Old Drugs, Older Bugs…and COVID?

  When we try to pick out anything by itself, we find it hitched to everything else in the universe!     – John Muir

Sars-Cov-2 has literally taken the world by storm with hundreds of thousands of deaths, numerous complications of COVID-19 still ongoing, and now renewed interest in the ‘vaccines’ used to prevent or mute this disease that may be less effective than we originally thought.  We are now learning about significant complications not only of the disease itself, but of the use of experimental ‘vaccines’ based on mRNA to viral spike protein. As the pandemic declines, the virus remains persistent will likely become more of an endemic condition. Meanwhile, we have learned much about SARS-COV-2 virus. Most viruses have a receptor or receptors that allow them to connect with and penetrate human cells. Li and others first described a receptor that allows binding, and the spike protein receptor binding domain that allows attachment to ACE2.[1] ACE2 was initially identified in 2000 as a homolog of the ACE receptor. Since the beginning of the COVID-19 pandemic, hypertension and diabetes have been correlated with higher risk of mortality. Initial reports speculated that angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), which are commonly used therapeutic agents, would up-regulate ACE2 expression, thus increasing the risk of severe illness. Recent evidence has challenged this hypothesis, demonstrating both mechanistically and in large cohort studies that ACEi and ARBs do not up-regulate ACE2 and are not associated with an increased mortality.  Studies on ACE2 up-regulation have shown that patient sex, various diseases and a number of drugs have often given confusing and even contradictory results. [2],[3]

Recently, the bile acid receptor farnesoid X receptor (FXR) has been shown to be a strong up-regulator of ACE2 expression by binding directly to the ACE2 promoter.[4] The FXR nuclear receptor family of transcriptional regulators has been shown to be upregulated or downregulated by various conditions, and is known to play a critical role in the regulation of bile acid synthesis, lipoprotein metabolism, glucose metabolism, and protection of the liver from toxins to mention to mention just a few of its actions. FXR activity is affected by the balance of unconjugated bile salts and those that are conjugated. One factor that has been shown to up-regulate FXR has been the presence of microbial bile salt hydrolases that break down various bile salt conjugates that suppress FXR activity.[4]  Ursodeoxycholate (UDC; Ursodiol) is one of those conjugated bile salts. It was approved for the treatment of gallstones in 1987, and has been a mainstay of the treatment of primary biliary cholangitis and cirrhosis. UDC reduces FXR stimulation of ACE2 by reducing the presence of FXR on the ACE2 promoter.  Bacterial bile salt hydrolases break down these inhibitory conjugated bile salts thus reducing their inhibitory effect on the FXR/ACE2 axis.[5]  In the human gut, a number of organisms can produce bile salt hydrolases. Among bacteria producing bile salt hydrolases the genus Bacteroides are the most abundant. Sun, et. al. studied the effects of metformin on the gut microbiota and found that the genus Bacteroides was substantially reduced in individuals given just 3 days of therapeutic doses of metformin.[6] Metformin has been a first-line antidiabetic medication for more than 60 years because of its distinct glucose-lowering effect and safety profile,  Metformin administered orally reaches high concentrations in the intestine with much lower serum concentrations; thus, the possibility cannot be excluded that its metabolic benefits might be due in part to actions in the intestine. Metformin was recently shown to alter the gut microbiome of individuals with T2D and has a number of effects on gut bacteria including suppression of Bacteroides spp,, enhancement of the presence of short chain fatty acid (SCFA) producing organisms as well as a substantial increase in the mucin degrading organism Akkermansia muciniphila.[7] [8]

Thus these two ‘old drugs’ (ursodeoxycholate and metformin) have effects on one or more of the ancient species of the gut microbiota to reduce the FXR effect on up-regulating ACE2 activity. This could be one of the mechanisms whereby metformin has been associated with a reduced severity of COVID-19 infections.[9] Sharma et al first proposed metformin’s beneficial effects occur through the activation of AMP-activated protein kinase (AMPK) in hepatocytes, and postulated that would lead to ACE-2 conformational and functional changes, resulting in decreased binding with SARS-CoV-2 and subsequently to a reduction in its infectivity.[10]  Sun et. al., however, showed that metformin inhibits intestinal FXR signaling via the gut microbiota in an AMPK-independent manner.[6] Thus the effect of metformin on suppression of some gut bacteria may be the mechanism at play for its beneficial effects in COVID-19 infections.

References:

1. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426(6965):450-4 doi: 10.1038/nature02145.

2. Chen J, Jiang Q, Xia X, et al. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 2020;19(7) doi: 10.1111/acel.13168.

3. Dambha-Miller H, Albasri A, Hodgson S, et al. Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review. BMJ Open 2020;10(9):e040644 doi: 10.1136/bmjopen-2020-0406

4. Brevini T, Maes M, Webb GJ, et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 2022 doi: 10.1038/s41586-022-05594-0

5. Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021;18(5):335-47 doi: 10.1038/s41575-020-00404-2

6. Sun L, Xie C, Wang G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018;24(12):1919-29 doi: 10.1038/s41591-018-0222-4.

7. Wu H, Esteve E, Tremaroli V, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 2017;23(7):850-58 doi: 10.1038/nm.4345.

8. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care 2017;40(1):54-62 doi: 10.2337/dc16-1324.

9. Scheen AJ. Metformin and COVID-19: From cellular mechanisms to reduced mortality. Diabetes Metab 2020;46(6):423-26 doi: 10.1016/j.diabet.2020.07.006.

10. Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: A possible role beyond diabetes. Diabetes Res Clin Pract 2020;164:108183 doi: 10.1016/j.diabres.2020.108183.

What does a seatbelt and rescue glucagon have in common?

Glucagon is like a seatbelt: we hope our patients never have to use it; however, when it is needed, it can save someone’s life. When managing diabetes, we each have the responsibility to make sure our patients have the right tools in their diabetes supply bag. Glucagon is an essential part of a diabetes supply kit, yet some data shows that only 47% of type 1 diabetes caregivers carry a form of glucagon with them at all times.  That number is cited even lower at 29% for adults with type 1 diabetes¹.

Historically, glucagon emergency kits (GEKs – Glucagon Emergency Kit-F/Glucagon Emergency Kit-L and Glucagen Hypokit) were the only available treatment option to treat hypoglycemia in persons with diabetes, involve multistep manual reconstitution processes, and require the ability to draw up the appropriate volume prior to injection. In times of medical urgency, the poor usability of these earlier GEKs likely placed a lot of stress on the person administering the glucagon. In turn, this is likely a contributing factor to the under prescribing of glucagon with some outpatient clinics, reporting a prescribing rate as low as 4.5%². The three newer glucagon therapies: Gvoke™, Baqsimi™, Zegalogue™, do not require reconstitution and have improved caregiver administration success rates.  However, my personal experience working within an Endocrinology clinical practice we have not seen a substantial increase in the prescribing of these second-generation glucagon treatment and glucagon analogs.

Who should be prescribed glucagon?

According to the 2022 National Diabetes Statistics Report, over 37 million people are living with diabetes and approximately 7 million Americans are treated with insulin³. The 2023 ADA guidelines state that glucagon should be prescribed for all individuals at increased risk of level 2 (moderate; glucose < 54 mg/dl) or level 3 (severe; mental or physical functioning is impaired) hypoglycemia. All patients on insulin have a chance of experiencing level 2 or 3 hypoglycemia⁴.

Which Glucagon Therapy is Best? 

The newer glucagon and glucagon analog formulations come in several forms, which gives people with diabetes options to choose from based on multiple factors some of which are outlined in Table 1. A 2022 systematic review indirectly compared the safety and efficacy of Baqsimi™ to Gvoke™ and Zegalogue^TM. All 3 treatments achieved > 98% treatment success (defined as an increase in blood glucose to >/= 70 mg/dL, or an increase of >/= 20 mg/dL from nadir blood glucose within 30 minutes) in both adults and children with T1 and T2 diabetes⁵. Given these findings, ultimately selection becomes a matter of patient and/or administrator device preference.

Table 1: Overview of second-generation glucagon treatments and glucagon analogs^,6,7,8

	Baqsimi™ (2021)	Gvoke™ (2021)	ZegalogueTM(dasiglucagon) (2021)
Indication	Severe hypoglycemia	Severe hypoglycemia	Severe hypoglycemia
Indicated Age	≥ 4	≥2	≥6
Available Formulations	Nasal Powder	Pre-filled Syringe or Auto-Injector	Pre-filled Syringe or Auto-Injector
Route	Intranasal (IN)	Subcutaneous (SC)	Subcutaneous (SC)
Dosage	3 mg/dose	For children 2-12 and those < 45 kg, 0.5 mg/dose.For those whose weight is ≥45 kg, 1 mg/dose	0.6 mg/dose
*if no response in 15 min, an additional dose can be given from another dispenser
Storage	<86°F in the shrink wrapped tube provided	68°F  to 77°F	36°F  to 46°F , or 68°F  to 77°F  for up to 12 months at room temperature
Expiration1	48 mo from date of manufacture	Adults: 30 mo from date of manufacture;Ped: 20 mo from date of manufacture	36 mo with refrigeration from date of manufacture
Cost	~$336	~$336	~$370
Savings Card Available	Yes; Must have commercial drug insurance coverage	Yes;  Must have commercial drug insurance coverage	Yes;  Must have commercial drug insurance coverage

^{1:By the time drug reaches pharmacies, 3-6 months may have already passed from the date of manufacture}

So why is glucagon under prescribed/utilized? 

1. Cost

The most common concern on why glucagon prescriptions are not filled at the pharmacy is due to cost. The list price for the various forms of glucagon is around $300 per device, but insured patients can download savings cards that reduce the cost significantly. 

We also need to be thinking about the costs associated with severe hypoglycemia when someone does not have access to glucagon. In treating diabetes, hypoglycemia remains a major barrier to optimal glycemic control and can often lead to detrimental costs associated with hospitalizations⁹. In fact, there were 242,000 emergency department visits for hypoglycemia in 2018¹⁰. When  compared with  people  receiving  no  glucagon  treatment,  6  persons would need to be treated with dasiglucagon (Zegalogue™), 9 with reconstituted glucagon (Gvoke™), 27 for nasal glucagon (Baqsimi™) and 59 for older generation injectable native glucagon to avoid 1 hospitalization¹¹. 

2. I Have a Continuous Glucose Monitoring (CGM) Device, I Don’t Need Glucagon!

As we all know, CGM is an instrumental tool in diabetes management. We all have a role in helping our patients with diabetes personalize their CGM alarms at initial set up and ongoing to help minimize hypoglycemia. Setting CGM alerts for hypoglycemia has been shown to decrease the risk of severe hypoglycemia but it is not fool proof. Just like always wearing a seatbelt in the event of an accident, having access to glucagon in the event of ONE severe hypoglycemia can prevent life-threatening complications. Additionally, if our patients tell us they never got in a car accident and they never had to use glucagon then that is a WIN WIN! 

3.  Lack of awareness of newer generation glucagon

The newer FDA-approved glucagon delivery systems add flexibility to glucagon administration. The concerns regarding correct administration is diminished with the newer glucagon delivery systems. We all have a role to educate providers on the novel routes of glucagon delivery as well as to make sure family members, friends and caregivers know the signs of hypoglycemia so they can help treat with glucagon if needed. Providing clinical updates through an electronic drug update, an in-service or even one on one conversations about glucagon can impact making sure more of our patients have access to glucagon in their tool kit. 

4. Lack of provider buy-in for avenues to increase glucagon prescribing

Even with long term use of glucagon as a rescue medication for hypoglycemia, provider support can be a barrier.  Providing information about ADA guidelines to support the use of glucagon prescribing can be challenged by some since the statements about glucagon are level E evidence which means it is based on expert opinion in which there is no evidence from clinical trials, in which clinical trials may be impractical, or in which there is conflicting evidence. 

Fasten Your Seatbelt and Work on Increasing Glucagon Prescribing

Severe hypoglycemia represents an urgent medical issue requiring intervention. Injectable glucagon kits have historically been used for the treatment of insulin-induced hypoglycemia for patients with diabetes. The 3 newer-generation glucagon products provide additional options that has simplified the process of glucagon administration. We need to put effort towards creating standards of practice to increase the prescribing of glucagon, initial and ongoing education about the use of glucagon along with the importance of keeping glucagon in everyone’s diabetes supply bag.

References:

1. Haymond MW, Liu J, Bispham J, Hickey A, McAuliffe AH Use of Glucagon in Patients With Type 1 Diabetes Clin Diabetes Sprig 2019; 37(2):162-166. https://doi.org/10.2337/cd18-0028

2.  Abdulwagid T, Lloyd J, Selk K. 955-P: Glucagon Prescription Rates in Insulin-Treated Patients with Diabetes at a Teaching Outpatient Clinic. Diabetes. June 1, 2022; 71 (Supplement_1): 955–P. https://doi.org/10.2337/db22-955-P

3. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2022. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2022.

4. American Diabetes Association Professional Practice Committee; 6. Glycemic Targets: Standards of Medical Care in Diabetes—2023. Diabetes Care. January 1, 2023; 46 (Suppl 1): S97-S110. https://doi.org/10.2337/dc23-S006

5. Gimenz M, Khunti K, Syring K, et al. 375-P: Indirect Treatment Comparison (ITC) of Three Ready-to-Use Glucagon Treatments for Severe Hypoglycemia: Baqsimi, Gvoke, and Zegalogue. Diabetes. June 1, 2022; 71 (Supplement_1): 375-P. https://doi.org/10.2337/db22-375-P

6.  Baqsimi (glucagon) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019

7. Gvoke (glucagon) [package insert]. Chicago, IL: Xeris Pharmaceuticals, Inc; 2021

8. Zegalogue (dasiglucagon) [package insert]. Soberg, Denmark: Zealand Pharma US, Inc; 2021

9. Philip E. Cryer; The Barrier of Hypoglycemia in Diabetes. Diabetes. December 1, 2008; 57 (12): 3169–3176. https://doi.org/10.2337/db08-1084

10. Maheswaran AB, Gimbar RP, Eisenberg Y, Lin J. Hypoglycemic Events in the Emergency Department. Endocr Pract. 2022;28(4):372-377. doi:10.1016/j.eprac.2022.01.006

Fasting: Friend or Foe of Diabetes?

IF…EF…TRF…ADF…What it all means?

“Fasting” has been all the rage recently, so let’s understand exactly what it means. Intermittent fasting, known as IF, is a way of eating in which you vary through a pattern of eating little to no calories for a set amount of time (this could be a few hours or all day) and a normal eating schedule. A common IF schedule might be alternate day fasting (ADF), where one day you consume very little food (about 500 calories or less) and the next day you resume your normal eating schedule, and then repeat every other day. Another method is periodic fasting (also known as 5:2 fasting), where you would reduce food consumption on certain days of the week (2 days, not sequential) but then eat regularly on the 5 other days. Time-restricted feeding (TRF) is like IF, with one major difference: you fast for a specific portion of each day, not the entire day. A common TRF schedule would be 18:6 fasting, which restricts the fasting window to 18 hours and the eating window to six hours a day (for example, you might only eat from 2 PM to 8 PM).  An extreme version of fasting, known as extended fasting (EF), is when the fast lasts for 2 days or longer. All these models aim to reduce the number of calories patients are consuming.

Fasting, metabolism and insulin resistance

When eating is restricted, our bodies run out of carbohydrates that we need to use for energy and instead breakdown stored fats and convert them into ketones. Metabolic switching, when our bodies change from using sugars to using ketones, is a process that many believe produces health benefits beyond weight loss. IF and TRF allow for us to turn this metabolic switching on in our own bodies.

Researchers are looking at how IF and TRF can affect blood sugar and insulin resistance, and the results are interesting:

• A literature review by Albosta and Bakke¹ looked at 8 studies in patients who participated in intermittent fasting. The review showed significant reductions in fasting glucose levels (an average decrease of 4.16 mg/dL; P = 0.003). Other important findings included a reduction in weight loss, A1C, and an increase in adiponectin.
• Borgundvaag and colleagues² performed a metanalysis that looked at 7 studies that compared IF to standard diet. They found that IF produced a larger decrease in body weight –1.89 kg (95% CI, –2.91 to –0.86 kg) when compared to regular diet. The weight loss seemed to be more pronounced when BMI was greater than 36. However, IF did not show additional A1C reduction compared to standard diet.
• Sutton, et al³ looked at TRF and metabolic parameters in prediabetic men. They found that early morning TRF did decreased insulin levels, improved beta-cell responsiveness, improved blood pressure, improved oxidative stress, and decreased insulin resistance in people with prediabetes. This can be translated into improvements in insulin sensitivity and insulin levels.

Things to consider before recommending fasting

• Determine goals: it is important for patients to have their goal in mind. Are they embarking on this journey to lose weight? Or to lower their A1C or time in range? Knowing the patients goal can help with expectations.
• Decide on what type: deciding on TRF or IF or even EF will help to have a solid plan to follow. It is important to consider the patient’s lifestyle and whether incorporating planned fasting and feeding times that are adaptable for the patient.
• Meal Planning: it is important for patient to plan out their meals for each day of the week. This will allow for quick meal preparation and avoid over consuming calories.
• Choose nutrient dense foods: since the patient is restricting calories, the calories they are consuming should be on the highest nutritional value. Avoid processed, low-nutrient foods.
• Monitor blood glucose: any type of fasting (IF or TRF) is a change that will require close monitoring of blood glucose and potentially frequent changes to medications.

While IF and TRF appear to be safe and effective for people with diabetes, fasting can increase the risk of hypoglycemia, and will require extra monitoring as patients embark on this new journey!

References:

1. Albosta, M., Bakke, J. Intermittent fasting: is there a role in the treatment of diabetes? A review of the literature and guide for primary care physicians. Clin Diabetes Endocrinol 7, 3 (2021). https://doi.org/10.1186/s40842-020-00116-1
2. Borgundvaag E, Mak J, Kramer CK. Metabolic Impact of Intermittent Fasting in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Interventional Studies. J Clin Endocrinol Metab. 2021 Mar 8;106(3):902-911. doi: 10.1210/clinem/dgaa926. PMID: 33319233.
3. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab. 2018 Jun 5;27(6):1212-1221.e3. doi: 10.1016/j.cmet.2018.04.010. Epub 2018 May 10. PMID: 29754952; PMCID: PMC5990470.

GTMRx Institute: The What, Why, and How

The What

At this point, you have inevitably heard of the GTMRx Institute or Get the medications right. 

Most likely, you already know that their vision is to “ensure appropriate and personalized use of medication” and promote a “team-based, systematic approach to medication use” by advocating for advancing the integration of comprehensive medication management (CMM). 

If you follow the E&M Twitter account or are diligent in reading most emails that come through the listserv, you have been urged to “BECOME A SIGNING MEMBER!” at one point or another. 

And while you might have clicked on the link redirecting you to the GTMRx website or spent some time skimming through the Membership page, a part of you is still wondering…”Why should I join?”. 

Valid question.

The Why

Medication use is abundant. Specifically, medications are utilized within 80% of all treatments and nearly 30% of adults in the U.S. used more than 5 prescriptions in 2019.¹ Additionally, their use is not always optimized. A study published by Watanabe et al in the Annals of Pharmacotherapy illustrated an estimated total of $528 billion a year spent on the morbidity and mortality related to non-optimized medications.² As pharmacists and medication experts, we know that the integration of pharmacists within settings that allow for CMM can positively impact patients, however we have also faced barriers to integrating these services including lack of acknowledgement, reimbursement, infrastructure, (and more) on the local and national level.³ Luckily, GTMRx has dedicated the last three years to educating patients, professionals, and stakeholders on how CMM impacts getting the medications right and advocating for payment and policy transformation to support the integration of CMM (including their most recent response to CMS regarding the Medicare Advantage Program). 

GTMRx is consistently educating key stakeholders through their monthly webinars, many of which are presented by familiar faces to ACCP, our health systems, and colleges of pharmacy. In fact, the voice of our members are being heard through their involvement in the four workgroups, with Marcia Buck, PharmD, FCCP, FPPAG serving as the executive lead of Practice and Care Delivery Transformation Workgroup and Kathy Pham PharmD, BCPPC as co-lead of Payment and Policy Solutions Workgroup, among many other members serving as workgroup participants.

While GTMRx has a variety of members within many different professions, it is important to continue to grow our presence as pharmacists and members of ACCP since WE are the key to getting the medications right!

The How

I can tell that, at this point, you are excited to get involved and contribute to the GTMRx mission. 

Me too!

Lucky for both of us, it is super easy (and free!) to become a signing member (Click here). Once you’re a member, it is just as easy to get access to many resources that help grow or strengthen your CMM practice. You can even join the many ACCP members who serve as participants in the GTMRx workgroups!

For at least three years now, the E&M PRN has been charged with learning more about the GTMRx initiative and promoting it’s mission through collaboration with multiple PRNs including Ambulatory Care, Clinical Administration, Geriatrics, and Education and Training. If you are interested in being involved in next year’s E&M GTMRx initiatives, reach out to myself or the Healthcare committee and let us know! We would love to have you on-board!

References

1. Watanabe J, et al. Cost of Prescription Drug–Related Morbidity and Mortality. Annals of Pharmacotherapy, March 26, 2018. Accessed 20 September 2022. http://journals.sagepub.com/eprint/ic2iH2maTdI5zfN5iUay/full
2. Hales CM, Servais J, Martin CB, Kohen D. Prescription drug use among adults aged 40–79 in the United States and Canada. NCHS Data Brief, no 347. Hyattsville, MD: National Center for Health Statistics. 2019.
3. Prudencio J, Cutler T, Roberts S, Marin S, Wilson M. The Effect of Clinical Pharmacist-Led Comprehensive Medication Management on Chronic Disease State Goal Attainment in a Patient-Centered Medical Home. Journal of Managed Care & Specialty Pharmacy, 24 (5): 423-429. 2018. doi: 10.18553/jmcp.2018.24.5.423.

A New Class of Diabetes Medications

With almost a decade since the approval of a first-in-class agent for the management of type 2 diabetes, tirzepatide, also known by the brand name Mounjaro, has the potential to make waves in the diabetes management arena. Its recent approval by the US Food and Drug Administration (FDA) in May 2022 was anticipated by many since the publication of the SURPASS-1 trial in 2021. Within this trial, the addition of tirzepatide resulted in 31-52% of patients achieving an HbA1c <5.7%, with more patients achieving this goal on higher doses of tirzepatide.¹ This is promising for the addition of a single agent in a group where the mean baseline HbA1c was 7.9%.

How it Works²

While there are a number of GLP-1 receptor agonists approved by the FDA with indications for type 2 diabetes and/or weight loss, tirzepatide has a novel mechanism of action as a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) receptor agonist. GIP, the potentially less familiar of the two incretins, has a role in both insulin and glucagon secretion in states of hyperglycemia and hypoglycemia, respectively. This dual mechanism at both receptors may be the reason for the enhanced glycemic control seen with tirzepatide.

How does tirzepatide stack up to other medications for type 2 diabetes management?

The SURPASS-2 trial provides a comparison between semaglutide and tirzepatide which is beneficial to provide a reference point from a medication that has been in use for several years now. Compared to semaglutide 1 mg weekly, tirzepatide 5 mg, 10 mg, and 15 mg weekly was found to be non-inferior and superior in regards to improved glycemic control and body weight reduction. Additionally, similar rates of gastrointestinal adverse effects were seen between groups, with rates increasing with higher doses of tirzepatide. There were higher rates of adverse effects leading to discontinuation in the tirzepatide groups.³ This suggests that tirzepatide may not be a better-tolerated alternative medication for patients who are unable to tolerate GLP-1 receptor agonists due to gastrointestinal adverse effects. Additionally, since semaglutide is now approved at higher doses for both type 2 diabetes and obesity management, the magnitude of difference is likely smaller with the use of maximum dose semaglutide. 

Check out the other SURPASS trials to see more on how tirzepatide performs in different clinical situations.

Weight Loss

With one benefit of GLP-1 receptor agonists being weight loss in patients with and without diabetes, it is important to understand how tirzepatide may compare. While not an FDA approved indication at this time, the SURMOUNT-1 trial showed a 15-20.9% weight reduction over 72 weeks in non-diabetic participants with obesity taking tirzepatide 5 mg, 10 mg, and 15 mg compared to placebo (3.1% reduction)⁴ – showing that tirzepatide promotes weight loss as well.

Administration⁵

Tirzepatide is a once-weekly subcutaneous injection that can be delivered in the upper arm, abdomen, or thigh without regard to meal time. The delivery device is a one time use auto-injector pen with a hidden needle that appears to be similar to the pen used for the delivery of dulaglutide, also known by the brand name Trulicity. Initiation should begin with the 2.5 mg weekly injection, for 4 weeks prior to increasing the dosage by 2.5 mg every 4 weeks until reaching the desired dosage. The current maximum dosage is 15 mg once weekly. Of note, the lowest dose of 2.5 mg weekly is for titration purposes only and is not proven to provide glycemic control. If a patient misses a dose, they can take it within 4 days or skip the dose and resume with their next scheduled dose.

Safety⁵

Adverse effects, warnings, and contraindications seen with tirzepatide are similar to those seen with GLP1 receptor agonists with nausea, vomiting, diarrhea, constipation, decreased appetite, and dyspepsia being the most common adverse effects. 

Drug Interaction⁵

Due to delayed gastric emptying that is generally more pronounced initially and diminishes with additional doses, the manufacturer recommends patients switch to non-oral contraceptives or use additional contraceptive methods during the first 4 weeks of taking tirzepatide and for 4 weeks following each dose increase.

Access

As we often see with newly approved medications, access to tirzepatide is limited with varying coverage from insurance companies and no patient assistance program available at this time. 

With these promising results, it is exciting to speculate what the future holds for type 2 diabetes management. What has been your experience with tirzepatide so far?

References

1. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155.
2. Bertsch T. An introduction to tirzepatide. Clin Diabetes. 2022;40(3): 371-372.
3. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515.
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.
5. Mounjaro. Package insert. Eli Lilly and Company; 2022.

Behind The Most Wanted Anabolic Agents

What comes to mind when you hear the term performance enhancing drug? Many of our minds go directly to the use of testosterone, the main endogenous androgen responsible for the growth and development of male sex organs, secondary sex characteristics, and lean body mass. Along with the FDA approved indications of hypogonadism, delayed puberty, and gender dysphoria, testosterone is historically the most used medication to increase image and performance in sports. Although its efficacy has been demonstrated in literature, testosterone is not without its less desirable androgenic side effects and its difficult administration.¹

Thus, the new(ish) kids on the block were created: Selective Androgen Receptor Modulators AKA SARMs.

Selective Androgen Receptor Modulators

SARMs are a class of synthetic non-steroidal androgen receptor ligands first discovered in the 1990s. The most common SARMs utilized include enobosarm (Ostarine, MK-2866), testolone (RAD-140), andarine (S-4), and ligandrol (LGD-4033). They selectively activate androgenic signaling to skeletal muscle and bone, while seemingly sparing the activity on the prostate, heart, and liver.² Not only does the selectivity appear to be a benefit over testosterone and its derivatives, SARMs have enhanced oral bioavailability which make administration painless. SARMs are currently being explored for the treatment of sarcopenia, cancer cachexia, stress urinary incontinence, osteoporosis, and breast cancer, though there are no current products approved by the FDA for clinical use. From a sport and recreational standpoint, SARMs are mainly used for the promotion of muscle mass and strength, reduction in fat mass, and assistance with physical recovery from exercise. In 2020, Efimenko and colleagues published results from an internet-based survey evaluating the use of SARMs in 441 individuals. Most individuals who reported SARM use also reported an increase in muscle mass (96.7%), increase in energy levels (53.2%), and increased libido (39.8%).³ Although anecdotal reports show perceived benefits, it should be noted that SARMs are not without their side effects. The top three reported side effects attributed to their use in the same study were mood swings (22.4%), decreased testes size (20.7%), and acne (15.2%). These were reported from participants who took SARMs for longer than 3 months. Less common side effects reported include hair loss, yellow vision, increased blood pressure, irritability, and lethargy.

Sports Considerations

SARMs are prohibited for use in most competitive sports including those events sanctioned by the World Anti-doping Agency and athletes competing with the National Collegiate Athletic Association.^4,5 Therefore, athletes who have a positive anti-doping test for the use of SARMs may undergo suspension and/or loss of results.⁶ Although SARMs are not to be legally sold for human consumption, they have been found in dietary supplements as illegal additives and adulterants. Many consumers purchase them via the internet without required consultation from a physician as “research compounds not intended for human consumption”.^3,7

Key Points for Pharmacists⁸

• SARMs are used for the promotion of muscle mass, strength, and recovery
• SARMs do not currently have any FDA approved indications, but can be purchased from the internet as research compounds and are not intended for human consumption
• The most common reported side effects of SARM use include mood swings, decreased testes size, and acne
• Competitive athletes may be subject to drug testing and at risk of testing positive for a prohibited substance with the use of SARMs
• Dietary supplements can be adulterated with SARMs, therefore it is recommended to consume only third-party tested dietary supplements approved for sport and/or consult a sports dietician for a food first approach to enhancing performance
• Pharmacists have the responsibility of providing quality education surrounding the benefits and risks of SARMs

Resources

1. Handelsman DJ. Performance Enhancing Hormone Doping in Sport. [Updated 2020 Feb 29]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK305894/
2. Narayanan R, Cross C, Dalton J. Development of selective androgen receptor modulators (SARMs).Mol Cell Endocrinol. 2018 April 15; 465: 134–142. doi:10.1016/j.mce.2017.06.013.
3. Efimenko I, Valancy D, Dubin J, Ramasamy R. Adverse effects and potential benefits among selective androgen receptor modulators users: a cross-sectional survey. Int J Impot Res (2021). https://doi.org/10.1038/s41443-021-00465-0
4. World Antidoping Agency. The World Anti-doping code international standard: prohibited list. World Anti-doping Agency website. January 1, 2020. Accessed July 2, 2020. https://www.wada-ama.org/sites/default/files/wada_2020_english_prohibited_list_0.pdf
5.  Drug Free Sport International. 2020-21 NCAA banned substances. Drug Free Sport Axis website. 2022. Access on June 30, 2022. https://dfsaxis.com/api/v1/wordpress_contents/media/2015/08/2021-22-NCAA_BannedSubstances.pdf
6. US Anti-doping Agency. (2022, March 4). Sanctions – anti-doping violations. U.S. Anti-Doping Agency (USADA). Accessed on June 30, 2022, from https://www.usada.org/news/sanctions/
7. Wagoner R, et al. Chemical composition and labeling of substances marketed as selective androgen receptor modulators and sold via the internet. JAMA. 2017;318(20):2004-2010. doi:10.1001/jama.2017.17069.
8. Burmeister M, Fincher T, Graham W. Recreational use of selective androgen receptor modulators. US Pharm;2020;45(60):15-18

Finerenone for Diabetic Kidney Disease?

Over the last couple of years, and with good reason, the sodium glucose co-transporter 2 inhibitors (SGLT2i) have gained a lot of press and increased recommendations for use by professional organizations. The recommendations are for a variety of disorders in patients with and without diabetes including diabetic kidney disease (DKD) and heart failure. The renal benefits of the agents studied for DKD within this class have provided clinicians with new ways to reduce the impact of DKD given that for nearly two decades prior our mantra in treating DKD was glycemic control, blood pressure control, and use of agents to block the renin angiotensin system. This past January, the American Diabetes Association (ADA) developed a stand-alone chapter devoted to chronic kidney disease in their annual Standards of Medical Care. [1] Embedded in the treatment recommendations for DKD, and new in 2022, was the recommendation for the use of finerenone to reduce the burden of DKD in certain patients. More specifically, the ADA recommends the use of this agent to reduce DKD progression and cardiovascular (CV) events in patients who are unable to use a SGLT2i, have progression of their DKD, or in patients at an increased CV risk.

                Finerenone (brand name Kerendia) is a nonsteroidal, selective, mineralocorticoid receptor antagonists. It received FDA approval in 2021 for reducing the risk of sustained eGFR decline, end stage kidney disease, CV death, non-fatal myocardial infarction (MI), and hospitalization for heart failure in patients with DKD. At first glance, that seems like it should compete significantly with the use of SGLT2i in the treatment of DKD. FDA indications based on composite renal or CV outcomes are not uncommon. The question is, does the agent really reduce the risk of these individual events or to what extent? Should the agent be used in lieu of a SGLT2i or in combination with a SGLT2i? There are two main studies that led to this approved indication, the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) and the Finerenone in Reducing Cardiovascular Mortality and Morbidity in DKD (FIGARO-DKD). [2,3] The two studies differed in their intent and DKD inclusion criteria though had many outcomes in common. (Table 1) FIDELIO-DKD’s primary purpose was to study finerenone’s effect on renal outcomes, secondarily assessing CV benefit while the FIGARO-DKD was the exact opposite. Baseline eGFR and degree of albuminuria were significantly worse in subjects in the FIDELIO-DKD compared to FIGARO-DKD though the latter was in a much larger patient population. (Table 2)

                Regarding renal outcomes, the FIDELIO-DKD study showed an 18% relative risk reduction in its composite outcome. (Table 1) This outcome was primarily driven by a reduction in those with a sustained (40%+) in eGFR from baseline as neither kidney failure nor renal death were significantly reduced. The FIGARO-DKD study failed to show a significant reduction in its composite renal outcome but did show a small (0.4%) absolute reduction in end-stage kidney disease (number needed to treat 250). Turning to the main CV outcomes, FIDELIO-DKD showed a modest 14% relative risk reduction in its composite CV outcome though none of the individual CV outcomes comprising the composite were significantly reduced. The FIGARO-DKD study also showed a modest (13%) reduction in its composite CV outcome which was primarily driven by a reduction in hospitalization for heart failure. None of the other individual CV outcomes were reduced. Neither study showed a CV or renal mortality benefit.

                More recently, the investigators of these two trials performed a prespecified pooled analysis of their data. [4] The composite CV outcome, as in the individual studies, was modestly reduced (14% relative reduction) and like the FIGARO-DKD study, it was driven by a reduction in hospitalization for heart failure while no other CV outcome or mortality was significantly reduced. The pooled analysis showed a 23% relative risk reduction in its renal composite outcome. Unlike in the individual studies, the pooled data showed a modest reduction in kidney failure (0.7% absolute reduction) but the composite outcome was primarily driven by a reduction in those with a sustained (57+%) decrease in eGFR from baseline.

                What’s that all mean and what role does this new agent have in the treatment of DKD? FDA-indications based on composite outcomes typically make an agent look better than it actually is. Yes, the CV composite outcomes were significantly improved. However, this is primarily due to a reduction in heart failure admissions. While an important outcome, there is no data to suggest it prevents MI, stroke, or CV death to a significant degree. Likewise, the composite renal outcomes were significantly reduced in the FIDELIO-DKD and pooled analysis primarily driven by the reduction in sustained decrease in eGFR. Again, an important outcome, but there is no strong evidence the agent reduces the risk of kidney failure and if it does, the number of patients needed to treat is quite large (143 in the pooled analysis). It should be noted the trials here were completed prior to the results of SGLT2is on renal outcomes in patients with or without diabetes. The data on concrete renal and CV outcomes appear more favorable with SGLT2is in the treatment of DKD than finerenone. Could there be an additive effect of adding finerenone on top of an SGLT2i? Possibly, but we have no clinical trial data to support it as very few patients were on an SGLT2i in the FIDELIO and FIGARO studies, and there is no ongoing trial to assess the combination in the treatment of DKD. So, a substitute for an SGLT2i to minimize CV and renal outcomes, finerenone isn’t. For those who can’t be placed on an SGLT2i for the treatment of DKD, finerenone may have a role. Any benefit of combining finerenone with an SGLT2i at this time is purely speculative.

Table 1

Study Inclusion Criteria and Key Outcomes/Results

Study	Renal Inclusion Criteria	Primary Outcome(s) HR (95% CI) Absolute Difference (%)* and NNT	Main Secondary Outcome HR (95% CI) Absolute Difference (%)* and NNT
FIDELIO-DKD	– Urine Alb/Cr ratio 30-299 and eGFR 25-59 or – Urine Alb/Cr ratio 300-5000 and eGFR 25-74	Composite kidney failure (long-term dialysis, kidney transplantation, or eGFR < 15) or renal death HR 0.82 (0.73-0.91) Ab Dif 3.3%  NNT 30	Composite CV death, nonfatal MI or stroke, or hospitalization for heart failure HR 0.86 (0.75-0.99) Ab Dif 1.8%  NNT 56
FIGARO-DKD	– Urine Alb/Cr ratio 30-299 and eGFR 25-90 or – Urine Alb/Cr ratio 300-5000 and eGFR 60+	Composite CV death, nonfatal MI or stroke, or hospitalization for heart failure HR 0.87 (0.76-0.98) Ab Dif 1.8%  NNT 56	Composite kidney failure (long-term dialysis, kidney transplantation, or eGFR < 15), sustained decrease of 40+% in eGFR, or renal death HR 0.87 (0.76-0.1.01) Ab Dif 1.3%  NNT NA
Pooled Analysis		Composite CV death, nonfatal MI or stroke, or hospitalization for heart failure HR 0.86 (0.78-0.95) Ab Dif 1.7%  NNT 59   Composite kidney failure (long-term dialysis, kidney transplantation, or eGFR < 15), sustained decrease of 57+% in eGFR, or renal death HR 0.77 (0.67-0.88) Ab Dif 1.6%  NNT 63	Composite kidney failure (long-term dialysis, kidney transplantation, or eGFR < 15), sustained decrease of 40+% in eGFR, or renal death HR 0.85 (0.77-0.93) Ab Dif 2.2%  NNT 45

All subjects were at least 18 years of age, had Type 2 diabetes with chronic kidney disease, and receiving maximum dose of an ACE-Inhibitor or angiotensin receptor blocker

* Difference between finerenone and placebo

HR = Hazards ratio, Ab dif = Absolute difference, NNT = Number needed to treat, NA not applicable

Table 2

Key Baseline Characteristics

Study	Subjects (n)	Age (yr)	Duration of DM (yr)	Median urine Alb/Cr ratio	Mean eGFR (ml/min/1.73 m2)
FIDELIO-DKD	5734	65.6	16.6	853	44.3
FIGARO-DKD	7437	64.1	14.5	308	67.8
Pooled Analysis	13,026	64.8	15.4	515	57.6

References:

1. American Diabetes Association. Chronic kidney disease and risk management: Standards of Medial Care in Diabetes-2022. Diabetes Care. 2022; 45 (Supl1): S175-S184.
2. Bakris G, Agarwal R, Anker S, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219-2229.
3. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252-2263.
4. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. European Heart Journal. 2022;43:474-484.

How to best “connect” with your MDI patients…

One of the everyday challenges I, and likely you too, experience daily in clinic are the difficulties of using multiple daily injections (MDI) with many of our patients. Connected insulin pens (CIP), formerly known as “smart pens” offer the opportunity to help with some of these challenges by enabling easier and more accurate dosing and dose recording, dose calculations, and sharing of data.

The American Diabetes Association, Standards of Care discuss the use of CIP and how they are useful in assisting patients dose insulin in real time as well as allowing clinicians to review the data and make informed dose adjustment decisions.¹ Studies have shown that real-time continuous glucose monitors (CGM) used with MDI are clinically equivalent and can be used at a lower cost than CGM used with insulin pumps.² This and other reasons, find us managing patients who are using MDI. However, use of MDI is not without its challenges. Issues seen frequently are missed or delayed doses, lack of numeracy skills, incomplete record keeping, and fears about hypoglycemia.² CIP allows for data-driven diabetes care in a time sensitive manner.^1,2 Warshaw et al, discusses the 3 hallmarks of data-driven care: (1) Identifying the right technology for the right patient, (2) configuring the technology to the patient’s lifestyle, and (3) ongoing collaboration.² The remainder of this blog is meant to aid you in the “identification” of the right technology for your patients!

For the last few years, the InPen™ was the only player in town. Recently however, Bigfoot Unity™ was approved and released to market, which gives clinicians like us a few things to think about. Table 1 compares the hardware used by each company. InPen™ is a device for a very specific patient and is dependent upon the patient actively engaging with the device. Bigfoot Unity™ is a passive system that doesn’t require anything from the patient for their data to become available on Clinic Hub, which allows for remote physiologic monitoring.

Table 1: Product Comparison

	Companion Medical InPen™	Bigfoot Unity™
FDA Approval Date	7/26/2016	5/10/2021
Manufacturer	Companion Medical	Bigfoot biomedical
Product	Smart Pen + App	-Bundle: pen caps for basal and bolus insulin, 2 Freestyle Libre sensors, pen needles, backup blood glucose meter/supplies. -Supplies: test strips, needles, alcohol pads replaced continuously. Black cap- Basal; White Cap-Bolus
Indication	People with diabetes under the supervision of an adult caregiver, or by a patient age 7 and older for the self-injection of a desired dose of insulin	Indicated for management of diabetes in persons 12 years and older
Type of Insulin	Bolus Only	Basal and Bolus
Insulin Brand Compatibility	-Humalog® U-100, Novolog® U-100, Fiasp® U-100 -Cartridges	-Compatible with all major rapid-acting, except Lyumjev® -Compatible with all major long-acting insulin brands -Pens
Dosing Increments	0.5 units	1 unit
CGM/Glucometers	Guardian™ and Dexcom® G5/G6 (3-hour delay) and Bluetooth enabled glucometers* (if the patient is using an iPhone)	Freestyle® Libre® 2 and glucometer
Calibrations	Minimum 2 per day if using Guardian sensor	None
Longevity	1 year; no charging necessary	2 years; rechargeable
Coverage	Pharmacy Benefit: $35+ with commercial insurance May require PA or additional costs for use of insulin cartridges	Medical Benefit: No upfront cost to patient, covered under Medicare and most commercial insurers, co-pays will vary
Payment Model	Fee For Service	Bundled Payment/Subscription
CPT + Billing	N/A	99453, 99454, 99457, 99458, 99091
NDC	62088000034, 62088000031	N/A
Alarms: Hypoglycemia	No	Mandatory at 55mg/dL and optional at 70mg/dl
Alarms: Missed dose	Bedtime alerts for missed doses, missed meal window reminders	After 24 hours in between basal dose
Smartphone Compatibility	-Apple (IOS 10 or later) -Android 6 or later	iPhone 7 or newer
App Main Features	-Dosing calculator -Dose reminders -Carb counting support -Digital logbook	-Dosing calculator -Dose reminders -Real-time glucose levels -History and trends
How it works	Connects to CGM, reports insulin usage data using Medtronic platform	Remote Physiological Monitoring: Data Collection, Data Transfer, Bigfoot Clinic Hub, Bigfoot Unity App
Miscellaneous	Tracks active insulin amount Monitors insulin temperature Can log long-acting insulin doses in App	Based on HCP recommendations Displays insulin dose on the pen cap each time

*Bluetooth enabled glucometers include: AgaMatrix Jazz Wireless 2, Ascensia Contour^, Next One, iHealth, Smart Lifescan One Touch Verio, Flex Lifescan One Touch Verio, Sync One Drop Chrome, Roche Accu-Chek, Aviva Connect Roche Accu-Chek^® Guide

What is unique about Bigfoot Unity™ is the business model and the potential to be a revenue generator in our clinics. Think of it like a ‘bundled subscription’. The product itself does not have an NDC number and therefore can’t be billed at the pharmacy level as a pharmacy product. Unity is prescribed using Clinic Hub. There is no upfront cost to the patient. Bigfoot handles all the insurance paperwork as soon as the prescription is signed.  Kits are mailed directly to the patient. The system is not available for purchase. This product can easily be used by anyone using insulin at a set dose. No need for carb counting or correction ratios.

What is easy about InPen™ is that the prescriber can use the EMR to e-scribe the insulin cartridges and the InPen™ products easily. The patient just has to download the ‘InPen: Diabetes Management’ app, you or the patient can enter the patients I:C, ISF, DIA, target BG, and max bolus and it’s ready to use. This product is tailored to be used in patients who understand carbohydrate counting and have shown proficiency in counting carbs, however, it can be set for a fixed dose or meal estimation (e.g. low carb, medium carb, high carb) as well. The patient that doesn’t want a pump or maybe can’t afford one, is likely a good fit for the InPen™ connected pen.

I am no expert in the use of this type of technology, in fact I have never used either of these products in patients, but I see their utility. InPen™ is for the patient that is comfortable with and likes to use technology to manage their diabetes. Bigfoot Unity™ is for patients who just want any easy answer to the question “How much insulin would my doctor recommend I take right now?”. On paper, I can see the advantages and disadvantages of each of these CIPs (Table 2).

Table 2: Advantages and Disadvantages

	Companion Medical InPen™	Bigfoot Unity™
Advantages	-Allows for carbohydrate counting -Tracks active insulin -Can be used with Apple and Android products -Half-unit dosing and use in pediatrics -Missed dose alert (even for basal) -Displays the insulin dose to be given	-Can use with basal and bolus insulins -Uses the same pens that the patient is currently using -Medical benefit with no co-pays -Allows for remote monitoring daily -Displays the insulin dose to be given -Allows for clinics to bill for services they are already providing -Hypoglycemia alarms
Disadvantages	-Can only use with bolus insulin -Pharmacy benefit with co-pays -No hypoglycemia alarms -Cost and accessibility of insulin cartridges -Cost and accessibility of Guardian™ and Dexcom® CGM -Delay in real-time data unless the Guardian™ CGM is being used	-Can only be used with iPhone 7 or newer -Approved for 12 years and older -No “missed meal” alerts

As always, it is our job as a pharmacist to have all the data and advocate for the best product for each individual patient. InPen™ is for that individual patient that everyone can think of. Bigfoot Unity™ is for most MDI patients looking for an easier, safer way to take insulin. Hopefully the information in this blog can help with that decision-making process!

References:

1. American Diabetes Association Professional Practice Committee; 7. Diabetes Technology: Standards of Medical Care in Diabetes—2022. Diabetes Care 1 January 2022; 45 (Supplement_1): S97–S112. https://doi.org/10.2337/dc22-S007
2. Warshaw H, Isaacs D, MacLeod J. The Reference Guide to Integrate Smart Insulin Pens Into Data-Driven Diabetes Care and Education Services. 2020;46(4_suppl):3S-20S.

Kickstart my heart with CGM!

According to the American Diabetes Association, adults with type 1 should engage in at least 150 minutes of moderate to vigorous exercise per week, with no more than two consecutive days without activity as well as muscle-strengthening activities 2-3 times per week.¹   Studies have shown that a regular exercise routine involving aerobic exercise along with the inclusion of short bursts of high-intensity exercise and/or resistance exercise may provide a level of protection against hypoglycemia during and shortly after exercise.²  One significant barrier to exercise is the fear of hypoglycemia. Glycemic management before, during and after exercise has become more manageable when utilizing continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems in order to learn individual responses.

The Device (CGM)

At rest, the interstitial glucose measured by CGM devices is roughly ~ 5-10 minutes behind blood glucose values that is known as “lag time”. It is important that persons with diabetes understand that when exercise causes rapid glucose changes, the CGM lag time can increase to at least 12-24 minutes.³ CGM accuracy is measured by the MARD that stands for the Mean Absolute Relative Difference and represents the difference between laboratory glucose readings and the actual reading from the CGM. It is known that the extended lag time during exercise makes the MARD higher, particularly at both glucose extremes. As seen by the schematic illustration below, a person with diabetes may not detect hypoglycemia in real time during or following exercise due to the lag time. A helpful strategy to compensate for the lag time would be to set a higher setting for a low alarm such as changing the low alarm up to 126 mg/dl prior to exercise. The utilization of trend arrows is key and some persons with diabetes might find it helpful to turn on the fall and/or rise rate alarm during and after exercise that can result in an earlier action to prevent low/high glucose levels. The use of a standard blood glucose meter in addition to the CGM device during physical activity is important to ensure safety.

Printed with permission from Moser et al. Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA). Schematic from full-length version of position statement on the EASD website.

Exercise and Glucose

In the terms of the type of exercise, the impact on glucose can depend on the timing and duration of anaerobic and aerobic exercise. When evaluating the type of exercise, aerobic exercise such as walking, cycling, jogging, and swimming tends to cause a fall in blood glucose levels. Often patients experience a smaller glucose drop in the morning due to insulin resistance that could be used as an advantage when struggling with exercise-related lows. Anaerobic exercises such as weight lifting, sprint running or swimming is different and can often cause blood glucose to rise. Anaerobic exercise uses less glucose and the counter regulatory hormones respond quicker and more significantly. A person with diabetes may want to consider performing resistance exercise later in the day when the activity may result in less hyperglycemia.⁴ And then of course the timing of the exercise relative to the last meal, last insulin dose and glucose level when starting to exercise can all make a difference.

Recently, a position statement on the use of continuous glucose monitoring (CGM) during exercise was published by some of the world’s leading diabetes organizations and emphasizes ways to look at CGM data to help determine risk for unwanted low and high glucose levels as a result of exercise. Some helpful pearls and practical tips will be highlighted below from the position statement to help evaluate and educate patients on how they can use their CGM to exercise.⁵  Keeping records and tracking patterns is the best way that someone can help incorporate regular exercise into their routine.

How to do it!

A person with diabetes should initially try to figure out how much the activity alone (no food or bolus insulin influence) changes their glucose levels with repeating the experiment a few times. Besides the type of exercise, some other key factors to think about before exercise include intensity, duration and time of day relative to meals, last bolus as well as insulin on board. Before exercise, people can administer insulin, take oral glucose, or delay the start of exercise depending on their pre-exercise glucose level and the direction of the CGM arrows. Exercising with insulin on board can be challenging especially since insulin absorption increases during activity. Persons with diabetes are less likely to experience lows if exercising before breakfast when only basal insulin would be present. To lower the risk of hypoglycemia, it is best to initiate exercise when mealtime insulin levels are low or about 90 min after the last carbohydrate-rich meal with a reduction in mealtime insulin by 25-75% depending on the type and intensity of exercise. To avoid delayed onset hypoglycemia, people with diabetes can also lower their basal insulin. People using multiple daily injections (MDI) of insulin could reduce the long-acting insulin dose by ~20%. Persons using traditional insulin pumps can decrease basal rates by up to 80% starting 60-90 minutes before and during activity in addition to a reduced basal rate by 20% before bedtime. It is important to have a rough idea of what each individuals target glucose range should be before exercising and how the glucose is trending before starting.

In general, starting exercise when glucose levels are between 126-180 mg/dL is ideal but it’s important that each individual knows themselves and makes the necessary adjustments. If glucose levels are below the individual glucose goal before exercise, 10-35 grams of carbohydrates may need to be consumed before exercise unless the type of exercise results in glucose levels to rise. If the glucose level is above 270 mg/dL, anaerobic exercise should be avoided but light aerobic activity is okay if ketone levels are low. Administering a correction bolus can cause hypoglycemia (during or after the workout) and therefore a 50% correction bolus is likely more appropriate knowing that a 1-unit bolus might lower glucose like a 2 or 4-unit bolus. In general, the glucose target during exercise is also 126-180 mg/dl. If glucose is < 126 mg/dL, people with diabetes should consider consuming 10-35 grams of carbohydrates, with the amount depending on the glucose level and direction of the trend arrows. If concerned about hypoglycemia, patients could increase low glucose alarm up to the 126 mg/dL level. If glucose rises with exercise and is >180 mg/dL with level or increasing arrows, a reduced correction insulin dosage could be considered. If the glucose is >270 mg/dL, ketones should be monitored and a 50% insulin correction may be needed. Persons with diabetes should stop exercise if glucose is > 270 mg/dl and spilling ketones. The glucose target after exercise is 80-180 mg/dl unless the patient is at high risk for hypoglycemia then 100-180 mg/dl may be more appropriate. Longer duration or repeated bouts of high intensity may result in delayed onset hypoglycemia for up to 24 hours after exercising but most commonly occurs after 6-12 hours. This may be prevented by decreasing insulin doses and/or “free” snacks consisting of slow acting carbs following activity. It is also a good idea to set hypoglycemic alert higher (such as 80 mg/dl) during night-time period for earlier proactive treatments. Eating a mix of high-fiber carbs, protein, and fat after exercise can also help prevent going low after working out.

What about Automated Insulin Delivery Devices

When persons with diabetes start an AID (Automated Insulin Delivery) system, it is important to provide education on the exercise “rules” that differ from traditional insulin pump therapy. It is common for a person with diabetes to eat carbs immediately prior to exercise in order to keep glucose levels from dropping, though this may not be a good idea with an AID unless the glucose is below target. Depending on the glucose level and glucose trend, AID systems may respond to the sudden rise in glucose levels by giving extra insulin before and during exercise, either by increasing basal rates and/or delivering an automatic correction dose of insulin. In order to prevent this extra insulin prior to exercise, it is likely better to NOT ingest extra carbohydrates, and in particular simple carbohydrates (sugar), if glucose levels are not low prior to the activity. Setting the AID exercise mode in advance and only eating carbs during activity if the glucose is trending low, are likely better approaches to avoiding lows during exercise. Prolonged exercise may require eating carbohydrates in smaller intermittent amounts.

A successful feature for exercise management when using an AID system is the ability to use the exercise setting which includes a higher glucose target/range:

AID system	Exercise Mode
Medtronic 670G or 770G system	Temp target 150 mg/dl
Tandem Control-IQ system	Target range: 140 – 160 mg/dl

For exercises that cause glucose levels to drop, the exercise setting should be turned on 60 to 120 minutes before the start of the activity. Using the exercise setting for up to 12 hours after a very prolonged and strenuous exercise session may help prevent delayed hypoglycemia after exercise. For exercises that cause glucose levels to rise, the AID insulin pump algorithm tends to work well on its own in bringing glucose levels back to range. If the high glucose tends to last > 30 minutes without starting to drop back down, a correction bolus may be needed. An open-label multisite randomized crossover trial with type 1 diabetes undertook 40 min of high intensity, moderate intensity, and resistance exercise in random order while using an AID system (Medtronic MiniMed 670G) with a temporary target set 2 h prior to and during exercise and 15 g carbohydrates if pre-exercise glucose was <126 mg/dL to prevent hypoglycemia. The time-in-range (70–180 mg/dL) for the 3 exercise types ranged between 80-91% for 0-14 h post–exercise commencement with no statistical difference between exercise types and the time-below-range was 0% for all exercise bouts.⁶  The hope is that future AID generations will be able to maintain glucose targets with unannounced exercise.

Summary

Variable glycemic responses to physical activity make uniform recommendations difficult. However, with so many different factors impacting glucose levels, it can take a while for a person with diabetes to learn how to manage their glucose with exercise. Trial and error and the use of CGM is the key for each individual to gain confidence in how to avoid significant glucose excursions with exercise. 

1. Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016; 39: 2065–79
2. Yardley JE, Sigal RJ.; Exercise Strategies for Hypoglycemia Prevention in Individuals with Type 1 Diabetes. Diabetes Spectrum 2015, 28(1): 32-38.
3. Zaharieva DP, Turksoy K, McGaugh SM, et al. Lag time remains with newer real-time continuous glucose monitoring technology during aerobic exercise in adults living with type 1 diabetes. Diabetes Technol Ther. 2019;21(6):313-321.
4. Toghi Eshghi SR, Yardley JE. Morning (fasting) vs. afternoon resistance exercise in individuals with type 1 diabetes: a randomized cross-over study. J Clin Endocrinol Metab. 2019;104(11):5217-5224.
5. Moser, O.; Riddell, M.C.; Eckstein, M.L.; Adolfsson, P.; Rabasa-Lhoret, R.; van den Boom, L.; Gillard, P.; Nørgaard, K.; Oliver, N.S.; Zaharieva, D.P.; et al. Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: Position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA). Diabetologia 2020, 63, 2501–2520
6. Paldus B, Morrison D, Zararieva DP, et al. A Randomized Crossover Trial Comparing Glucose Control During Moderate-Intensity, HighIntensity, and Resistance Exercise With Hybrid Closed Loop Insulin Delivery While Profiling Potential Additional Signals in Adults With Type 1. Diabetes Care 2022;45:194–203

“C” is for Comprehensive

Last year about this time, I wrote a Healthcare Committee blog entitled “Getting on the CMM Train”. I mentioned the work of the Comprehensive Medication Management (CMM) Primary Care Research Team, and their discovery of a fair amount of variability in how the processes that make up CMM were defined and implemented. This created a need for more education and training surrounding CMM.  At the time, I noted that some training in CMM was going to be part of the ACCP Clinical Practice Forum portion of the 2021 Spring Form held that April.  During the intervening year, Dr. Shawn McFarland and Dr. Marcia Buck published a blog on the GTMRx website that honed in on the fact that much of what many of us call CMM is actually more Medication Therapy Management (MTM).  Medication optimization through MTM, the goal of the 2003 legislation promoting it for Medicare Part D recipients, developed in different ways over time, but in each of them it was medication focused, and not patient focused!  A comprehensive approach that was more of a patient care process, became a more desirable goal and operational definitions that explicitly outline all the steps to deliver the intervention we call CMM were outlined. The result is the 10 ‘pillars’ of CMM aptly described in the GTMRX Issue Brief “Putting CMM in Practice”, developed by Dr. Annie Ideker and Dr. Mary Roth McClurg.  This detailed, example filled brief puts together significant amounts of research regarding CMM as well as a graphic patient example. 

The GTMRx Institute has been at the forefront of developing various resource documents on CMM and toolkits that support the implementation of CMM tailored to specific groups such as physicians, patients/consumers, employers, and Accountable Care Organizations (the latter, still under development). Most recently in addition to these resource ‘toolkits’, working groups within GTMRx have developed an evidence document on quality, access and costs of CMM in team-based care.  This valuable resource is a large collection of examples of the value of various gradations and applications of CMM in regards to patient care. 

As many of you know, GTMRx is a large organization made up of a variety of pharmaceutical and medical device companies, non-medical corporations, healthcare associations and societies, laboratory and other medical organizations, as well as several government agencies.  It has approximately 1500 signing members, many of whom are involved in workgroups developing the resources mentioned above.  Membership as a ‘Signing Member’ is free, and allows access to a variety of blogs, issue briefs, webinars, etc.  as supporting documents for the implementation of CMM.  All of our PRN members should be signing members of GTMRx.  Several days ago, Dr. Marcia Buck, ACCP Director of Clinical Advancement on behalf of GTMRx forwarded an invitation to participate in a new GTMRx registry designed to provide a current estimate on the availability of CMM services. I would encourage all of you to take the survey by the January 13^th deadline. Clinical pharmacy services vary from place to place. GTMRx, ACCP and other groups are promoting CMM services in many different ways to make them the standard of care in patient management.  Are YOUR practice site and YOUR activities the full pallet of CMM practice?  I strongly recommend taking the Comprehensive Medication Management Practice Management Tool to see how you stack up!