May 2016 FAQs

What are the key changes to drug therapy recommendations in the 2016 AACE type 2 diabetes algorithm? 

Introduction

Diabetes affects 29.1 million Americans with an additional 8.1 million people undiagnosed.¹ People with diabetes are at an increased risk for serious microvascular and macrovascular complications including renal failure, heart disease, and stroke. Clinical practice guidelines for the management of patients with type 2 diabetes are published by both the American Diabetes Association (ADA) as well as the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) with the goal of improving outcomes and preventing these long-term complications.^2-3 The ADA guidelines are published in the form of a position statement which incorporates evidence-based recommendations for patient-focused care.² AACE makes recommendations regarding the step-wise approach to managing the metabolic complications of type 2 diabetes that are presented in the form of a treatment algorithm.³ The AACE algorithm was updated in 2016 and the pertinent medication changes are highlighted in this summary.

Glycemic Control

Lifestyle modification with a goal of weight reduction remains the preferred initial treatment of hyperglycemia in patients with diabetes.³ A number of oral and injectable anti-hyperglycemic treatment options are available for patients with type 2 diabetes for whom lifestyle modification alone is insufficient to obtain the goal hemoglobin A1C (A1C). In patients with an A1C less than 7.5%, single agent drug therapy is recommended, while initiation with dual therapy is recommended for patients with an A1C greater than or equal to 7.5%. Use of triple therapy may be required to enhance treatment efficacy. Finally, it is recommended to initiate insulin therapy for patients with an initial A1C exceeding 9% and symptoms of hyperglycemia. For those that are asymptomatic, it is recommended to start combination oral antihyperglycemics.

There are currently 7 classes of oral agents and 2 classes of injectable agents that are approved for the treatment of type 2 diabetes for which AACE continues to provide a hierarchy of preference for use in type 2 diabetes (see Table).³ The level of recommendation for each agent is based off of the relative efficacy, safety, as well as the tolerability and side effect profile of each individual agent. Only 1 change to this hierarchy has been made from the 2015 guidelines ‒ thiazolidinediones are now preferred over alpha-glucosidase inhibitors.^3,4 The guidelines do not provide an explicit reason for the change in recommendation, but do discuss how the gastrointestinal adverse effects of alpha-glucosidase inhibitors have largely limited their use.

Table. Hierarchical treatment algorithm for patients based on initial HbA1c.³

Dyslipidemia

Patients with type 2 diabetes are at an increased risk for atherosclerotic cardiovascular disease (ASCVD) events such as stroke and coronary heart disease.³ In addition to glycemic control, the management of dyslipidemia is necessary to reduce the risk of ASCVD. Again, lifestyle modifications, such as weight loss and smoking cessation, are the first step in managing dyslipidemia. Moderate to high-intensity statins are the mainstay of therapy and are recommended for all patients with diabetes who have dyslipidemia as they have been shown to significantly reduce the risk of cardiovascular events and death in patients with type 2 diabetes.⁵ If goal cholesterol (including low density lipoprotein [LDL], triglycerides, and non-high density lipoprotein [HDL]) levels are not achieved on maximally tolerated doses of statin therapy, or if a patient is statin intolerant, there are a number of other medication classes that can be utilized to achieve goal cholesterol levels.³ 

Changes to the treatment algorithm for LDL lowering

Since the publication of the 2015 AACE treatment algorithm, a new class of dyslipidemia medications, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, were approved by the Food and Drug Administration (FDA) and are included in the updated 2016 algorithm. AACE includes the PCSK9 inhibitors in the list of first-line adjunctive therapy to statins to achieve goal cholesterol levels. In clinical trials, the PCSK9 inhibitors have shown substantial reductions in LDL levels.⁶ Compared to placebo, alirocumab showed a 39% to 62% reduction in LDL and evolocumab showed a 47% to 56% reduction. However, the effect of these agents on cardiovascular outcomes needs to be further evaluated.

Additional recommendations

In addition to the above changes in medication therapy, the AACE treatment algorithm also contains new recommendations for lifestyle modifications. Specific recommendations on nutrition, exercise, sleeping habits (including screening for obstructive sleep apnea), behavioral support, and smoking cessation based on the patient’s degree of obesity are made.

Conclusion

The 2016 update to the AACE treatment algorithm contains only 2 medication-related updates to the 2015 algorithm which includes the incorporation of the PCSK9 inhibitors for the treatment of dyslipidemia and the preference of thiazolidinediones over alpha-glucosidase inhibitors. The preference of thiazolidinediones does not appear to be based on any new clinical data, but rather a re-evaluation of clinical tolerability and adverse effects. However, the management of patients with type 2 diabetes must be tailored to patient-specific factors to ensure optimal outcomes.

References

1. Estimates of diabetes and its burden in the United States. Centers for Disease Control and Prevention website. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Updated 2014. Accessed April 4, 2016.
2. American Diabetes Association standards of medical care in diabetes. Diabetes Care. 2016;39(suppl 1):1-119.
3. Garber AJ, Abrahamsom MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm‒2016 executive summary. Endocr Pract. 2016;22(1):84-113.
4. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology‒clinical practice guidelines for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2015;21(suppl 1):1-87.
5. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008; 371(9607):117-125.
6. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 Inhibitors–The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015;373(17):1588-1591.

Prepared by:
Clare Kane, PharmD                                      
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago

April 2016

The information presented is current as April 11, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the clinical implications of the 2016 American Epilepsy Society (AES) guidelines for status epilepticus?

Status epilepticus (SE) is a neurologic emergency with a high mortality rate. Traditionally, SE was defined as at least 30 minutes of either continuous seizure activity (clinical and/or electrical) or recurrent seizure activity without recovery between seizures.^1,2 Given the large morbidity and mortality component, the definition of clinically significant SE has recently been refined to include continuous seizure activity for 5 minutes or longer.

Up to 150,000 Americans experience SE each year.² The mortality rate is up to 30% in adults but < 3% in children.² A retrospective analysis of SE rates among hospital discharges from 1979 to 2010 found that the incidence of SE increased from 3.5 to 12.5 cases per 100,000 total discharges during this time.³ Over the past 2 decades a number of treatment guidances have been published. Most recently the American Epilepsy Society (AES) published a detailed treatment algorithm.² Prior to this, evidence-based management strategies for SE came from the 2012 Neurocritical Care Society (NCS) treatment guidelines.¹

Comparison of the 2012 and 2016 guidelines

Historically, SE was defined as at least 30 minutes of unrelenting seizures. The 2012 NCS guidelines created an operational definition where at least 5 minutes of unrelenting seizures qualified for SE.¹ This change acknowledged the established high mortality rate of refractory SE (more likely when convulsive seizures last > 30 minutes) as well as the known neuronal damage that occurs with 30 minutes of unrelenting convulsive seizures. The guideline also recognizes that seizures of longer duration are less likely to self-abort without the use of medications. The 2016 AES guidelines kept the 5-minute operational time cutoff for SE.² This change ensures that more patients in SE are identified before seizures progress and become increasingly difficult to control.

The management of SE is highly variable in clinical practice because there is an overall paucity of evidence to validate using one treatment over another. The goal of the 2012 guidelines was to better standardize pharmacologic care for SE patients by creating an evidence-based guideline stating which therapies were best supported for the different etiologies of SE.¹ The 2016 guidelines, on the other hand, sought to further optimize SE pharmacologic care by creating an algorithm stratifying current treatment options into first-, second-, and third-line choices based on the time course into management of a convulsive SE episode.² Table 1 highlights a few key features of the 2012 and 2016 SE clinical treatment guidelines.

Table 1. Key features of SE treatment guidelines.^1,2

In effect, the 2012 NCS guidelines made recommendations for effective anticonvulsant therapies but did not formally stratify treatment strategies as first-, second-, or third-line options. The 2016 AES guidelines provided a single algorithm stratifying treatment options based on a consensus of the included evidence, applicable both to adults and children.

2016 AES guidelines

The 2016 AES guidelines sought to answer 5 critical, clinical questions.² Answers to each question with evidence in both adult and pediatric patients were provided in the guideline. In general, the evidence supporting effective drug therapies in the 2016 guidelines is consistent with the recommendations for effective drug therapies provided in the 2012 guidelines. The 5 key questions are reviewed below.

Which anticonvulsants are efficacious as initial and subsequent therapy?

In adults, therapy is initiated with an intravenous (IV) benzodiazepine, usually lorazepam and diazepam.² If no IV access is available, intramuscular (IM) midazolam is an acceptable initial option. When the above options are unavailable, IV phenobarbital, rectal diazepam, or midazolam administered via the buccal or intranasal routes are options. Second-line therapy after failure of initial benzodiazepine therapy can be achieved with IV valproic acid, IV phenytoin, or continuous infusion diazepam.

For pediatric patients, initial therapy can be achieved with IV lorazepam or diazepam, but there is also the option of alternate routes of benzodiazepine administration with rectal diazepam or IM/intranasal/buccal midazolam.² Second-line therapy after failure of benzodiazepines includes agents such as IV valproic acid or IV phenobarbital, with valproic acid being better tolerated.

The guidelines state that there is insufficient evidence for or against levetiracetam as initial or second-line therapy for both adults and children.² Phenytoin is also still unsupported for use in pediatrics.  

What adverse effects are associated with anticonvulsant administration?

In both adults and children, serious adverse effects of anticonvulsant use include respiratory depression and cardiac effects (hypotension and dysrhythmias).² In adults, there is no difference in cardiac or respiratory adverse events between phenytoin and benzodiazepines. Specific to pediatrics, there is no substantial difference in rates of respiratory depression among midazolam, lorazepam, or diazepam when administered by any route.

Which is the most effective benzodiazepine?

In adults who do not have established IV access, IM midazolam is more effective than IV lorazepam.² The evidence for this recommendation comes primarily from the 2012 RAMPART randomized controlled trial (RCT), where IM midazolam met not only the non-inferiority criteria but was also superior to IV lorazepam.⁴ In this study IM midazolam led to a significantly higher rate of total seizure cessation compared to IV lorazepam (73% vs 63% of patients; 95% CI, 4.0 to 16.1; P<0.001). There was no significant difference in efficacy detected between lorazepam and diazepam upon review of the available evidence.

In pediatric patients there was no significant difference in efficacy detected between IV lorazepam and IV diazepam, but midazolam given via alternative non-IV routes (e.g., IM, intranasal, and buccal) may potentially be more effective than IV or rectal diazepam.²

Is IV fosphenytoin more effective than IV phenytoin?

There was insufficient evidence available directly comparing the efficacy of phenytoin and fosphenytoin.² Fosphenytoin is the preferred option due to better patient tolerability, but phenytoin remains a viable anticonvulsant option if fosphenytoin is unavailable. Included clinical trials featured different rates of fosphenytoin and phenytoin administration, but all looked at patient tolerability and reported more pain at the infusion site and more cardiac adverse effects (hypotension and dysrhythmias) with phenytoin.

When does the anticonvulsant efficacy drop significantly (i.e., after how many different anticonvulsants does status epilepticus become refractory)?

Four RCTs were included to answer this clinical question.² There is more conclusive evidence in adults than in pediatrics to suggest that the second anticonvulsant administered is less effective than the first, and that the third anticonvulsant administered is even less effective than the first in fully controlling seizures in SE. Despite this, only 1 randomized trial directly addressed this exact question.⁵ Treatment success was defined as stopping seizures within 20 minutes of starting an anticonvulsant infusion and having no seizure recurrence within 60 minutes of the infusion. Patients were randomized to subsequent treatment arms if the prior treatment(s) were unsuccessful. Overall success rate of the first administered drug was 55.5%, the second drug attempted conferred an additional 7.0% success rate, and the third drug attempted conferred an additional 2.3% success rate.

2016 AES algorithm

The 2016 AES treatment algorithm is divided into 4 phases with specific management strategies for each.² Time 0 is considered as the moment the first seizure activity starts. Patients who respond successfully can be removed from further algorithmic treatment and receive standard medical care.

Table 2. American Epilepsy Society SE treatment algorithm.²

In the pipeline

There is an ongoing, international, multicenter, phase 3, clinical trial known as the Established Status Epilepticus Treatment Trial (ESETT) to assess what, if any, is the preferred sequence of giving the second-line antiepileptic agents (fosphenytoin, valproic acid, and levetiracetam) in benzodiazepine-refractory SE.^6,7  The researchers are still actively recruiting participants and there are no interim results available, but the study aims to provide more guidance on how to best approach antiepileptic treatment after failure of first-line benzodiazepine therapy. Results from this study could prove critical in further refining the recommendations for anticonvulsant therapy for SE management as embodied in the 2016 AES treatment algorithm.

Conclusion

In conclusion, the 2016 AES guidelines provide time-sensitive recommendations for first-, second-, and third-line treatment options for managing convulsive SE. During the initial stabilization phase, standard first aid techniques for seizures should be started. Benzodiazepines are first-line anticonvulsants of choice during the initial therapy phase. If seizures persist or recur, the second therapy phase begins, and a single dose of an alternative agent (IV fosphenytoin, IV valproic acid, or IV levetiracetam) can be attempted. For seizures requiring further therapy, a dose of any second-line agent can be repeated or anesthetic-grade doses of sedatives with continuous EEG monitoring can be attempted. Despite these clear recommendations in this new stepwise approach to SE, it is important to note that there is currently no clear evidence to guide the course/sequence of therapy during the second and third phases.

References

1. Brophy GM, Bell R, Claassen J, et al on behalf of the Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23.

2. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: Report of the guideline committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61.

3. Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care. 2014;20(3):476-483.

4. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600.

5. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339(12):792-798.

6. Cock HR; ESETT Group. Established status epilepticus treatment trial (ESETT). Epilepsia. 2011;52(suppl 8):50-52.

7. U.S. National Institutes of Health. Established Status Epilepticus Treatment Trial (ESETT) study record details website. https://clinicaltrials.gov/ct2/show/NCT01960075?term=ESETT&rank=1. Updated October 30, 2015. Accessed March 18, 2016.

Prepared by:
Melissa Santibañez, Pharm.D.
PGY-1 Pharmacy Practice Resident

April 2016

The information presented is current as of April 25, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the clinical evidence for the use of sugammadex (Bridion®)?

Introduction

Sugammadex (Bridion®) is a modified gamma cyclodextrin that is indicated for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery.¹  Table 1 provides a summary of key labeled information for sugammadex.  The drug exerts its therapeutic effect by forming a complex with rocuronium or vecuronium and reducing the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction.  Sugammadex was originally developed by Organon in the 1990s and has been used extensively in Europe, Asia, and Central and South America for many years.²  Approval of sugammadex in the United States occurred on December 15^th, 2015.  The approval of sugammadex was delayed here pending the completion of additional clinical trials.

Table 1.  Sugammadex highlights.¹

Clinical Evidence

Since its initial approval outside the United States, sugammadex has been administered to over 9 million patients and approximately 500 articles have been published related to various aspects of the medication and its use.³  With its approval in the United States, more recent reviews of the clinical efficacy and safety of sugammadex have been published;^4-6 however, there are 5 pivotal clinical trials that led to its Food and Drug Administration (FDA) approval.  These trials are summarized in Table 2.  Overall, the results of these trials showed sugammadex to be associated with a significantly faster recovery of neuromuscular function when compared to neostigmine^7-10 or spontaneous recovery following succinylcholine.¹¹

Table 2.  Sugammadex – pivotal clinical trials.^7-11

Conclusion

Sugammadex is a medication that works through a unique mechanism of action to reverse the effects of rocuronium and vecuronium.  Sugammadex has been used successfully worldwide for several years in millions of patients; however, the FDA only approved it in December 2015 pending the completion of additional clinical trials.  The pivotal clinical trials of sugammadex have consistently shown the agent to result in faster recovery of neuromuscular function, with a similar safety profile, as compared to neostigmine.  Additionally, the drug has also been shown to result in faster neuromuscular function recovery after high-dose rocuronium as compared to spontaneous recovery after succinylcholine administration.

References

1.  Bridion [package insert].  Whitehouse Station, NJ: Merck & Co., Inc.; 2015.

2.  Welliver M, Cheek D, Osterbrink J, McDonough J.  Worldwide experience with sugammadex: implications for the United States.  AANA J. 2015;83(2):107-115.

3.  Ledowski T.  Sugammadex: what do we know and what do we still need to know? A review of the recent (2013 to 2014) literature.  Anaesth Intensive Care. 2015;43(1):14-22.

4.  Jahr JS, Miller JE, Hiruma J, Emaus K, You M, Meistelman C.  Sugammadex: a scientific review including safety and efficacy, update on regulatory issues, and clinical use in Europe.  Am J Ther. 2015;22(4):288-297.

5.  Partownavid P, Romito BT, Ching W, et al.  Sugammadex: a comprehensive review of the published human science, including renal studies.  Am J Ther. 2015;22(4):298-317.

6.  Abad-Gurumeta A, Ripolles-Melchor J, Casans-Frances R, et al.  A systematic review of sugammadex vs neostigmine for reversal of neuromuscular blockade.  Anaesthesia. 2015;70(12):1441-1452.

7.  Blobner M, Eriksson LI, Scholz J, Motsch J, Della Rocca G, Prins ME.  Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomized, controlled trial   Eur J Anaesthesiol. 2010;27(10):874-881.

8.  Khuenl-Brady KS, Wattwil M, Vanacker BF, Lora-Tamayo JI, Rietbergen H, Alvarez-Gomez JA.  Sugammadex provides faster reversal of vecuronium-induced neuromuscular blockade compared with neostigmine: a multicenter, randomized, controlled trial.  Anesth Analg. 2010;110(1):64-73.

9.  Lemmens HJM, El-Orbany MI, Berry J, Morte Jr JV, Martin G.  Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine.  BMC Anesthesiol. 2010;10:15.

10. Jones K, Caldwell JE, Brull SJ, Soto RG.  Reversal of profound rocuronium-induced blockade with sugammadex.  Anesthesiology. 2008;109(5):816-824.

11. Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M.  Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium.  Anesthesiology. 2009;110(5):1020-1025.

April 2016

The information presented is current as April 25, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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