 2019. https://assets.americashealthrankings.org/app/uploads/ahr_2019annualreport.pdf. Published December 2019. Accessed April 10, 2020.
  3. Kochanek KD, Murphy SL, Xu JQ, Arias E. Deaths: final data for 2017. 2019; 68(9).
  4. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity and severe obesity among adults: United States, 2017–2018. NCHS Data. 2020;288, 1-8. Accessed April 10, 2020.
  5. American Heart Association/American College of Cardiology. 2019 ACC/AHA Guideline on the primary prevention of cardiovascular disease. J Am Coll Cardiol. 2019; 74(10), 177-232. DOI: 10.1016/j.jacc.2019.03.010
  6. American College of Cardiology. 2018 Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2018; DOI: 10.1016/j.jacc.2018.11.003
  7. American Diabetes Association. Standards of medical care in diabetes – 2020. Diabetes Care. 2020; 43(1), S32-S36.
  8. Edward Y, Malik VS, Hu FB. Cardiovascular disease prevention by diet modification: JACC health promotion series. J Am Coll Cardiol. 2018; 72(8): 914–926. doi:10.1016/j.jacc.2018.02.085.
  9. International Food Information Council Foundation. Is label literacy a key to healthier food choices?. https://foodinsight.org/food-labeling/. Published on January 24, 2019. Accessed on April 10, 2020.
  10. American Society of Hospital Pharmacy. Ohio Health Center tests healthy food prescriptions. https://www.ashp.org/news/2019/06/19/ohio-health-center-tests-healthy-food-prescriptions. Published on June 20, 2019. Accessed on April 10, 2020.
  11. Bryce R, Guajardo C, Ilarraza D, et al. Participation in a farmers’ market fruit and vegetable prescription program at a federally qualified health center improves hemoglobin A1C in low income uncontrolled diabetics. Preventative Medicine Reports. 2017;176-179
  12. Cacanagh M, Jurkowski J, Bozlak, C Hastings J, and Klein A. Veggie Rx: an outcome evaluation of a healthy food incentive programme. Public Health Nutr. 2017; 20(14): 2636–2641. doi:10.1017/S1368980016002081

 

Initiate insulin in a patient newly diagnosed with type 2 diabetes and A1c more than 10%? – Almost never

The current American Diabetes Association guidelines state to consider early initiation of insulin in a patient with type 2 diabetes and an A1c greater than 10%. Although there are circumstances, such as signs and symptoms of catabolism, in which I have initiated insulin and metformin in patients with high A1cs upon diagnosis, with the current armamentarium of treatments available, I find initiating insulin this early generally unnecessary and potentially counterproductive.

Insulin has the disadvantages of weight gain and hypoglycemia. Although theoretically weight gain is avoidable with insulin use, I find that even my patients who are very careful with what they eat begin to gain weight after insulin initiation. Weight gain worsens insulin resistance which leads to insulin dose increases or additional medications. The clinic that I work in serves a low health literacy and indigent population. Food insecurity is often an issue and my patients often struggle with understanding how to balance carbohydrate intake despite education. Irregular carbohydrate intake leads to high hypoglycemia risk. The resultant hypoglycemia feels terrible and leads to non-adherence.

In contrast, there are many non-insulin medications available that are either weight neutral or weight reducing and don’t cause hypoglycemia. Sometimes, a patient with very high A1cs experiences signs and symptoms of hypoglycemia when their blood sugar is lowered at blood sugars higher than 70 mg/dl. Generally it takes a couple weeks before their body equilibrates to the lower overall blood sugars. I have found that as long as I counsel patients that this can occur and let them know that it takes a couple weeks, most patients are OK with this and will successfully ride out the temporary symptoms.

Additionally, if insulin is added before a patient’s diet is addressed, the additional calories ingested tend to worsen insulin related weight gain. Dietary adjustments can lower A1c up to 3%. One of my patients loved donuts. His A1c was 12%. I made a deal with him to decrease his donut intake to one per day. His A1c came down to 9%. Sometimes patients are not willing to make dietary adjustments unfortunately. I have a patient whose A1c was less than 6.5% on metformin and a GLP-1 receptor agonist, but now his A1cs are rising due to his inability to give up ice cream. Glycemic control can be achieved temporarily with medications, but without controlling diet, my experience has been that the number of medications needed to achieve control rapidly escalates. Another patient’s A1c increased after basal insulin was added to her regimen. She admitted that she thought once insulin was added she could eat whatever she wanted, but discovered that it wasn’t true. One of my patients struggles with limiting soda intake. He is an immigrant and where he grew up, soda was a luxury and unaffordable. In the U.S., soda is readily available, so he started drinking it instead of water. Now he feels deprived without it and has gained 30 pounds. I have tried to help him taper soda intake, try diet soda or switch to a less caloric caffeinated beverage like coffee or tea, but he is unable. Other patients simply did not know that some of their dietary habits were worsening their blood sugar. One of my patients described his wife lovingly making him a large glass of Tang, an orange drink, every day before and after work. Another was eating multiple tablespoons of honey with apple cider vinegar daily in an effort to lose weight. One patient, a truck driver, would keep a bag of grapes in the passenger seat of his truck, and would eat the grapes throughout the day as he was driving. In my experience, medication alone seldom results in glycemic control long-term. If a patient presents with an A1c of greater than 10%, assessing diet is essential for long-term success.

Lastly, there is exercise. I find that this is one of the most difficult lifestyle changes to get individuals to initiate and continue consistently. However, individuals who are able to increase activity levels even slightly, have objectively measureable benefits. One of my patients who suffers from pain related to bone spurs was advised to wear slippers when at home to prevent pain from walking barefoot on a hardwood floor. This simple change resulted in a decrease of his A1c from 6.5% to 6.2% because he was walking more even though his weight slightly increased. Another patient who works in the construction industry requires dose increases every winter and dose decreases every summer because his activity level changes when he is working. One of my physically active geriatric patients had an unusual increase in his A1c. After some discussion, I discovered that he wasn’t using his stationary bike, because their family Christmas tree goes up where his bike usually is and the tree had not been taken down yet.

Exercise can be challenging in patients on insulin therapy, particularly for patients with low health literacy. One of my patients was generally sedentary with high A1cs and irregular eating patterns. As her basal insulin dose was increased and her A1cs lowered, her blood sugar would drop dramatically once a month and she would experience sequential blood sugars in the 40s. After discussion, I discovered that these episodes occurred the evening and day after she cleaned her church.  We came up with a plan that included a lower basal insulin dose the evening before she was scheduled to clean. Another patient, also on basal insulin, would exercise intensely for 1.5 hrs for 3 days per week. She noticed that her blood sugars were dropping the next day, so she stopped taking her basal insulin on alternate days resulting in widely fluctuating blood sugars and an elevated A1c.  Hypoglycemia can also occur with exercise in patients on sulfonylureas, but is much less problematic in patients on the other non-insulin medications. Ultimately, exercise is beneficial beyond just blood sugar control. It improves mood, blood pressure, bone density, stability and cognition. We want patients to exercise, so anything that impedes exercise should be minimized as much as possible.

Insulin therapy is a valuable treatment that has its role in the treatment of type 2 diabetes, but it has several side effects that often lead to non-adherence or worsening insulin resistance.  For the vast majority of patients with newly diagnosed type 2 diabetes, even if their A1cs are greater than 10%, lifestyle modifications and non-insulin medications should be tried first to reach A1c goals.

References

1. American Diabetes Association. Standards of Medical Care in Diabetes—2020. Diabetes Care 2020 Jan;43(Suppl. 1). Available at https://care.diabetesjournals.org/content/43/Supplement_1

Updates to the American Diabetes Association’s (ADA) Living Standards of Medical Care (SOMC) in Diabetes: What’s New for 2020?

Keeping up with new and emerging literature in our field of work can be arduous – especially if governing/regulatory/advisory bodies don’t update their consensus statements or guidelines in a timely fashion.

Hunting through and analyzing clinical trials – while a necessary and important aspect of being a clinical pharmacist – could be a full-time job in and of itself!  I think I speak for MANY of us when I say that I am so, so grateful to the ADA for being prompt and thorough in updating their SOMC at least every year. It’s like an extra Christmas present in January that I look forward to and cannot wait to open!

Several key updates came out in 2019 that will influence pharmaceutical care in 2020 – for both children and adults. Here’s my take:

2020 ADA SOMC1 UpdateMy Take on Implications for Pharmacy Practice
New section added to address “Migrant and Seasonal Agricultural Workers”Be mindful of Social Determinants of Health (SDoH).2 Refer these patients to social work and community resources. Overarching concerns are lack of regular income and follow-up, language barriers, and unfamiliarity with communities.
If indicators of high risk* or established ASCVD, CKD, or HF exist, consider evidence-based SGLT-2i or GLP-1 RA independently of baseline A1c or individualized A1c goalRegardless of current glycemic control or goals, add the following – in the absence of contraindication, in the order of priority, for the condition that predominates:
–High risk*/established ASCVD:
1) GLP-1 RA: injectable liraglutide or semaglutide
2) SGLT-2i: empagliflozin, canagliflozin, dapagliflozin
–CKDα/HFβ:
1) SGLT-2i: empagliflozin, canagliflozin, dapagliflozin
2) GLP-1 RA: injectable liraglutide or semaglutide

Choice of agent within class likely 2/2 cost preferred by insurance and should include evaluation of baseline GFR for initiation of
SGLT-2i.
Oral semaglutide approved by FDA in September 2019Has not demonstrated same cardioprotective benefit as injectable semaglutide and is not typically preferred by insurances over injectable, cardioprotective GLP-1 RAs. May consider for those patients without ASCVD who would benefit from a GLP-1 RA for weight loss, glycemic control who can afford higher tier medication and/or have needle phobia.
Liraglutide approved by FDA in June 2019 for pediatric patients ≥ 10 yearsGiven the obesity epidemic, need to be more proactive in considering this option for pediatric patients who have not met glycemic targets with metformin and who have none of the contraindications to use for liraglutide.
Adoption of continuous glucose monitoring (CGM) metrics into clinical practiceFor patients with Type 1 or patients with Type 2 on complicated insulin regimens, use of the actionable, standardized reports with visual cues from CGM can be helpful to interpret data, such as time in range. Trends in reported data may be influential   treatment decisions.
E-cigarette use should receive cessation counseling in addition to tobacco-containing productsIt takes time to review all of the social history, but it is imperative to not only encourage cessation from cigarettes but from vaping products as well. Help patients understand that e-cigarettes are not a healthy bridge to smoking cessation but a health risk in and of themselves.

*High risk is defined as age ≥ 55 years with coronary, carotid, or lower extremity artery stenosis > 50%, or LVH
αSpecifically, eGFR 30-60 mL/min/1.73m2 or UACR > 3 mg/g, particularly UACR > 30 mg/g
βParticularly HFrEF (LVEF < 45%)

How will these changes influence your practice? What updates do you foresee coming down the road for 2021 and beyond?

Leave your thoughts in the comments below!

References

  1. American Diabetes Association. Standards of Medical Care in Diabetes—2020. Diabetes Care 2020 Jan;43(Suppl. 1). Available at https://care.diabetesjournals.org/content/43/Supplement_1
  2. Social Determinants of Health. Office of Disease Prevention and Health Promotion. Healthy People 2020 website https://www.healthypeople.gov/2020/topics-objectives/topic/social-determinants-of-health. Updated January 15, 2020. Accessed January 20, 2020.

R73.03: A Case for CMM

We commonly think of diabetes in terms of the ‘cutoff’ values of 126mg/dL of FPG and the 6.5% A1C as a diagnostic turning point.  We swing into action and follow guidelines to initiate lifestyle counseling, diabetes education, nutritional counseling and metformin therapy which are all justified by this new diagnosis.  But we all know that diabetes doesn’t flip a switch and become a problem at 126 mg/dL and have no consequence at say 125 mg/dL, or 115 mg/dL, etc.  Between the values of 100 and 126 mg/dL is an area of ‘increased risk’ of developing diabetes… the netherworld of ‘pre-diabetes’.  A1C categories for increased risk are from 5.7 to 6.4%. When a provider sees a patient during this time, he or she can use one of the Abnormal Glucose codes in the ‘R73.x family’ from ICD-CM-10. A code that is commonly used is that of prediabetes (R73.03). The most important part, however, is not which code to use but what you do NOW with the patient.  Indeed, what you do now, can influence when (or if) the patient goes on to develop frank diabetes according to the diagnostic parameters already mentioned. The results of the now famous Diabetes Prevention Program (DPP)were published over 15 years ago.(1) It was clear from that study that rigorous lifestyle modification could prevent the development of diabetes in people with impaired glucose tolerance 58% of the time, and in a separate arm of the study, metformin (850 mg twice daily) administration had a lower, but nonetheless significant reduction of 31% compared with placebo. A subsequent cost effectiveness study showed that the lifestyle and metformin interventions were cost effective. (2) A study in the American Journal of Preventive Medicine looked at the potential impact of lowering the HbA1c cutoff for prediabetes.  Assuming a conventional $50,000/QALY cost-effectiveness benchmark, the HbA1c cutoffs of 5.7% and higher were found to be cost effective vis-à-vis implementing measures known to be effective at reasonable cost. Lowering the cutoff from 5.7% to 5.6% also may be cost effective, however, if the ‘costs of preventive interventions were to be lowered.’(3) A published 10-year follow-up of the cost effectiveness of lifestyle or metformin interventions initiated in the DPP study concluded that “…from a payer perspective, lifestyle was cost effective and metformin was marginally cost-saving compared with placebo.(4) Influenced in part by these findings, the American Diabetes Association (ADA) has been recommending that “Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI ≥35 kg/m2, those aged <60 years, and women with prior gestational diabetes mellitus.”(5)  At 15 years follow-up of the participants in the original study, the average annual incidence of diabetes compared to placebo was 27% lower in patients originally randomized to lifestyle intervention and 18% lower in those randomized to metformin.(6) No significant safety issues related to metformin have been detected with long-term use, although decreases in hemoglobin and hematocrit have occurred during the first year of treatment.  Vitamin B12 deficiency has been reported and lactic acidosis may occur rarely in patients with severe renal impairment or hepatic failure. (7)

A national sample of 17 352 working-age adults with prediabetes insured for 3 continuous years between 2010 and 2012 assessed the percentage of health plan enrollees with prediabetes who were prescribed metformin. Only 3.7% of patients with prediabetes were prescribed metformin over the 3-year study window. After adjustment for age, income, and education, the predicted probability of metformin prescription was almost 2 times higher among women and obese patients and more than 1.5 times higher among patients with 2 or more comorbid conditions…but still totaling only 3.7%. (8) A separate retrospective study of 7102 low income patients enrolled in Medicaid during roughly the same time period as the Moin study found only 7.4% were prescribed metformin for prediabetes. Less than half of the patients prescribed metformin began treatment within 30 days after diagnosis of prediabetes, and 25% of those prescribed metformin took 280 days or longer to initiate treatment after diagnosis of prediabetes.(9) In a smaller retrospective study, only13 patients out of 160 prediabetes patients in the study population were prescribed metformin for an overall metformin initiation rate of 8.1 percent. The metformin initiation rate for the three individual groups; history of GDM, aged less than 60 years, and BMI greater than 35 kg/m2 were 0 percent, 9.0 percent, and 17.5 percent respectively. (10)

Our understanding of the glucoregulatory mechanisms associated with metformin therapy has increased over the years. (11) Our appreciation of the value of metformin in prediabetes and diabetes has increased over time. Our understanding of the subgroups of patients with prediabetes that are most likely to benefit, and the role of adherence to the benefit derived from metformin therapy have both increased as well. (13, 14) Importantly, our discussion of the pharmacist role in Comprehensive Medication Management has developed over time, helping to define how pharmacists can help to “Get the Medications Right.” However, the record for prescription and use of metformin for prediabetes has been abysmal. Let’s all work on getting this medication right for people with prediabetes!

References

1) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393–403.

2) Costs associated with the primary Prevention of Type 2 Diabetes Mellitus in the Diabetes Prevention Program. The Diabetes Prevention Program Research Group. Diabetes Care. 2003;26: 36–47.

3) Alternative HbA1c cutoffs to identify high-risk adults for diabetes prevention: A cost-effectiveness perspective. Zhuo X, et al. Amer J  Preventive Med 2012;42:374-381

4) The 10-Year Cost-Effectiveness of Lifestyle Intervention or Metformin for Diabetes Prevention: An intent-to-treat analysis of the DPP/DPPOS. The Diabetes Prevention Program Research Group. Diabetes Care 2012; 35: 723-730

5) Standards of Medical Care in Diabetes [Section 3.Prevention or Delay of Type 2 Diabetes]. American Diabetes Association. Diabetes Care 2019;42(Suppl 1):S29-S33

6) Long-term effects of lifestyle intervention or metformin in diabetes development and microvascular complications over 15-year follow-up of Diabetes Prevention Program Outcomes Study. Diabetes Prevention Program Research Group. Lancet Diab Endocrinol 2015;3:866-875

7) Metformin for Prediabetes. Medical Letter on Drugs and Therapeutics. JAMA 2019;317:1171-1172

8) Metformin. Metformin Prescription for insured adults with prediabetes from 2010-2012: A retrospective cohort study. Moin T,, Li J, and Duru OK., Ann Intern Med 2015;162:542

9) Metformin prescribing in low-income and insured patients with prediabetes. Wu, J. et al. J Amer Pharm Assoc 2017;57:483-487

10) Prescribing Patterns of Metformin in High-risk Patients with Prediabetes. Stirling DL, et al. J La State Med Soc. 2015;167:257-62

11) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Foretz M, Guigas B, Viollet B. Nat Rev Endocrinol. 2019;1:569-589

12) Long-term effects of metformin on diabetes prevention: identification of subgroups that benefited most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Prevention Program Research Group. Diabetes Care 2019;42:601–608

13) Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study Perreault, L, et al. for the Diabetes Prevention Program Research Group. Lancet 2012; 379: 2243–51

14) https://www.accp.com/docs/positions/misc/CMM%20Brief.pdf. Accessed 12/21/19

SGLT-2 inhibitors – The New Kids on the Block for Management of Diabetic Nephropathy?

By: Lina Le, Pharm.D. Candidate 2020 – University of North Texas System College of Pharmacy

As we know, uncontrolled diabetes mellitus can lead to nephropathy and have the risk of progressing to end-stage renal disease (ESRD).1 Approximately 40% of patients with diabetes will develop kidney disease in their lifetime.1 Sodium-glucose cotransporter (SGLT)-2 inhibitors, empagliflozin (Jardiance®) and canagliflozin (Invokana®), have gained recent attention with emerging evidence of their renoprotective benefits. In light of the new evidence from the EMPA-REG and CANVAS trials, the American Diabetes Association (ADA) now suggests the use of SGLT-2 inhibitors as an add-on agent in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).2 Additionally, the CREDENCE trial, which analyzed the effects of canagliflozin on outcomes of ESRD, doubling of the serum creatinine (SCr) level, or death from renal in patients with T2DM and albuminuric CKD, resulted this past April with additional evidence for renal benefits.3

Historically, the ADA and Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with diabetes and nephropathy for blood pressure control and kidney disease progression prevention.2,4 ACE inhibitors and ARBs cause efferent glomerular arteriole vasodilation, which in turn decreases intraglomerular pressure and albuminuria.4 Studies have supported these recommendations and have shown that ACE inhibitors and ARBs significantly reduce proteinuria, SCr, and renal-related deaths.5,6

So how does the mechanism of SGLT-2 inhibitors compare to ACE inhibitors and ARBs for use in renoprotection? In terms of glycemic control, we know that SGLT-2 inhibitors increase urine glucose excretion to regulate blood glucose by blocking SGLT receptors in the proximal renal tubules to facilitate a reduction in glucose reabsorption.7 The proposed mechanism behind SGLT-2 inhibitors and their effects on renal function is related to decreased glomerular hyperfiltration.7 Glomerular hyperfiltration is a hallmark indication of early renal damage, defined as eGFR greater or equal to 135 mL/min/1.73m2.7 Hyperfiltration occurs due to excessive blood glucose, leading to increased glucose and sodium chloride (NaCl) renal reabsorption.7 This causes decreased NaCl delivery to the macula densa of the distal tubule, causing renal vasodilatory response to increase NaCl delivery to the distal tubules and maintain hemodynamic stability.7 Renal vasodilation results in hyperfiltration, increased glomerular pressure, and kidney injury.7 SGLT-2 inhibitors decrease glucose reabsorption to restore NaCl delivery to the distal tubules and hemostasis to the kidneys.7 Decreased hyperfiltration and pressure within the glomerulus may serve to decrease albuminuria and slow the progression of kidney disease.7  With that being said, do the results from the clinical trials of empagliflozin and canagliflozin reflect this hypothesis?

The EMPA-REG trial conducted a post-hoc analysis for renal outcomes in patients with diabetes, existing cardiovascular disease (CVD), and eGFR of >30 mL/min/1.73m2.8 Wanner and colleagues found that empagliflozin significantly reduced the incidences of worsening nephropathy, progression to macroalbuminuria (> 300 mg of albumin per gram of creatinine), doubling of SCr level accompanied by eGFR < 45 mL/min/1.73m2, and initiation of renal replacement therapy (RRT) in comparison to placebo (Table 1).8  In addition, the CANVAS trial saw significant reductions in the progression to albuminuria and increased regression of albuminuria with use of canagliflozin versus placebo (Table 2).10

The CREDENCE trial observed the effects of canagliflozin on end stage renal outcomes in patients with diabetes and existing albuminuric CKD, including participants with eGFR of 30 to 89 mL/min/1.73m2.3 When compared to EMPA-REG and CANVAS, participants in CREDENCE were also required to be on standard therapy of an ACE inhibitor or ARB.3 Primary outcome measures were a composite of kidney transplantation, eGFR < 15 mL/min/1.73m2 for 30 days, dialysis for 30 days or more, doubling of SCr levels from baseline for 30 days, and death from cardiovascular or renal disease (Table 3).3 In the canagliflozin group, there was 4% absolute risk reduction for the primary composite.3

Despite recent evidence, manufacturer labeling endorses the initiation or continuation of empagliflozin and canagliflozin in patients with T2DM and an eGFR >45 mL/min/1.73m.9,11 However, the results with respect to renal outcomes have influenced the ADA to comment on the use of empagliflozin and canagliflozin to an eGFR of >30 mL/min/1.73m2, especially favored in patients with macroalbuminuria.2

SGLT-2 inhibitors have come a long way since canagliflozin first came onto the market in 2013 with indications for treatment of T2DM.11 Jardiance® and Invokana® have gained FDA approved indications for risk reduction of major cardiovascular events in patients with T2DM.9,11 So, what does the future hold for SGLT-2 inhibitors? One pending study, estimated to complete in December 2019, hypothesizes that dapagliflozin (Farxiga®) reduces proteinuria in patients without diabetes (Clinicaltrials.gov Identifier: NCT03190694). Will the use of the SGLT-2 inhibitor drug class expand beyond glycemic control of T2DM and will the FDA approve indications for use in diabetic nephropathy next?

 

Table 1
EMPA-REG OUTCOME8
Empagliflozin 10 mg, 25 mg, versus placebo
Renal outcomes Empagliflozin Placebo Hazard Ratio

(95% CI)

P Value
Incidence of worsening nephropathy 525/4124 388/2061 0.61 (0.53-0.70) <0.001
Progression to macroalbuminuria 459/4091 330/2033 0.62 (0.54-0.72) <0.001
Doubling of SCr level accompanied by eGFR <45 mL/min/1.73m2 70/4645 60/2323 0.56 (0.39-0.79) <0.001
Initiation of Renal Replacement Therapy 13/4687 14/2333 0.45 (0.21-0.97) 0.04

 

Table 2
CANVAS Program10
Canagliflozin 100 mg versus placebo
Renal Outcomes Canagliflozin (per 1000 patient-years) Placebo  (per 1000 patient-years) Hazard Ratio

(95% CI)

P Value
Regression of albuminuria 293.4 187.5 1.70 (1.51-1.91) 0.4587
Progression of albuminuria 89.4 128.7 0.73 (0.67-0.79) 0.0184

 

Table 3
CREDENCE3
Canagliflozin 100 mg versus placebo
Renal Outcomes Canagliflozin Placebo Hazard Ratio

(95% CI)

P value
Primary composite* 245/2202 340/2199 0.70 (0.59-0.82) 0.00001
Doubling of SCr level 118/2202 188/2199 0.60 (0.48-0.76) <0.001
End-stage kidney disease 116/2202 165/2199 0.69 (0.54-0.86) 0.002
eGFR <15 mL/min/1.73m2 78/2202 125/2199 0.60 (0.45-0.80) N/A
Initiation of dialysis or kidney transplantation 76/2202 100/2199 0.74 (0.55-1.00) N/A
Renal death 2/2202 5/2199 N/A N/A

*Primary composite outcomes: end-stage renal disease (ESRD), doubling of the serum creatinine level, or death from renal or cardiovascular causes

 

References:

  1. de Boer IH. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011;305(24):2532.
  2. Microvascular complications and foot care: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2018;42(Supplement 1):S124-S138.
  3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Eng J Med. 2019;380(24):2295-2306.
  4. Chapter 2: Lifestyle and pharmacological treatments for lowering blood pressure in CKD ND patients. Kidney Int Suppl. 2012;2(5):347-356.
  5. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Eng J Med. 2001;345(12):861-869.
  6. Lioudaki E, Whyte M, Androulakis E, Stylianou K, Daphnis E, Ganotakis E. Renal effects of SGLT-2 inhibitors and other anti-diabetic drugs: clinical relevance and potential risks. Clin Pharmacol Thera. 2017;102(3):470-480.
  7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme Inhibition on diabetic nephropathy. N Eng J Med. 1993;329(20):1456-1462.
  8. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–597.
  9. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Eng J Med. 2016;375(4):323-334.
  10. Jardiance (empagliflozin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; October 2018.
  11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Eng J Med. 2017;377(7):644-657.
  12. Invokana (canagliflozin) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals; October 2018.

Mentored by: Megan Wesling, Pharm.D., BCPS

The InPen: A Smart Insulin Pen Review

Rachel Long, PharmD, BCPS, CPP

As practitioners our goal is to help patients on insulin improve their blood glucose control and minimize risks, one of the most important being hypoglycemia. Too often providers are limited in their treatment recommendations or prescribing efforts due to lack of information. This often leads to clinical  inertia and can be very frustrating for providers. I was discussing a patient case with my colleague and he suggested researching the InPen Smart Pen by Companion Medical. The device was approved by the FDA in December 2017 for patients age 12 and older.(1) As I learned more about the device, I thought to myself “Why have I not heard of this or seen any patients using this device?” If this is the case for me, I figure maybe there are other practitioners who also have not looked into the device and may have patients who would benefit from this technology. Let’s start with reviewing the device itself and its technology. 

InPen Smart Pen Injector

The pen is available in 3 different colors (blue, pink, and gray) and is compatible with Lilly Humalog ® and Novo Nordisk Novolog ® U-100 3 mL pen-fill cartridges. The device dispenses insulin in 0.5 unit increments with a dose range of 0.5 units to 30 units of insulin in a single injection. Each pen remains charged for 1 year and does not require recharging by the patient. At the end of the year, patients will need to replace their pen if they wish to continue having full functionality.(2) If patients choose not to purchase a new pen at the end of the year, they can continue to use the pen and manually enter their blood glucose and calculate the prescribed dose using the InPen app. 

InPen Mobile Application Functionality

The Bluetooth technology which enables the pen injector to interface with Apple and Android smart phones is what makes this device stand out from other diabetes applications (app) and an advancement in diabetes care. Like insulin pumps, patient specific parameters are programmed into the InPen app. These parameters are prescribed by the provider and include insulin sensitivity factor, insulin-to-carbohydrate ratio, duration of insulin action, and target glucose range. The device tracks the amount and timing of each insulin dose administered. Patients check their blood glucose and enter the value and amount of carbohydrates they plan to consume into the app. The dose calculator will then provide a recommended dose based on the patient specific parameters. It can also recommend how many carbohydrates a patient should consume in order to prevent hypoglycemia based on the amount of insulin on board. The app is compatible with certain Bluetooth enabled glucometers and continuous glucose monitors (CGMs), such as OneTouch Verio, AccuCheck, and Dexcom (through Apple Health). The product website lists compatible devices under the FAQ tab. All of the data is saved in the app and can be exported into a custom report, Insights by InPen. Patients can send a PDF of their report to a provider via email or print out for their next patient appointment. Last month, Companion Medical announced they will be partnering with Glooko to share data from the InPen to the GlooKo® Mobile app and Glooko® Enterprise diabetes data management system for healthcare professionals.(3) Earlier this year, Tidepool posted on their blog that InPen is not a supported device through Apple Health and insulin doses can be uploaded along with data from other devices.(4) Adherence with medications is such an important factor in disease state control and the makers of this device took that into consideration as well. Patients  set a standard mealtime (2-hour window) for each meal of the day. If the device has not recorded an administration in that time period, it will remind the patient to ensure they do not forget. There is also an alarm patients can set to remind them to administer their basal insulin or check their blood glucose 2 hours after administering insulin. There are other features of the device, such as temperature monitoring and alerting patients when their insulin cartridge is expired.(2) Anyone can download the InPen Mobile app to their phone; however, you cannot utilize the app until it is paired with the pen injector. 

Coverage and Cost

The technology sounds promising and will provide practitioners with more data to make educated and informed treatment decisions. So what are the logistics of obtaining the device for your patient? Companion Medical has made it fairly seamless for patients. Patients can go to the InPen website and click “Get InPen”. By completing the form with basic information and a photocopy of the front and back of their insurance card, Companion Medical will perform a benefits investigation and determine if the device is covered and at what cost. The company will then reach out to the patient, provide the cost information, and assess interest in obtaining the device. If the patient would like to proceed, Companion Medical will contact the provider’s office to request a prescription for the device. Note, patients need a separate prescription for the insulin cartridges. Providers can also access an order form from the manufacturer’s website and submit on the patient’s behalf. Approximately 50% of insurance companies currently cover the device. Co-pays were previously quoted to range from $0-$120.(5) The cost without insurance was previously listed as $549 and the company works with patients without insurance to make it affordable if possible.(6)  

Some may ask why this device and technology is so important or ground breaking. Research has shown the lack of accurate documentation of insulin therapy is a barrier to achieving glycemic goals and improved patient outcomes.(7) Smart pen injectors can address two major barriers to optimal use of insulin: poor adherence or inadequate insulin titration. One study found insulin was omitted or administered late on average at 1 out of 4 meals throughout the day.(8) The reports created with this technology can provide that information to clinicians and enable them to have the full information when making treatment decisions. The report includes information such as 7-, 30-, and 90- day average blood glucose, recorded high and low blood glucose levels, average carbohydrate intake and percentage of dose overrides.(2) This technology may also be particularly useful in certain scenarios such as patients with recurrent hypoglycemia or hypoglycemia unawareness or often under or over treat resulting in large glucose variability.(7) Patients may also have difficulty calculating the correct dose due to lack of numeracy skills. The dose calculator can help patients ensure they are administering the correct dose. This technology provides access to advanced technology to patients on MDI insulin who have shied away or been unable to obtain an insulin pump in the past for whatever reason.  

There are still limitations to the technology that make it unsuitable for some patients. Patients must be able to count carbohydrates and check their blood glucose frequently in order to accurately calculate recommended insulin doses. Patients who do not have access to a smartphone will not be able to utilize the technology with this device. However, based on data from 2018, over 81% of Americans own a smart phone with the breakdown by age as follows: 92% of millennials (23-37yrs), 85% of GenXers (38-53yrs), 67% of baby boomers (54-72yrs), and 30% of silent generation (73-90yrs) own smartphones.(9) As always, technology is slow to be adopted and there will likely be providers and patients who are skeptical.

Overall, I was very impressed with the information I found on the InPen and its technology and will likely educate patients on the available technology as well. I hope future research or studies are published with real world patient outcomes with the use of the Smart Pen. I am very interested to hear feedback from you all about your experience as a prescribe or patients’ opinions on the device.

  1. Companion medical announces U.S. commercial launch of smart insulin pen system; December 14, 2017. Available at: https://www.prnewswire.com/news-releases/companion-medical-announces-us-commercial-launch-of-smart-insulin-pen-system-300571413.html. Accessed July 17, 2019.
  2. Companion Medical, Inc. InPen. Available from http://www.companionmedical.com/inpen. Accessed 20 July 2019.
  3. Companion Medical and Glooko Announce Partnership Agreement to Integrate Insulin Data for Multiple Daily Injections; June 5, 2019. Available at: https://www.prnewswire.com/news-releases/companion-medical-and-glooko-announce-partnership-agreement-to-integrate-insulin-data-for-multiple-daily-injections-300862293.html?tc=eml_cleartime. Accessed July 30, 2019.
  4. One step closer to an integrated diabetes management ecosystem – a guest post from Companion Medical. Tidepool. Available at: https://www.tidepool.org/blog/companion-medical-guest-post-inpen-integrated-diabetes-management. Accessed July 31, 2019.
  5. Juicebox Podcast. Episode 174: InPen Is Like Other Pens, But Smarter. 11 July 2018. http://www.ardensday.com/episodes/jbp174?rq=174. Accessed July 17, 2019.
  6. Kerr D, Warshaw H, and Choi N. Smart insulin pens will addresse critical unmet needs for people with diabetes using insulin. Endocrine today. 2019, May. 
  7. Klonoff DC, Kerr D. Smart pens will improve insulin therapy. J Diabetes Sci Technol. 2018;12(3):551-553. Norlander LM, et al. Late and Missed Meal Boluses with Multiple Daily Insulin Injections. Diabetes. 2018;67 (Supplement 1) 992-P.
  8. Norlander LM, et al. Late and Missed Meal Boluses with Multiple Daily Insulin Injections. Diabetes. 2018;67 (Supplement 1) 992-P.
  9. Pew Research Center. Internet and Technology, Mobile Fact Sheet. https://www.pewinternet.org/fact-sheet/mobile/ (Accessed July20, 2019)

A New Item on the Menu for Oral Options for Treatment of Type 2 Diabetes?

Christie Baker, Pharm.D. Candidate

Zoe Lowery, Pharm.D. Candidate

Brian Terrell, Pharm.D., BCACP

Currently the American Diabetes Association (ADA) guidelines recommend adding a GLP-1 (glucagon-like peptide 1) receptor agonist fairly early to treatment; these medications are especially beneficial in patients with established atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD).1 GLP-1 receptor agonists are also a preferred injectable over insulin when oral therapy is subtherapeutic due to its lower incidence of hypoglycemia and weight loss benefit.1 However one of the main barriers to using this class of medication is that they are currently only available as injectable medications, dosed either once weekly or one-two times daily.1 Fortunately, there is an oral formulation of semaglutide under investigation. In this post we will discuss some of the evidence that has been published regarding this new dosage form.

First, you may be asking yourself, how are they giving a peptide orally? Well, reader, that is a very good question. They are using (the aptly named) sodium N-[8(2-hydroxylbenzoyl) amino] caprylate (SNAC) to protect semaglutide from proteolytic degradation and provide adequate absorption.2, 3 There have been several trials that have assessed the efficacy and safety of this agent.4-8 We will review several of the published articles in the table below and spend a little extra time on the cardiovascular outcome trial (PIONEER 6).

Semaglutide table.png

All of the above trials also assessed adverse effects of this medication and found it to be comparable to injectable GLP-1 receptor agonist side effects.

The effect on cardiovascular outcomes is of particular interest with all new diabetes medications. Oral semaglutide recently had these outcomes published in the results of the PIONEER 6 study.9 The injectable formulation of semaglutide has previously shown cardiovascular benefit.10 In the trial of the oral formulation, 3183 patients were randomized to either oral semaglutide titrated to 14 mg or placebo for an average of 16 months.9 The assessed population was purposefully at elevated cardiovascular risk, defined as >50 years old with established ASCVD or CKD, or >60 years old and had ASCVD risk factors.9 The primary outcome investigated was a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke.9 The average patient in the trial was a 66 year old obese male with a duration of diabetes greater than 10 years, a baseline HbA1c of 8.2% and established ASCVD or CKD.9 Most patients were taking metformin or insulin, antihypertensive, lipid lowering and antiplatelet/antithrombotic medications.9 The primary outcome occurred in 3.8% of the semaglutide group and in 4.8% of the placebo group (HR 0.79; 95% CI 0.57 to 1.11) and the authors claimed noninferiority to placebo.9  Individual components of the primary outcome resulted as follows: death from CV causes [0.9 % vs 1.9% (Hazard Ratio (HR) 0.49; 95% CI 0.27 to 0.92)], nonfatal MI [2.3% vs 1.9% (HR 1.18; 95% CI 0.73 to 1.90)], and nonfatal stroke [0.8% vs 1.0% (HR 0.74; 95% CI 0.35 to 1.57)].9 Other endpoints of note were death from any cause [1.4% vs 2.8% (HR 0.51; 95% CI 0.31 to 0.84)], unstable angina [0.7% vs 0.4% (HR 1.56; 95% CI 0.60 to 4.01)] and heart failure hospitalizations [1.3% vs 1.5% (HR 0.86; 95% CI 0.48 to 1.55)].9 HbA1c decreased more in the oral semaglutide group (-1.0% vs -0.3%) as did weight (-4.2 kg vs -0.8 kg).9 The authors also reported that no unexpected adverse events were noted in the trial, and the majority of those seen with oral semaglutide were of gastrointestinal origin ( nausea > vomiting > diarrhea).9

In conclusion, this is an exciting new development for the treatment of type 2 diabetes. The ability to prescribe a GLP-1 receptor agonist in patients who previously would have shied away from an injectable will allow many more people to reap the benefits seen with this class of medication. It is interesting that investigators did not see the same cardiovascular benefit between two different formulations of the same chemical entity. However, the SUSTAIN-6 study was of a longer duration and had more events than this trial which may lend to some explanation of the differences.10 There are other PIONEER (Peptide Innovation for Early Diabetes Treatment) trials that have preliminary results available on the manufacturer’s website if the reader is interested.11

References:

  1. American Diabetes Association. Standards of Medical Care in Diabetes- 2019. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2019; 42(Suppl 1):S90-S102.
  2. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017; 318(15):1460-1470; doi: 10.1001/jama.2017.14752.
  3. Hess S, Rotshild V, Hoffman A. Investigation of the enhancing mechanism of sodium N-[8-(2-hydroxybenzoyl) amino] caprylate effect on the intestinal permeability of polar molecules utilizing a voltage clamp method. Eur J Pharm Sci. 2005; 25(2-3):307-12. doi: 10.1016/j.ejps.2005.03.003.
  4. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes. Diabetes Care. 2019; Jun 11. doi: 2337/dc19-0749.
  5. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: The PIONEER 3 randomized clinical trial. JAMA. 2019; 321(15):1466-1480. doi:10.1001/jama.2019.2942.
  6. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019 Jun 7; doi: 1016/S0140-6736(19)31271-1.
  7. Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomized, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jun 6; doi: 1016/S2213-8587(19)30192-5.
  8. Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicenter, open-label, randomized, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jun 6; doi: 1016/S2213-8587(19)30194-9.
  9. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Jun 11; doi: 1056/NEJMoa1901118.
  10. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375:1834-1844.
  11. Novo-Nordisk. Oral semaglutide showed superior reductions in blood sugar vs Jardiance® and non-inferior blood sugar reductions vs Victoza® in adults with type 2 diabetes at 26 weeks. Accessed 6/16/19. Available at: https://www.novonordisk-us.com/media/news-releases.html?122965.

 

Continuous Glucose Monitoring – An Opportunity for an Expansion of Pharmacist Services

Many of us in the Endocrine PRN are heavily invested in the care of patients with diabetes mellitus.  Due to this we are constantly seeking out opportunities that will improve the care we are able to provide to patients.  Continuous Glucose Monitoring (CGM) is that new frontier for me.  A number of my patients are on complex insulin regimens that can require frequent Self-Monitoring of Blood Glucose (SMBG).  At times it is difficult for my patients to provide me with sufficient SMBG values to make the best decision for their care.  This can be due to many factors including cost, the demanding nature of frequent SMBG, and health-literacy concerns.  This is why I have decided to pursue utilizing office-based CGM for my practice. 

           There are two main types of CGMs on the market: real-time CGM, such as Dexcom, and intermittently scanned CGM, such as Freestyle Libre.  Both types of CGMs have their use supported by the ADA and the AACE, though outcome data is more prevalent for real-time CGMs.  [1,2] For my practice we have sought to use the Freestyle Libre Professional version.  The Libre Pro only provides retrospective data to clinicians, unlike the Dexcom G4 Pro which can provide both real-time and retrospective data.  However, the Libre provides substantial cost savings starting at just $65 for the reader, and $240 for a box of 4 sensors. 

Providing this service is reimbursable by both Medicare and private insurances, and at a rate that is significantly higher than billing a 99211 E/M code, for which many outpatient pharmacists are restricted to. 

[3],
https://provider.dexcom.com/file/cpt-code-chart-2018png.

While intermittently scanned CGM does not have as much data supporting its use as real-time CGM, there is still data showing improved patient outcomes as compared to standard care.  CGMs have the opportunity, likely within the near future, to replace standard SMBG for Type 2 patients who are at high risk from hypoglycemia due to complicated insulin regimens. [4,5,6]  The primacy concern for their use, just as with many diabetes therapies, will be cost.  Hopefully, as demand increases for these systems costs will come down allowing for their regular use. Will you consider using a CGM in your practice? Or are you already doing so?  If so consider commenting below an mention some best practices that you may have, or what you would like to know!

  1. Alan J. Garber, Martin J. Abrahamson, Joshua I. Barzilay, Lawrence Blonde, Zachary T. Bloomgarden, Michael A. Bush, Samuel Dagogo-Jack, Ralph A. DeFronzo, Daniel Einhorn, Vivian A. Fonseca, Jeffrey R. Garber, W. Timothy Garvey, George Grunberger, Yehuda Handelsman, Irl B. Hirsch, Paul S. Jellinger, Janet B. McGill, Jeffrey I. Mechanick, Paul D. Rosenblit, and Guillermo E. Umpierrez (2019) CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM – 2019 EXECUTIVE SUMMARY. Endocrine Practice: January 2019, Vol. 25, No. 1, pp. 69-100.
  2. American Diabetes Association. 7. Diabetes technology: Standards of Medical Care in Diabetesd2019. Diabetes Care 2019;42 (Suppl. 1):S71–S80
  3. https://provider.dexcom.com/file/cpt-code-chart-2018png. Accessed 4/12/19
  4. Norwegian Institute of Public Health. FreeStyle Libre flash glucose self-monitoring system: a single-technology assessment [Internet], 2017. Available from http://www.fhi.no/en/publ/ 2017/freestyle-libre-systemet-for-egenmaling-avblodsukker-en-hurtigmetodevurder/. Accessed 22 October 2018
  5. Palylyk-Colwell E, Ford C. Flash glucose monitoring system for diabetes. In CADTH Issues in Emerging Health Technologies. Ottawa, ON, Canadian Agency for Drugs and Technologies in Health, 2016 [Internet]. Available from http:// http://www.ncbi.nlm.nih.gov/books/NBK476439/. Accessed 22 October 2018
  6. Leelarathna L, Wilmot EG. Flash forward: a review of flash glucose monitoring. Diabet Med 2018;35:472–482