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

Patient-Centered Care?

By: Shereen Salama, PharmD Candidate 2020 and Trisha Benjamin, PharmD

The Centers for Disease Control and Prevention (CDC) released the National Diabetes Statistics Report in 2017, which indicated that in 2015 there were 30.3 million Americans who had diabetes. Interestingly, of those individuals diagnosed with diabetes, 7.4% were non-Hispanic whites, 8% were Asian Americans, 12.1% were Hispanics, 12.7% were non-Hispanic blacks, and 22% were American Indians/Alaskan Natives (Table 1c).1 Diabetes is growing to become a disease of the minorities.

New data regarding the use of glucagon-like peptide-1 receptor agonists (GLP-1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) is being released with exciting and promising results related to the prevention of microvascular and macrovascular events which has impacted the 2019 American Diabetes Association Standards of Care. Surprisingly, when you look at the trials that impacted the way these guidelines are written you will find that, repeatedly, these trials are conducted in primarily White Caucasian populations. If most of our diabetes patients are of minority groups, can we be certain that extrapolating the results of the Cardiovascular Outcomes Trials to these populations will have the same degree of benefit? Although these new drugs have shown us significant weight loss, improved glycemic control, how do we know that our treatment choices are BEST for our different patient populations?

For example, did you know that a few studies have shown that African Americans may respond to metformin treatment better than non-Hispanic White Americans?2-3 Additionally, for the DPP-4 inhibitors that show only “intermediate efficacy” in the new guidelines, studies show that they are more efficacious in Asian populations than patients of other race.4 A few studies have also shown that African Americans exhibit lower GLP-1 concentrations and increased inflammatory response.5 What could this mean for the efficacy of GLP-1-RAs in this population? As for the SGLT2is, limited studies show similar efficacy among non-Hispanic and Hispanic patients.6 However, would the same efficacy be seen with the use of SGLT2i amongst African Americans, Native Americans and Middle Easterners? The use of both the GLP1-RAs and SGLT2is have rarely been studied in patients of varying ethnic decent. This leads one to wonder how these agents were able to rise to second-line therapy options in the new guidelines especially considering that the cardiovascular outcomes trials (CVOTs) did not include diverse patient populations. Would the same results be seen?

Our hope for the future is to be more culturally competent and aware. Now that we have evidence in the literature that these medications provide benefit in patients with diabetes, we need to study the way that they work in different ethnic populations. From here, we can tailor our care for patients to truly be patient-centered. When talking about patient-centered care, we should always try and ask ourselves what exactly are we choosing to center our care around? Are we treating A1c levels, self-monitored blood glucose readings, lipid levels, BMI, frequency of hypoglycemic events or other clinical outcomes? Or are we treating the human that is behind those numbers?

 

References:

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2017.
  2. Williams LK, Padhukasahasram B, Ahmedani BK, et al. Differing effects of metformin on glycemic control by race-ethnicity. J Clin Endocrinol Metab. 2014;99(9):3160-8.
  3. Florez JC. It’s not black and white: individualizing metformin treatment in type 2 diabetes. J Clin Endocrinol Metab. 2014;99(9):3125-8.
  4. Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. 2013;56(4):696-708.
  5. Velasquez-Mieyer PA, Perez-Faustillini S, Cowan PA, et al. Racial Disparity in Glucagon-Like Peptide 1 and Inflammation Markers Among Severely Obese Adolescents Diabetes Care 2008 Apr; 31(4): 770-775.
  1. Davidson JA, Aguilar R, Lavalle González FJ et al. Efficacy and Safety of Canagliflozin in Type 2 Diabetes Patients of Different Ethnicity. Ethn Dis. 2016 Apr 21;26(2):221-8. doi: 10.18865/ed.26.2.221.

Non-Inferiority Trials and a Potential Concern in Endocrine Medicine

About a year ago I came across an intriguing article by Vinay Prasad (@VPrasadMDMPH) titled “Non-inferiority Trials in Medicine: Practice Changing or a Self-Fulfilling Prophecy?”.[1] The article discusses the results of Aberegg et al. (@medevidenceblog) regarding the consequences of non-inferiority trial design and the potential impact these trials have on patient care.[2] Non-inferiority trials are a useful tool for comparing new therapies to an active control when the use of a placebo control is not ethical.  The expectation of these trials is that the new therapy provides patients an advantage over the active control.  A great example of their appropriate use is in trials that led to the approval of Direct Oral Anticoagulants.  It would not be ethical to run a placebo-controlled trial for patients with an active thrombus, and these new agents provide potential significant advantages to our current standard of care in vitamin K antagonists.

            One startling point identified by Aberegg and colleagues in their analysis was that 77% of included trials showed either superiority or non-inferiority of the new therapy.  This is significantly more than the 50% seen in standard superiority trials.[2] So why might non-inferiority trials have this improved rate of success?  A key factor is the selection and justification of the non-inferiority margin.  A permissive margin allows for an investigator to claim benefit, when in fact a therapy may be inferior to its comparator.  While a margin that is too conservative may increase the rate of a type 2 error. 

Investigators who perform a non-inferiority trial should first attempt to estimate the effect of the active comparator to placebo from historical randomized controlled trials.  Then investigators must apply clinical judgement to determine the percent of that effect that must be preserved by the new therapy, otherwise known as the preserved fraction.  In general, a preserved fraction of 50% has become commonplace.[3,4] One example of this can be found in the Rocket-AF trial.  The non-inferiority margin was set at 1.46.  The investigators generated this margin after evaluating trials comparing warfarin to placebo and generating a risk ratio of 2.63 (95% CI 1.92-3.57).  The investigators then took 50% of the most conservative end of the confidence interval, 1.46, to set as their non-inferiority margin.[5] While the Rocket-AF investigators appropriately documented their reasoning for their margin, this is not commonplace in most non-inferiority trials. 

            Non-inferiority trials are now frequently seen in the endocrine world due to the Food and Drug Administration’s (FDA) mandate that new diabetes therapies show no increased cardiovascular risk.  The FDA requires manufacturers to show that their medication has less than a 30% increase in cardiovascular morbidity and mortality, or a non-inferiority margin of 1.3, as compared to placebo.[6] This margin was recommended as “the majority of the [FDA] committee members felt that the hazard ratio of 1.2 to 1.4 is reasonable, given the benefits of lowering HbA1C and decreasing microvascular complications are well-known”.[7, 8] Some argue it is too demanding of manufacturers, while others believe that this standard is too liberal given the lack of need to show a clear benefit to morbidity and mortality.   

However, the use of non-inferiority trials in our field are not restricted to FDA mandates.  Manufactures are regularly utilizing non-inferiority trials outside of the drug approval process to showcase how new therapies compare to an active control or even a placebo.  For example, in the Duration trial series which investigated exenatide, Duration 4, 5, and 6 were all designed as non-inferiority trials.[9-11] One could be very critical of their use in this setting given the lack of a clear ethical concern or advantage over traditional therapies.  Another example showcasing the importance of this topic is in a comparison of linagliptin to glimepiride.  The results of this trial show superior A1C reductions with glimepiride (-0.36% vs -0.16%, difference of 0.2% 97.5% CI 0.09-0.3) but as the difference in A1C reduction met a non-inferiority margin of <0.35% the authors noted this as a positive result for linagliptin.  The investigators did not specify in their manuscript or supplementary appendix why they selected a margin of 0.35%.[12] 

            In a lasting quote Prasad summarizes well the first step clinicians should take when interpreting non-inferiority trials, “When you read a non-inferiority study, ask yourself: is the new therapy cheaper, more convenient, less invasive, or less toxic than the older one? If the answer is no read no further.”[1] As we wade into the future of endocrine therapies, we must not let a proliferation of non-inferiority trials influence our treatment decisions other than when appropriate.[13] This topic is a frequent discussion point for students and residents on rotation with me, providing one of those “light-bulb” moments for them in how to appropriately gauge the clinical impact of a trial.  Granted, I may be scarring them for life but hopefully that scar comes with a story to tell.

Citations:

  1. Prasad V. Non-Inferiority Trials in Medicine: Practice Changing or a Self-Fulfilling Prophecy? J Gen Intern Med. 2018. 33: 3. https://doi.org/10.1007/s11606-017-4191-y.
  2. Aberegg SK, Hersh AM, Samore MH. Empirical Consequences of Current Recommendations for the Design and Interpretation of Noninferiority Trials. J Gen Intern Med. 2018. 33:88. doi: https://doi.org/10.1007/s11606-017-4161-4.
  3. Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), Food and Drug Administration, U.S. Department of Health and Human Services. Guidance for industry non-inferiority clinical trials [online]. 2010; Available from: URL:http://www.fda.gov/ downloads/Drugs/Guidances/UCM202140.pdf Accessed: 2/4/19
  4. Rothmann MD, Wiens BL, Chan IS. Design and analysis of noninferiority trials. Boca Raton, Florida: Chapman & Hall/CRC, 2012.
  5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011; 365:883-891. https://doi.org/10.1056/NEJMoa1009638.
  6. U.S. Food and Drug Administration. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes [Internet], 2008. Available from http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf
    Accessed: 2/4/19
  7. Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting [Internet], 2008. Available from http://www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4368m-Final.pdf. Accessed: 2/4/19
  8. Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting [Internet], 2013. Available from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM388936.pdf.
  9. Buse JB, Nauk M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013; 381: 117-24. http://dx.doi.org/10.1016/S0140-6736(12)61267-7.
  10. Blevins T, Pullman J, Malloy J, et al. DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301–10. https://doi.org/10.1210/jc.2010-2081.
  11. Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Effi cacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 2012; 35: 252–58. https://doi.org/10.2337/dc11-1107.
  12. Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012; 380:475-83. http://dx.doi.org/10.1016/S0140-6736(12)60691-6.   
  13. Murthy VL, Desai NR, Vora A, et al. Increasing Proportion of Clinical Trials Using Noninferiority End Points. Clin Cardiol. 2012. September; 35(9):522-523. https://doi.org/10.1002/clc.22040.  

SGLT-2 Inhibitors and the CVOTs that evaluated them

Today I’m going to address the question, “Is it a class effect or specific drug effect?” 

Back in 2017, we started to see additional FDA labeled indications for empagliflozin (Jardiance®) and liraglutide (Victoza®) to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes mellitus (DM2) and established cardiovascular disease.  Since that time, further evidence continues to be released for SGLT-2 inhibitors, adding canagliflozin (Invokana®) to the list of medications with this indication.   Most recently, the ADA Standard of Medical Care 2019, the ADA/EASD Consensus Report 2018, and the 2018 ACC Expert Consensus Decision Pathway recommend preferred utilization of these medications in combination with metformin in patients living with DM2 and preexisting cardiovascular disease.[1-3]  As evidence began to roll out, starting with EMPA-REG (empagliflozin), then CANVAS (canagliflozin), many thought reduction of MACE  must be a class effect.[4-6]  However, then came DECLARE-TIMI 58 (dapagliflozin), reporting a lack of reduction in MACE.[7]  How then do we reconcile the utility of dapagliflozin (Farxiga®)?  In a summary of results, you’ll notice the question has not been completely answered.  Or has it??? 

Is the lack of MACE reduction in DECLARE-TIMI 58 due to trial design and the overall healthier population studied?  Or is MACE reduction really a drug specific benefit only seen with empagliflozin and canagliflozin and not with dapagliflozin?  Does DECLARE-TIMI-58 really evaluate the same overall outcome as EMPA-REG and CANVAS, secondary prevention of MACE in patients with established ASCVD, or is this newer article looking at the primary prevention of MACE in patients at risk of ASCVD, with the majority of the patients enrolled in DECLARE-TIMI-58 only being at risk for ASCVD?

Recently, similar results from the use of dapagliflozin were released by Norhammer, et al.[8]  In a real-world observational study, following the inclusion criteria of DECLARE-TIMI 58, patients were matched to form the DECLARE-like population.  Norhammer, et al. reported similar reductions in heart failure hospitalizations or cardiovascular mortality (HR 0.79, 95%CI 0.69-0.92) with no significant difference for the reduction of MACE (HR 0.90, 95%CI 0.79-1.03). This study somewhat confirms the results of DECLARE-TIMI 58, but also fails to answer the question left by DECLARE-TIMI 58.  With similar patient types, only 34% of patients having established ASCVD, are these trials really evaluating dapagliflozin for the primary or secondary prevention of MACE? 

The ADA algorithm points to CVOT evidence, recommending SGLT2-inhibitors as a preferred add-on treatment to metformin and lifestyle modifications, in patients with established ASCVD. They further recommend empagliflozin over canagliflozin, having “modestly stronger” evidence for reducing CVD events.[1]   Not likely to receive this indication, based on DECLARE-TIMI 58 and the results from A DECLARE-like observational study, dapagliflozin will not make this list of preferred agents.  Further, the newest approved SGLT2-inhibitor, ertagliflozin (Steglatro®), which ironically is now the preferred formulary item for many of my patients, has not published the CVOT results yet.  So, should we strictly follow available evidence and only start or even switch patients to empagliflozin or canagliflozin OR should we hold onto our belief that MACE reduction is a class effect and utilize all SGLT2-inhibitors available?

The ACC publication, albeit prior to the release of DECLARE-TIMI 58, suggest the MACE reduction benefit to be a class effect, which is evidenced by the first two trials completed (EMPA-REG and CANVAS), as well as multiple international observational studies utilizing claim, national registry, and electronic medical record data.[3]  This publication promotes the involvement of CV specialists in the utilization of these medications for their patients with ASCVD and DM2…a recommendation that might be considered a bit self-serving for ACC. 

As for me, I’m excited to see the use of SGLT-2 inhibitors (and GLP-1 receptor agonists) as preferred treatment add-ons in these populations.  Many of my patients currently use and see the benefit of these medications.  However, despite disparate results from initial CVOTs, insurance will continue to be one of the main determinants as to which medications or even classes of medications patients will utilize.  Overall, the shift away from just targeting blood sugar and considering the treatment of the associated metabolic processes involved in CV and renal risk is an appreciated paradigm shift.   Perhaps with the potential weight loss, minor blood pressure lowering, and moderate A1c reduction, these medications will rise to the occasion, help slow the progression of insulin resistance and weight gain, and lead to better health outcomes in the short and long-run.

What do you think?  Class or Drug?

  1. American Diabetes Association. Standards of medical care in diabetes–2019. Diabetes Care. 2018;42(Suppl 1):S1-S194.  http://doi.org/10.2337/cd18-0105
  2. Davies, M.J., D’Alessio, D.A., Fradkin, J. et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018. https://doi.org/10.1007/s00125-018-4729-5
  3. Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018. https://doi.org/10.1016/j.jacc.2018.09.020
  4. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
  5. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334.
  6. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
  7. Wiviott SD, Mosenzon BO, Kato ET, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018. doi: 10.1056/NEJMoa1812389
  8.  Norhammar A, Bodegard J, Nystrom T, et al. Dapagliflozin and cardiovascular mortality and disease outcomes in type 2 diabetes patients similar to the DECLARE-TIMI 58 participants: a nationwide observational study. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13627. [Epub ahead of print]