Authors: Julia Wu, PharmD; James Unverferth, PharmD, PGY-1 Pharmacy Practice Residents

Mentor: Davina Dell-Steinbeck, PharmD, BCPS

Learning Objectives

• Identify the unique mechanism of SGLT2 inhibitors
• Differentiate dosing and mechanisms of action between the different SGLT2 inhibitors
• Identify specific concerns with the use of SGLT2 inhibitors in T1DM
• Describe the proposed mechanism of action of SGLT2 inhibitor-mediated euglycemic DKA
• Describe the results of relevant studies looking at the safety and efficacy of SGLT2-inhibitors in Type 1 Diabetes Mellitus

Background

Type 1 diabetes (T1DM) is a chronic condition in which the pancreas produces little or no insulin. The exact cause of type 1 diabetes is unknown. Most commonly, the body's own immune system mistakenly destroys pancreatic islet β-cells, thereby disabling the body’s ability to produce insulin in response to elevated blood sugars. Other possible causes include genetics, exposure to viruses, and other environmental factors. Approximately 1.25 million Americans have Type 1 diabetes and an estimated 40,000 people are diagnosed with Type 1 diabetes each year. By 2050, 5 million people are expected to be diagnosed with Type 1 diabetes. This disease state is also costly for the patients: there are $14 billion in Type 1 diabetes-associated healthcare expenditures and lost income each year, mostly through medication cost and complications associated with the disease state. Preliminary data from T1 International’s 2018 access and supply survey reported 1 of every 4 US respondents have rationed insulin due to cost, and less than a third of patients consistently achieve target blood glucose levels.¹⁷

Because the hallmark of type 1 diabetes is absent or near-absent β-cell function, insulin treatment is essential for individuals with type 1 diabetes⁹. Over the past three decades, evidence has accumulated supporting multiple daily injections of insulin or continuous subcutaneous administration through an insulin pump as providing the best combination of efficacy and safety for people with type 1 diabetes⁹. However, other treatment options have been studied and proposed as adjunct therapy for patients unable to reach their A1c and blood glucose goals on insulin alone. This is partially due to unfavorable adverse effects associated with insulin therapy, which include blood glucose variability, hypoglycemic events, and weight gain. These agents, listed in Table 1, all provide their own unique benefits and disadvantages in this particular patient population. SGLT2 inhibitors specifically were identified as a possible adjunct therapy due to their added A1c benefit and increased glycemic control through minimizing glycemic variability.

SGLT2 Inhibitors

There is an interest in SGLT2 inhibitors as adjunct therapy to insulin due to their unique mechanism of action. These agents work by lowering the renal threshold for glucose and increasing urinary glucose excretion by interfering with the reabsorption of renally-filtered glucose across the tubular lumen of the proximal renal tubules. Through this mechanism, glucose excretion is continuous and proportional to serum glucose levels, thus minimizing risk of hypoglycemia. This would help to lower A1c without introducing additional risk for hypoglycemia that is associated with insulin, thus partially negating this adverse effect. Table 2 illustrates the different agents available and their dosing schemes, currently only approved for Type 2 Diabetes by the US FDA.

Concerns with SGLT2 Inhibitor Use

There have been several common adverse effects associated with SGLT2 inhibitors including genital and urinary tract infections, hypotension and hypovolemia, acute kidney injury, intestinal side effects, diabetic ketoacidosis, foot amputations, bone fractures, and cancer.¹⁰ Though the incidence and actual risk of some of these may be debated, the adverse effect of primary concern in patients with T1DM is diabetic ketoacidosis (DKA). In traditional DKA, an excessive rise in glucagon levels during states of relative insulin deficiency stimulates hepatic glycogenolysis despite presence of excessive blood glucose levels. This fuels lipolysis, which provides a source of free fatty acids that are shunted through the ketosis pathway and converted into different ketone bodies. The overwhelming build-up of glucose and ketone bodies in the presence of insulin deficiency culminates in elevated anion gap metabolic acidosis with potentially fatal outcomes if DKA is not diagnosed and treated in a timely fashion.¹⁸

Timely diagnosis of DKA in patients with T1D taking SGLT2 inhibitors may be difficult as they can develop a phenomenon known as euglycemic DKA. This occurs when the ultimate manifestations of traditional DKA arise in the absence of elevated blood glucose, one of the hallmark and easily identifiable symptoms of traditional DKA, making early recognition and treatment more difficult. SGLT-2 inhibition lowers the renal threshold for glucose excretion, reducing blood glucose levels and thereby reducing insulin secretion from pancreatic β-cells.²⁰ This decline in circulating insulin levels results in a reduction of the anti-lipolytic effects of insulin. Following this, substrate utilization shifts from carbohydrates to fat oxidation and production of ketone bodies, which in turn poses a theoretical risk for euglycemic ketoacidosis. Evidence also suggests that SGLT2 inhibitors stimulate glucagon secretion, either directly through effects on pancreatic α-cells or indirectly through decreasing insulin secretion. Finally, another mechanism of euglycemic DKA is thought to occur through renal effects on ketone excretion: during starvation, renal re-absorption of ketones increases in proportion with serum ketone levels, but renal utilization of ketone bodies is reduced. It is thought that SGLT2 inhibitors mimic starvation conditions and cause an increase in ketone renal reabsorption, thereby continuing to produce glycosuria and render the body susceptible to acidemia through ketogenesis. Factors associated with increased risk of DKA while taking an SGLT2 inhibitor include:

• Inappropriate insulin dose reduction or omission
• Diminished food and fluid consumption
• Low carbohydrate diets
• Alcohol abuse
• Infection
• Abdominal crisis
• Thyrotoxicosis
• Myocardial infarction
• Surgery
• Trauma

Literature Review

Due to increased interest in use of SGLT2 inhibitors in Type 1 Diabetes, several efficacy and safety outcome trials have been performed to investigate these agents as adjunct therapy to insulin. Most of the trials had similar designs; however, differences between inclusion and exclusion criteria, primary endpoints, risk mitigation strategies, and definitions of hypoglycemia and DKA are of particular importance as they may misrepresent the results of one study compared to another. Because of this, these differences will be highlighted in each trial.

Most DEPICT-1 participants were white and all were from Europe. The mean age was 43 years and the mean time since type 1 diabetes diagnosis was 20 years. Mean baseline HbA1c was 8.53% and mean baseline bodyweight was 82.4 kg.

DEPICT-2 was performed in an effort to include a more diverse population. Most participants were white and from Europe, except a small contingent from Japan that made up ~20% of the study population. The mean age of the study population was 43 years, with a mean time since diagnosis of type 1 diabetes of 19 years. The mean baseline HbA1c was 8.4% and mean baseline body weight was 79.2 kg.

Both trials concluded that dapagliflozin was a promising adjunct treatment to insulin to improve glycemic control, promote weight loss, and decrease daily dose of insulin requirements for patients with T1DM. Results were statistically significant for both strengths of dapagliflozin compared to placebo. In DEPICT-1 there was no difference realized in hypoglycemia or DKA events in the dapagliflozin group compared to placebo. However, this could be due to the fact that almost every participant in all treatment groups experienced a hypoglycemic event. Additionally there were very few DKA events, likely due to the lack of definition to use for diagnosis of the disease state. DEPICT-2 found an increase in DKA events associated with dapagliflozin treatment independent of the dose that patients received compared to placebo. Dapagliflozin was approved for treatment of T1DM by the European Commission in March 2019 and was also approved as an adjunct to insulin for T1DM in Japan but was rejected by the FDA for this indication in July 2019.

EASE (2015, 2018)^12,13

The EASE trials were all multinational, randomized, double-blinded, placebo-controlled trials that investigated the efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes. Two of these trials utilized a unique strength of empagliflozin, 2.5mg, which was specifically made for the indication of T1DM.

EASE-1 had a notably smaller sample size of 75 patients, randomized patients to empagliflozin 2.5 mg, 10 mg, 25 mg, or placebo as adjunct to insulin, and followed their patients for 28 days. In addition, patients underwent a 2-week run-in period during which they received diet and exercise counseling. Notably, 100% of patients enrolled were white, and a majority were male. The primary outcome was the change in 24-hour urine glucose excretion on day 7, and the trial found that empagliflozin as adjunct to insulin increased UGE, improved HbA1c, and reduced weight with lower insulin doses compared to placebo without increasing episodes of hypoglycemia.

EASE-2 had a much larger sample size of 730 patients and studied empagliflozin 10 mg and 25 mg only compared to placebo, and only looked at change in HbA1c after 26 weeks. Patients were required to have a C-peptide level <0.7 ng/mL and underwent a 6-week insulin intensification period prior to randomization.

EASE-3 studied 977 patients, added empagliflozin 2.5 mg back in as a study group, and continued to look at the change in HbA1c after 26 weeks. Both EASE-2 and 3 slightly improved the diversity of the population studied over EASE-1, with about 3% black and Asian patients, but still had a high percentage of white patients at about 94%.

The EASE-2 and EASE-3 trials found that empagliflozin improved glycemic control and weight without increasing episodes of hypoglycemia. Results were consistent and statistically significant among all strengths of empagliflozin. Between EASE-1 and 2, it was found that ketoacidosis rates were increased in the 10 mg and 25 mg groups, but not the 2.5 mg group.

The EASE trials corroborated the results from DEPICT-1 and 2: empagliflozin improved glycemic control and decreased weight in T1DM without increasing episodes of hypoglycemia, but there was an increased risk of ketoacidosis associated with the higher doses. Similar to dapagliflozin, in November 2019 an FDA advisory committee declined to recommend approving use of empagliflozin T1DM, citing insufficient data for efficacy with increased risk of DKA.

inTandem (2018,2018,2017)^14-16

The inTandem trials investigated the efficacy and safety of sotagliflozin as adjunct to optimized insulin in patients with type 1 diabetes. All three trials were multinational, double-blind, randomized placebo-controlled studies. inTandem 1 occurred in North America, inTandem 2 occurred in Europe, and inTandem 3 occurred across multiple continents in 19 different countries.

Both inTandem 1 and 2 randomized patients to sotagliflozin 200 mg, 400 mg, or placebo, and the primary outcome was the change in HbA1c after 24 weeks and 52 weeks. Patients were required to undergo insulin optimization in the 6 weeks before randomization, which was continued throughout the trial, and were excluded if they had elevated beta-hydroxybutyrate (BHB) levels, which is the primary ketone body found in patients who develop DKA. Patients were provided with urine ketone strips and monitors, blood BHB meters, and extensively educated on signs and symptoms of ketoacidosis. Patients in both studies were primarily white (92% and 96% respectively) and around 45 years old on average. Both inTandem 1 and 2 found that sotagliflozin was associated with sustained HbA1c reduction, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo. Results were statistically significant for both doses of sotagliflozin.

inTandem 3, which randomized patients to only sotagliflozin 400 mg or placebo, looked at HbA1c <7.0% without episodes of severe hypoglycemia or DKA as their primary outcomes. Patients were similarly provided with urine ketone strips, blood BHB meters and strips, and extensive education. The majority of patients were also white (88%) and had similar average age of about 42 years old. They found that the proportion of patients who achieved HbA1c < 7.0% without severe hypoglycemia or DKA was larger in the group that received sotagliflozin than in the placebo group. However, rates of DKA were also higher in the sotagliflozin group, similar to both the DEPICT and EASE trials, despite more robust attempts to screen out patients at higher risk of DKA and providing monitoring supplies and education.

Sotagliflozin has a unique mechanism of action, inhibiting both SGLT1 and 2. SGLT1 receptors are located in the intestine, and inhibition results in delayed glucose absorption and reduced post-prandial blood glucose levels.21 The combination of these mechanisms is thought to have a greater impact on efficacy in treatment of diabetes. There are also hypotheses involving SGLT1 receptors in the myocardium and the effect of sotagliflozin on cardiovascular outcomes: the SOLOIST-WHF Trial is currently ongoing and seeks to demonstrate superiority of sotagliflozin in reducing cardiovascular mortality and morbidity in patients with T2DM. It is currently approved for use in Europe but was denied by the FDA via split decision in January 2019 due to concern for increased risk of DKA. Based on clinical trial data, use of sotagliflozin in patients with T1DM would be expected to cause an additional 5000 cases of DKA and 20 deaths each year, assuming around 10% of patients would be using it. At this present time, sotagliflozin is not available in the US and will likely require further efficacy and safety investigation before it is approved for use.

Conclusions

Based off of the studies described above, SGLT2 inhibitors as a class have demonstrated increased efficacy in improving glycemic control in patients with type 1 diabetes. Additionally, certain agents showed decreased insulin requirements with limited hypoglycemia events, but an increased risk of diabetic ketoacidosis among all agents. Therefore, these agents are a viable option as adjunct to insulin in select patients with Type 1 Diabetes (see Figure 2 for characteristics of ideal candidates). Some final considerations when deciding to initiate therapy: as mentioned previously, none of these agents are approved yet in the US for the treatment of T1DM due to a mixture of efficacy and safety concerns. At this time, the cardiovascular benefits demonstrated by SGLT2 inhibitors in patients with T2DM may not be extrapolated to patients with T1DM, which negates that potential added benefit. Additionally, these agents are expensive and can run close to $20 per tablet without insurance. Lastly, in several of the studies discussed, patients were provided with a means to monitor blood ketones as a way of minimizing the risk of DKA. These machines are not widely available in the US, are not likely covered by insurance, and purchasing outright could increase out-of-pocket costs to unmanageable levels. Urine ketone strips were also provided in several studies; however, separate studies have shown that urine ketone strips are not effective at detecting development of DKA, and these tests still pose an expense barrier. In addition, the studies that provided these monitoring devices still found a statistically significant difference in DKA risk, which may indicate that their use does not actually help to mitigate DKA occurrence. If a patient is interested in initiating therapy, it should be a provider-patient decision that weighs these risks and benefits, especially knowing that this is not a currently FDA-approved indication in the US.

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References

1. Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 2004; 21: 1204–1212.
2. Edelman S, Garg S, Frias J, et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 2006; 29: 2189–2195.
3. Meng H, Zhang A, Liang Y, Hao J, Zhang X, Lu J. Effect of metformin on glycaemic control in patients with type 1 diabetes: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2018; 34: e2983.
4. Petrie JR, Chaturvedi N, Ford I, et al.; REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017; 5: 597–609.
5. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects of insulin plus glucagon-like peptide-1 receptor agonists (GLP-1RAs) in treating type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Ther 2017; 8: 727–738.
6. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care 2015; 38: 2258–2265.
7. Dandona P, Mathieu C, Phillip M, et al.; DEPICT-1 Investigators. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5: 864–876.
8. Patoulias D, Imprialos K, Stavropoulos K, Athyros V, Doumas M. SGLT-2 inhibitors in type 1 diabetes mellitus: a comprehensive review of the literature. Curr Clin Pharmacol. 7 August 2018 [Epub ahead of print].
9. Standards of Medical Care in Diabetes – 2019.
10. Dellepiane S, Nasr M, Assi E, et al. Sodium Glucose Cotransporters Inhibitors in Type 1 Diabetes. Pharmacological Research 2018; 133: 1-8.
11. Mathieu C, Dandona P, Gillard P, et al. Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial. Diabetes Care 2018; 41 (9): 1938-1946.
12. Pieber TR, Famulla S, Eilbracht J, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015; 17: 928-935.
13. Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care 2018; 41: 2560-2569.
14. Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 study. Diabetes Care 2018; 41: 1970-1980.
15. Danne T, Cariou B, Banks P, et al. HbA1C and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 study. Diabetes Care 2018; 41: 1981-1990.
16. Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med 2017; 377: 2337-2348.
17. 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.
18. Goldenberg R, Gilbert J, Hramiak I, Woo V, Zinman B. Sodium-glucose co-transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol. Diabetes Obes Metab 2019: 1-11.
19. Rawla P, Vellipuram A, Bandaru S, Raj J. Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep 2017: 17-0081.
20. Gajjar K, Luthra P. Euglycemic Diabetic Ketoacidosis in the Setting of SGLT2 Inhibitor Use and Hypertriglyceridemia: A Case Report and Review of Literature. Cureus 2019: e4384.
21. Cefalo CMA, Cinti F et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovascular Diabetology 2019, https://doi.org/10.1186/s12933-019-0828-y.

By: Elizabeth Ridgway, Pharm.D. Candidate 2020

and Paul Juang, Pharm.D., BCPS, BCCCP, FASHP, FCCM; Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy

Definition and Subtypes

Delirium, as it is defined by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders-IV, is a change in consciousness and cognition that develops over hours to days.¹ Evidence suggests that there are different degrees of delirium in critically-ill patients, ranging from subsyndromal to clinical delirium, both of which are associated with poor prognosis as compared to no delirium.² Clinical delirium may be further divided into subtypes, including hyperactive, hypoactive, and mixed delirium, based on the presence of psychomotor symptoms. Hypoactive delirium is characterized by decreased responsiveness and withdrawal, conversely hyperactive delirium is characterized by restlessness and agitation.1 Mixed delirium shows characteristics of both hyperactive and hypoactive delirium intermittently.^1-5

Prevalence and Prognosis

Per the Society of Critical Care Medicine 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) in Adult Patients in the ICU, delirium affects approximately 50% of mechanically ventilated patients.³ However, delirium is believed to be underdiagnosed, with the prevalence of delirium in critically-ill patients varying between 20% to 89% in literature and being dependent largely on the diagnostic criteria utilized, disease severity, and the population studied.^1-5 Pure hyperactive delirium is relatively rare affecting only 2% to 11% of patients, while hypoactive delirium is far more common.^4,5 Comparatively, long-term cognitive impairment is more common with hyperactive delirium, while mortality is more common in patients with hypoactive delirium.4 Regardless of subtype, delirium is an independent risk factor for prolonged hospitalization, neuropsychologic dysfunction, morbidity, and mortality.^3,5 Furthermore, delirium is associated prolongation in the duration of hospitalization and mechanical ventilation, resulting in increased healthcare expenditure, averaging $15,000 per patient.^3,6

Pathophysiology

Several pathophysiological mechanisms are believed to contribute to delirium in critically-ill patients. Notably, none of these theories are well validated in this patient population.¹

Risk Factors and Predictive Models

The PADIS Guidelines list several risk factors for the delirium, which are shown below.³

Non-modifiable

• Increased age
• Dementia
• Prior coma
• Emergency surgery
• Trauma
• Organ dysfunction

Modifiable

• Benzodiazepine use
• Blood transfusions

Predictive models, using these risk factors, have been validated and are capable of estimating the onset of delirium in critically-ill patients, when used within 24 hours of admission to the intensive care unit.³

Assessment

Due to the prevalence of delirium, critically-ill patients should be regularly assessed for the presence of delirium using validated tools, such as the Delirium Triage Screening (DTS) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).³

Prevention and Treatment of Delirium

Nonpharmacological Management

The PADIS Guidelines recommend the use of multicomponent nonpharmacological regimens for both the prevention and treatment of delirium in critically-ill patients.³ Multicomponent regimens should consist of the following.³

• Optimizing sleep (minimizing light and noise)
• Early mobilization
• Use of hearing aids and glasses in the hearing and vision impaired patients, respectively
• Patient reorientation (clocks, windows, and cognitive stimulation)

Furthermore, single-component regimens using only light therapy are not recommended per the findings of the following studies.³

Ramelteon

Ramelteon, a melatonin receptor agonist, has shown variable benefit in critically-ill patients as demonstrated by the two studies described below. Neither were incorporated into the PADIS Guidelines.3

These findings suggest the ramelteon may be effective for the prevention of delirium, however is unlikely to be efficacious for the treatment of delirium.^9,10 More research is needed to fully validate these findings.

Dexmedetomidine

The PADIS Guidelines suggest that dexmedetomidine, an α2-agonist, is the preferred sedative for most critically-ill patients, however it should not be added specifically for delirium prevention.³ Recent studies examining use of dexmedetomidine specifically for prevention and the acute management of delirium are detailed below.

Notably, dexmedetomidine is appropriate for the treatment of delirium in critically-ill patients only if agitation is preventing extubation per the PADIS Guidelines.³

Anti-psychotics

The PADIS Guidelines do not recommend the use of anti-psychotics for the prevention or treatment of delirium in critically-ill patients. This recommendation is supported by the MIND-USA study, a large, multicenter, randomized, placebo-controlled, phase 3 trial, published in 2018. MIND-USA demonstrated that neither haloperidol nor ziprasidone impacted the days alive without delirium or coma (haloperidol: 7.9 days, 95% CI 4.4 to 9.6; ziprasidone: 8.7 days, 95% CI 5.9 to 10.0; placebo: 8.5 days, 95% CI 5.6 to 9.9; p=0.26) in mechanically-ventilated patients.⁵ Therefore, the use of anti-psychotics for the treatment of delirium is not recommended at this time.

Statins

Hydroxymethylglutaryl-CoA reductase inhibitions, also called statins, have been suggested as potential agents for the prevention and management of delirium due to their anti-inflammatory activity.^3,15 Despite their theoretical benefit, the current PADIS Guidelines do not recommend the use of statins for delirium prevention or treatment.³ A systematic review and meta-analysis, published in 2017, which included 6 studies, found that there was no benefit with statin administration in critically-ill patients with regard to delirium prevention (RR 1.05, 95% CI 0.85 to 1.29, p=0.56).¹⁴ More recently in 2017, a randomized control trial examining the effect of simvastatin in critically-ill patients found that simvastatin had no impact on days alive without delirium or coma (mean difference vs placebo 0.4 days, 95% CI 1.3 to 2.1, p=0·66).¹⁵

Ketamine

Ketamine, an NMDA antagonist, is currently not recommended for either the treatment of prevention of delirium per the PADIS Guidelines.³ Despite this recommendation, one study published in 2018 demonstrated that low doses of ketamine reduced the incidence (37% vs 21%, p=0.03) and duration (5.3 ± 4.7 days vs 2.8 ± 3 days, p=0.005) of delirium in post-operative patients.¹⁶ However, these findings are insufficient to support the use of ketamine in the majority of critically-ill patients.

Summary

• Delirium, characterized by acute cognitive impairment, is a common complication in critically-ill patients.
• Assessment of critically-ill patients with validated tools, such as the DTS or CAM-ICU, is recommended at scheduled intervals.
• Multicomponent regiments consisting of optimizing sleep, early mobilization, and reorientation are recommended for all critically-ill patients.
• Ramelteon may be effective for the prevention of delirium, when started prior to the onset of delirium.
• Dexmedetomidine is associated with reduced incidence and duration of delirium, as compared to propofol and benzodiazepines.
• Anti-psychotics, statins, and ketamine are not recommended for the treatment of delirium in critically-ill patients based upon the available data.

References

1. Girard TD, Pandharipande PP, Ely EW. Delirium in the intensive care unit. Crit Care. 2008;12(Suppl 3):S3.
2. Ouimet S, Riker R, Bergeon N, et al. Subsyndromal delirium in the ICU: evidence for a disease spectrum. Intensive Care Med. 2007;33(6):1007-13.
3. Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-73.
4. Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med. 2014;370(5):444-54.
5. Girard TD, Exline MC, Carson SS, et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506-16.
6. Vasilevskis EE, Chandrasekhar R, Holtze CH, et al. The cost of ICU delirium and coma in the intensive care unit patient. Med Care. 2018;56(10):890-7.
7. Simons KS, Laheij RJ, van den Boogaard M, et al. Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomized controlled trial. Lancet Respir Med. 2016;4(3):194-202.
8. Smonig R, Magalhaes E, Bouadma L, et al. Impact of natural light exposure on delirium burden in adult patient receiving invasive mechanical ventilation in the ICU: a prospective study. Ann Intensive Care. 2019;9(1):120.
9. Nishikimi M, Numaguchi A, Takahashi K, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit Care Med. 2018;46(7):1099-1105.
10. Thom R, Bui M, Rosner B, et al. Ramelteon is not associated with improved outcomes among critically ill delirious patients: single-center retrospective cohort study. Psychosomatics. 2019;60(3):289-297.
11. Reade MC, Eastwood GM, Bellomo R, et al. Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: a randomized clinical trial. JAMA. 2016;315(14):1460-8.
12. Su X, Meng ZT, Wu XH, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomized, double-blind, placebo-controlled trial. Lancet. 2016;388(10054):1893-1902.
13. Skrobik Y, Duprey MS, Hill NS, Devlin JW. Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2018;197(9):1147-56.
14. Vallanbhajosyula S, Kanmanthareddy A, Erwin PJ, Esterbrooks DJ, Morrow LE. Role of statins in delirium prevention in critical ill and cardiac surgery patients: A systematic review and meta-analysis. J Crit Care. 2017;37:189-196.
15. Page VJ, Casarin A, Ely EW, et al. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2017;5(9):727-737.
16. Perbet S, Verdonk F, Godet T, et al. Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedative ICU patients: a randomized double-blind trial. Anaesth Crit Care Med. 2018;37(6):589-595

By: Kathryn Renken, PharmD Candidate 2021, St. Louis College of Pharmacy

Mentor: Diane Klueppel, PharmD, SSM Health Rehabilitation Hospital

Depression Background 

Major depressive disorder is a condition “characterized by discrete episodes of at least 2 weeks’ duration … involving clear-cut changes in affect, cognition, and neurovegetative functions and inter-episode remissions,” distinct from normal sadness and grief.¹ Symptoms include depressed mood, decreased interest or pleasure in activities, significant weight loss or gain in a short period of time, changes in sleep patterns, excessive fatigue, feelings of worthlessness, indecisiveness, and suicidal ideation. According to the National Institute of Mental Health’s 2017 National Survey on Drug Use and Health, an estimated that 17.3 million U.S. adults, or 7.1% of all adults in the United States, have experienced at least one major depressive episode.² Out of these, it is estimated that 11 million, or 4.5% of all U.S. adults, have experienced severe impairment as a result, which can negatively affect an individual’s quality of life. Given that major depression can also lead to suicidal thoughts or behaviors, it is essential to identify and treat symptoms as quickly as possible. 

Treatment of depression often requires both pharmacologic and behavioral interventions. Pharmacologic interventions, including antidepressants, can take up to four weeks to reach full effect.³ First-line antidepressants typically include selective serotonin reuptake inhibitors (SSRIs) and, if unsuccessful, the patient may be switched to a different agent from the same or another class, requiring an additional four weeks to reach therapeutic effect. Due to the severe consequences of allowing depression to go untreated, it is crucial to find a medication that works for a patient as soon as possible. The longer a patient goes without proper treatment, the more likely that patient is to suffer severe consequences of the disease.⁴ 

Esketamine (Spravato)  

In March of 2019, the Food and Drug Administration approved esketamine nasal spray for use alongside a daily oral antidepressant for the treatment of resistant depression, defined as depression that has failed to respond to at least two other forms of antidepressants taken at appropriate doses and duration.¹ During the induction period, patients receive an initial dose of 56 mg intranasally on day one, followed by 56 or 84mg twice weekly during weeks one through four based on efficacy and tolerability. Based on the results of this initial phase, patients go on to receive a maintenance dose during weeks five through eight of either 56 or 84 mg once weekly, followed by 56 or 84 mg every two weeks or once a week during week nine and thereafter.⁵ Patients using this medication can expect to experience its full effects within one month. 

The active ingredient of this nasal spray, esketamine, is a derivative of ketamine.⁵ It works by blocking the N-Methyl-D-Aspartate receptors in the brain to prolong the response of oral antidepressants, which necessitates the combination of the oral antidepressant and the nasal spray. Ketamine is currently a Schedule III drug, and the nasal spray is approved for use only in healthcare settings registered through the Spravato REMS program and under direct supervision of a healthcare professional.⁶ 

Esketamine may cause an increase in blood pressure and should be used with caution in patients with underlying cardiovascular and cerebrovascular conditions. For this reason, prior to each dose, the patient’s blood pressure should be obtained, and if either the systolic pressure is greater than 140 mmHg or the diastolic pressure is greater than 90 mmHg, the physician must determine whether potential benefits of therapy outweigh the risks. If the patient is deemed appropriate for treatment, the first dose will be administered and the physician will monitor the patient’s blood pressure approximately forty minutes after administration and as clinically indicated over the next two hours to ensure that it remains at, or returns to, baseline prior to discharge. In addition to blood pressure, the healthcare professional will also monitor the patient for adverse events, such as extreme sedation or dissociation. Patients must remain at the clinic under observation for a minimum of two hours following nasal spray administration before they can be allowed to leave.⁶ 

The FDA has issued black box warnings for sedation, dissociation, abuse, and misuse.⁷ Additional adverse effects include dizziness, nausea, reduced sensations, anxiety, lack of energy, increased blood pressure, vomiting, and feeling intoxicated.⁶ Patients and their family members or caregivers should be instructed to monitor for these effects and to contact their appropriate provider as indicated. 

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression: A Randomized Control Trial⁸ 

From October of 2015 to February of 2018, researchers conducted a randomized controlled trial to investigate long-term efficacy of esketamine compared to placebo. Prior to randomization, all patients underwent screening, induction, and optimization with esketamine nasal spray. Those who achieved either stable response, defined as a steady improvement in depressive symptoms, or stable remission, defined as the cessation of depressive symptoms, by the end of the optimization phase were randomized to the control or experimental groups. These patients entered the maintenance phase of the study and were assessed for continued safety and efficacy of the drug. The experimental groups received treatment with their previously prescribed oral antidepressant and esketamine nasal spray, while the control groups received treatment with their previously prescribed oral antidepressant and placebo nasal spray. All randomized patients were included in the data analysis. 

This randomized control trial found that, compared with the placebo group, the esketamine group experienced significantly delayed relapse in depressive symptoms. The researchers found that the risk of relapse decreased by 51% among patients in stable remission following optimization and by 70% among patients in stable response following optimization. Further, safety data revealed that the most common adverse effects following esketamine administration included dysgeusia, vertigo, dissociation, somnolence, and dizziness, with the majority of these observed immediately after dose administration, recorded as mild to moderate, and resolved within the same day. No deaths occurred during the study. Serious adverse events included autonomic nervous system imbalance, disorientation, hypothermia, lacunar stroke, sedation, simple partial seizures, and suicidal ideation. These were reported in only six patients and occurred only during the induction phase, with no serious adverse effects noted during either optimization or maintenance phases of treatment.  

Conclusion

Esketamine (Spravato) nasal spray shows much promise in the treatment of resistant depression. Prior to its FDA approval for this indication, safety and efficacy data from clinical trials showed strong positive results in patients randomized to active treatment compared with placebo. Under close monitoring by a healthcare professional registered through the Spravato REMS program, more patients may soon find relief of their treatment-resistant depression through the use of this drug.

References:

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.
2. National Institute of Mental Health. Major depression. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Updated February 2019. Accessed March 2, 2020.
3. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. 2010. doi:10.1176/appi.books.9780890423363.48690
4. Greden JF. The burden of recurrent depression: Causes, consequences, and future prospects. J Clin Psychiatry. 2001;62:5-9. Published January 8, 2001. Accessed March 2, 2020.
5. SPRAVATO [package insert]. Titusville, NJ: Jannsen Pharmaceuticals, Inc; 2019.
6. Janssen Pharmaceuticals, Inc. Nasal spray treatment for treatment-resistant depression. https://www.spravato.com/. Published 2019. Updated June 2019. Accessed March 2, 2020.
7. United States Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; Available only at a certified doctor’s office or clinic. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Published March 5, 2019. Accessed March 2, 2020.
8. Daly EJ, Trivedi MH, Janik K, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. Published June 5, 2019. Accessed March 2, 2020.

By Kathryn Rechenberg, PharmD Candidate 2021 and Alannah Yoder, PharmD, BCACP 

Introduction 

Recently known as a popular weight loss diet, the ketogenic diet was originally introduced as a medical treatment plan for patients with epilepsy. Developed in the 1920s by collaborating physicians including Dr. Russell Wilder, this diet was found to control seizures in patients that did not respond to antiepileptic medications alone.¹ Currently, implementing the ketogenic diet requires the involvement of a well-rounded medical team in order to overcome barriers and attain remission of seizures in patients. Pharmacists are key members that can aid in combating drug formulation challenges, offer drug therapy to counteract side effects, and provide resources to patients and healthcare teams.  

Background and Clinical Use of Ketogenic Diet 

The ketogenic diet is comprised of low carbohydrates, high fats, and adequate protein.^1,3 Consuming minimal carbohydrates forces the body to use fat as the main energy source. Ketones, such as beta-hydroxybutyric acid and acetoacetic acid, are produced from the utilization of fats for energy.³ The increased level of ketones signifies that the body is in a state of ketosis. This state has been proven beneficial in controlling seizures by reducing neuronal excitabiliy.^1,6 The exact indication of the ketogenic diet in treating seizures remains somewhat contested between its use as an alternative therapy option or as an actual therapeutic plan.⁶ There has been evidence with proven efficacy to support using the ketogenic diet to induce remission in several types of refractory generalized and partial seizures.¹ However, implementing the diet should be patient specific and responses vary case by case.  

Challenges in Drug Formulations 

Patients on the ketogenic diet require close medication management to limit carbohydrate content. Pharmacists are responsible to review their patients’ medications and determine the carbohydrate count prior to initiating this diet. This includes all over-the-counter medications, herbals, and vitamins. Pharmacists should provide guidance to prescribers in terms of formulating a treatment plan that adheres to the ketogenic dietary restrictions along with educating patients on medication ingredients to avoid.  

There can be significant variations in the carbohydrate content of medications based on differences in non-active ingredients between branded and generic medications. Commonly used non-active ingredients that contain carbohydrates are cornstarch, ascorbic and lactic acid, glycerin, mannitol, sucrose, fructose, and maltodextrin.⁶ Liquid drug formulations should be avoided since most are primarily compounded in carbohydrate-rich suspensions. For example, 5 ml of ethosuximide syrup, used for absence seizures, contains 3.625 g of carbohydrates which may cause this medication alone to fulfill the daily carbohydrate allowance.⁴ A pharmacist’s role is to make drug delivery adjustments to ensure their patients remain in ketosis and prevent the loss of seizure control. This includes switching to drug formulations with less carbohydrate non-active ingredients or establishing innovative compound recipes that are ketogenic friendly.  

Side Effects and Monitoring  

The common side effects in the early stages of starting the ketogenic diet include fatigue, hunger, vomiting, and constipation.^1,5 Long-term effects arise due to the body’s change in primary energy source. Additionally, antiepileptic medications cause over-lapping side effects. Patients may experience changes in their sleep pattern, constipation, development of kidney stones, and decreased bone mineral density.⁵ Pharmacists can recommend sleep hygiene techniques to aid in managing sleep. Polyethylene glycol is a preferred option for constipation since it does not contain carbohydrates. Other pharmacologic management of the ketogenic diet side effects include Polycitra K^TM to prevent kidney stones and supplementing vitamin D and calcium to minimize bone density loss. ^1,5 Pharmacists can also aid in mitigating complications like metabolic acidosis by administering sodium bicarbonate and can treat hypoglycemia by supplementing glucose.^2,5 The healthcare team should monitor these side effects, serum bicarbonate and blood glucose levels, and attain blood and urine tests every 1 to 3 months when initiating the ketogenic diet.¹   

Available Resources  

It can be challenging to review carbohydrate content of medications as limited information is often available. The Charlie Foundation is a non-profit organization that provides information to patients on the ketogenic diet. Their website offers additional patient-friendly resources and a low/no carb product list which may be helpful for over-the-counter medications.⁶ Medication package inserts generally do not specify carbohydrate content of products; however, they list all active and non-active ingredients. Pharmacists can differentiate which ingredients are carbohydrates versus non-carbohydrates by utilizing the Charlie Foundation website as a resource and should be prepared to contact manufacturers directly to obtain reliable carbohydrate content information.  

Conclusion

In summary, the ketogenic diet may be an effective treatment option in patients with intractable epilepsy. In order to maintain a state of ketosis in patients, a multifaceted medical team is needed. It is important that patients are receiving oversight and supervision by an appropriately trained medical team, including a neurologist and trained dietician. Pharmacists can aid in drug delivery, ensure appropriate medication management and formulations, and provide resources to patients and medical teams.

1. Arulappan J, Karkada S, Jayapal S, Seshan V. Ketogenic Diet- An Evidence Based Direction for Seizure Control. International Journal of Nutrition, Pharmacology, Neurological Diseases. 2019;9(1):37-40.
2. SANDU C, MAGUREANU SA, ILIESCU C, POMERAN C, CRAIU DC. Ketogenic Diet Treatment for Status Epilepticus. Farmacia. 2019;67(2):218.
3. Freeman JM. The Ketogenic Diet: A Treatment for Children and Others with Epilepsy. Vol 4th ed. New York: Springer Publishing Company, Inc; 2007.
4. Thomas J. F. Carbohydrate and Alcohol Content of 200 Oral Liquid Medications for Use in Patients Receiving Ketogenic Diets. Pediatrics. 1996;(4):506.
5. Epilepsy Foundation. (2020). Epilepsy Foundation. [online] Available at: https://www.epilepsy.com [Accessed 23 Jan. 2020]
6. Charlie Foundation for Ketogenic Therapies. (2020). How to Get Started With the Ketogenic Diet. [online] Available at: https://charliefoundation.org [Accessed 23 Jan. 2020].

By Sara Lauterwasser, Pharm.D. 

Learning Objectives: 

1. Identify the differences between PCV13 and PPSV23 vaccines 

1. Describe previous recommendations made by the Centers for Disease Control (CDC) and Prevention regarding pneumococcal vaccinations in patients over the age of 65 

1. Discuss effectiveness of pneumococcal vaccinations and effect on population carriage and transmission 

1. Analyze available literature that supports the CDC’s recommendation for pneumococcal vaccination administration 

1. Identify patients that need PCV13 administration based on updated CDC’s recommendations  

 

Introduction: There are two types of pneumococcal vaccinations approved by the Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC).  Recently, on November 22, 2019, the Advisory Committee on Immunization Practices (ACIP) released their Morbidity and Mortality Weekly Report that included a change in the previous recommendations for the administration of the pneumococcal vaccines in the population of adults 65 years of age and older.  It is important, as pharmacists, that we are aware of this recommendation so that we can recommend the appropriate vaccinations to our patients and be able to provide them more information about this change, if we are asked to do so.  

Background: The two types of pneumococcal vaccines are the 13-valent pneumococcal conjugate vaccine (PCV-13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV-23). The PPSV-23 includes 12 of the same strains included in the PCV-13 along with 11 other common strains of pneumococcal disease.  Before the recent update, the previous recommendation from 2014 state that all adults ages 65 and above should receive one dose of the PCV-13, followed by the PPSV-23 at least one year later¹ .  

New Recommendation: The newest recommendation published on November 22, 2019 does not require all adults 65 and older to receive the PCV-13.  Instead, the recommendation now is that the decision for vaccination should be made between the provider and the adult on a case by case basis.  However, ACIP still recommends administration of PCV-13 if the adult has an immunocompromising disease state, a cerebral spinal fluid (CSF) leak, or a cochlear implant and they have not received the PCV-13 in the past².  Additionally, they acknowledge that there are certain disease states that may put adults 65 years of age and above at higher risk of complications from pneumococcal disease.  

Patient populations in which are at a higher risk for exposure to PCV13 serotypes: 

• Nursing facilities / LTAC 

• Living in an area with low pediatric PCV13 uptake 

• Traveling to an area with no pediatric PCV13 administration  

Disease states with higher risk of complications of pneumonia:  

• Chronic heart, lung, or liver disease 

• Diabetes 

• Alcoholism 

• Cigarette smokers 

• More than one chronic medical condition 

Rationale behind the update: This update can easily be explained by the concept of carriage and transmission.  Simply stated, if there are more children and young adults vaccinated, there will be a decreased number of people in the population that are carriers of the strains that can cause pneumococcal disease.  If there are a lower number of people carrying the strains, then the rate of transmission will be much lower too.  In 2007, the 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced to the pediatric population.  Followed by the PCV-13 vaccine that was introduced to the same population in 2010.  Finally, in 2014, the recommended PCV-13 vaccine was introduced in the adult population of people ages 65 and up.  

Recently, there have been several studies published that reviewed how effective the carriage and transmission theory was at protecting our older patient population against pneumococcal disease when we appropriately vaccination our pediatric population.  The ACIP Pneumococcal Vaccine Work Group evaluated 20 studies and included them in their GRADE table that was used to publish this most recent recommendation update.   

In regard to the effectiveness of the PCV-13, Pilishvili T, et al.^3,4 found that this vaccine is 47-59% effective at preventing invasive pneumococcal disease.  Likewise, McLaughlin M, et al.⁵ and Prato R, et al.⁶, found that the PCV-13 is 38-70% effective at preventing non-invasive pneumococcal disease.  Two other studies found that the PCV-13 is 6-11% effective against all causes of pneumonia, not just the strains covered in the vaccine^7,8.  There have not been any studies that reviewed the impact of the PCV-13 on mortality.   

In regard to the safety of the PCV-13, studies found that the adverse effects were similar to those experienced when patients were injected with a placebo⁹. 

Another study by Pilishvili, et al.¹⁰, found that from the year 2000 until the year 2014, there was a 71% decrease in the rate of PCV-13 type invasive pneumococcal disease.  If you remember from the timeline stated earlier, this was before the ACIP recommended the PCV-13 to adults 65 years of age and older.  When this recommendation was finally made in 2014, it was expected that we would see a further decrease in these rates when we started to vaccinate this population.  There has been adequate coverage of the vaccine across this population.  In 2018, it was reported that  47% of adults 65 years of age and older were covered with PCV-13 and 62% were covered with any pneumococcal vaccine¹¹. However, Pilishvili, et al.¹², states that there has been no reduction in invasive pneumococcal disease since 2014, with an incidence rate estimated at 5 cases per 100,000 people.  

There have also been economic analyses that demonstrate it is not economically beneficial for every adult to receive the PCV-13 vaccine.  

Given all of this data, the ACIP published their recommendation that the decision to receive the PCV-13 vaccine should be a decision made between the patient and their provider as long as the patient is not immunocompromised, does not have a CSF leak and does not have a cochlear implant.   

Conclusion: It is important to remember that even though the recommendation states that PCV-13 does not have to be given to all patients over the age of 65, it is still a vaccine that is safe and effective for this population.  If the PCV-13 vaccine is appropriate for an adult 65 years of age and older that is not immunocompromised, have a CSF leak or have a cochlear implant, it should be administered at least one year prior to the PPSV-23 vaccine.  The PCV-13 vaccine and PPSV-23 should never be administered together.  The ACIP still recommends one dose of PPSV-23 vaccine for adults 65 years of age and older.  No recommendations have changed for the administration of the pneumococcal vaccinations for pediatrics and adults younger than the age of 65.  Below, there is a table, created by the CDC, which lists the current recommendations to assist you in helping your patients make the most appropriate decision.  

Current recommendation table from CDC² 

Take CE Quiz

References: 

¹ Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014;63:822–5.

² Matanock A, Lee G, Gierke R, et al. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥ 65 Years. MMWR. 2019;68(46);1069–1075.7

³ Pilishvili T, Almendares O, Nanduri S, et al. Evaluation of pneumococcal vaccines effectiveness against invasive pneumococcal disease (IPD) among U.S. Medicare beneficiaries ≥65 years old. Presented at the International Symposium on Pneumococci and Pneumococcal Diseases, Melbourne, Australia; April 15–19, 2018.

⁴ Pilishvili T, Almendares O, Xing W, et al. Effectiveness of pneumococcal vaccines against invasive pneumococcal disease (IPD) among adults >65 years old. Presented at the International Symposium on Pneumococci and Pneumococcal Diseases, Melbourne, Australia; April 15–19, 2018.

⁵ McLaughlin JM, Jiang Q, Isturiz RE, et al. Effectiveness of 13-valent pneumococcal conjugate vaccine against hospitalization for community-acquired pneumonia in older US adults: a test-negative design. Clin Infect Dis 2018;67:1498–506.

⁶ Prato R, Fortunato F, Cappelli MG, Chironna M, Martinelli D. Effectiveness of the 13-valent pneumococcal conjugate vaccine against adult pneumonia in Italy: a case-control study in a 2-year prospective cohort. BMJ Open 2018;8:e019034.

⁷ Gessner BD, Jiang Q, Van Werkhoven CH, et al. A public health evaluation of 13-valent pneumococcal conjugate vaccine impact on adult disease outcomes from a randomized clinical trial in the Netherlands. Vaccine 2019;37:5777–87.

⁸ Lessa FC, Spiller M. Effectiveness of PCV13 in adults hospitalized with pneumonia using Centers for Medicare & Medicaid data, 2014–2017. Presented at the Advisory Committee on Immunization Practices meeting, Atlanta, GA; February 2019.

⁹ Food and Drug Administration. Highlights of prescribing information (package insert). Pneumovax 23 (pneumococcal vaccine polyvalent). Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2017.

¹⁰ Pilishvili T, Gierke R, Xing W, et al. Changes in invasive pneumococcal disease (IPD) among adults following 6 years of 13-valent pneumococcal conjugate vaccine use in the U.S. Presented at the International Symposium on Pneumococci and Pneumococcal Diseases, Melbourne, Australia; April 15–19, 2018.

¹¹ Matanock A. Considerations for PCV13 use among adults ≥65 years old and a summary of the evidence to recommendations framework. Presented at the Advisory Committee on Immunization Practices meeting, Atlanta, GA; June 2019.

¹² Pilishvili T, Gierke R, Xing W, et al. Changes in invasive pneumococcal disease (IPD) among adults following 6 years of 13-valent pneumococcal conjugate vaccine use in the U.S. Presented at the International Symposium on Pneumococci and Pneumococcal Diseases, Melbourne, Australia; April 15–19, 2018

By: Zachary Hitchcock, PharmD Candidate 2021 and Nathan Hanson, PharmD, MS, BCPS

In sports and in life, you need a solid game plan in order to be successful. This is also true in advocacy. So what are the components to a winning pharmacy advocacy game plan? Caring, prioritization, education, and persuasion. Advocacy begins with caring. We have to care about our patients and colleagues enough to put the effort into making a difference. Next, prioritization. Good leadership is all about deciding what is most important. Right now, and in the future. From there, advocacy is all about education and persuasion. Our elected representatives go to work every day with the goal to make life better for the people that they serve. It is our job to explain to them the ways that we think they should make that difference. They don’t know a lot about our world, so we need to educate them and persuade them to care about the things that we care about.

Once your game plan is in place, the next step is forming a winning team. Students play an important role on our advocacy team. Here is one student’s story of his advocacy journey:

A Student’s Perspective on Professional Advocacy

My first face-to-face encounter with professional advocacy occurred following my first year of pharmacy school at UMKC in July of 2018. That summer, I had the privilege of attending the APhA-ASP Summer Leadership Institute in Washington, DC. Part of this experience involved visiting Capitol Hill and advocating for pharmacy issues, specifically provider status and the opioid crisis. Despite spending significant time reviewing the talking points, I recall feeling incredibly nervous walking into Representative Sam Graves’ office and later into Senator Claire McCaskill’s office. Thankfully, I was able to attend these meetings with peers who were more experienced than me, and they coached me on how to be effective in these meetings. Upon sitting down with staffers for each of these legislators, the nerves subsided, and I realized that they were there to hear our perspectives on what could be done to improve patient care. Unfortunately, we are still fighting for change on these issues and others, but I believe that if pharmacists and student pharmacists take personal responsibility for advocating, then we will see the changes we wish to see and improve the care we can provide for patients.

Advocating for pharmacy is a team sport, much like football. Being from Kansas City, I am incredibly excited that the Chiefs won the Super Bowl. A big component of their success was that they pulled together as a team. They were unstoppable when the receivers ran the correct routes and the offensive line blocked their assignments, allowing Patrick Mahomes to complete pass after awe-inspiring pass and lead the team to victory. This is similar to pharmacy advocacy; if the many team members involved in pharmacy advocacy are going in different directions and not working together, then it will be more difficult for us to improve our profession. A simple unifying idea is that our pharmacy advocacy team should always begin with the best interests of patients in mind. A good team must have all of the players, including pharmacists, technicians, and student pharmacists. I am a student, and I have learned much about advocating for our patients and profession from experienced mentors who have a wealth of knowledge to share. By passing knowledge along to students and young pharmacists who are new to the profession, we will be able to build upon what is already being done instead of re-developing knowledge and tactics for advocacy that have already been formed.

I have been asked why I care about advocating for the profession and why student pharmacists should care about advocacy. For me, the answer is simple: I want to be able to provide the best care possible to patients, and I want to enhance the care I can provide throughout my career. Student pharmacists are preparing to embark on a career that will span decades. In order to optimize what we can accomplish over the course of that career, we must take personal responsibility for advocating for our patients and the future of the profession. This personal responsibility includes multiple forms of advocacy. As the medication experts, it is one of our responsibilities to advocate for our patients as a member of the healthcare team. It is also our responsibility to send letters to legislators and make phone calls to encourage legal changes that will help us better serve our patients. This includes actively seeking opportunities to advocate for issues on both the state and federal levels. Oftentimes, this can start with something as simple as attaching your name to a form letter and sending it to a legislator. It can also grow into attending Legislative Day, which was on April 1st this year, or setting up a personal meeting with a representative or staffer. As long as the members of our advocacy team do their part and continue fighting, we will see the changes we want to see and continue providing the best care possible for patients.

Author: Lourdes M. Vega, PharmD; St. Louis College of Pharmacy/Department of Public Health PGY1 Pharmacy Resident

Mentor: Justinne Guyton, PharmD, BCACP; St. Louis College of Pharmacy Associate Professor of Pharmacy Practice, PGY1 Pharmacy Residency Program Director

Introduction

Fasting practices vary significantly between religious and cultural backgrounds, regions, families, and persons, ranging from giving up a specific food or ingredient to abstaining from food and water entirely. A prolonged fast is defined as abstinence from all food for greater than eight hours while awake. This prolonged fast comes with risk when practiced by patients with type 2 diabetes and is an opportunity for a pharmacist to reevaluate pharmacotherapy selection.¹

Risks and Complications Associated with Prolonged Fasting

Continuous glucose monitoring of patients with diabetes practicing prolonged daytime fasting over four weeks revealed dangerously low drops in blood glucose between meals followed by dangerously high spikes after consumption of the meal that breaks the fast.² During prolonged periods without food, glycogen stores are depleted, increasing the risk for hypoglycemia. Additionally, this risk is furthered with strenuous activity performed throughout the fast. On the other hand, hyperglycemia, due to eating large, frequently carbohydrate-heavy meals to break the daily fast can also be problematic for the patient. In some extreme cases, diabetic ketoacidosis (DKA) can occur. Because of the often drastic changes in caloric consumption, a previously therapeutic medication plan can become dangerous or ineffective during a prolonged fast. Along with complications from changes in eating patterns, some fasting practices refrain from intake of water increasing the risk for dehydration and associated complications.

Assessing and Adjusting Care Plans

Pre-Fast Assessment:

Patients who fast without a fasting-focused education program have a fourfold increase in hypoglycemia than those who do not, and unfortunately the majority of primary care providers do not routinely inquire about fasting practices.^{3, 4} The American Diabetes Association (ADA) and International Diabetes Federation (IDF)/ Diabetes and Ramadan (DAR) International Alliance provide recommendations for patients who fast during Ramadan. The data from this population can be applied to others who also fast for a prolonged period. Recommendations include performing a pre-fast assessment in any patient intending to participate in a prolonged fast six to eight weeks prior to the fast. This should include performing a risk stratification based on the following: medical history, diabetes medications, fasting duration and type, experience during previous fast, and ability to detect and treat hypoglycemia.^{5, 6}

Education:

Fasting-focused education should include discussion about monitoring blood glucose, diet, exercise, and breaking the fast when needed. Significant times to check blood glucose include mid-fast, pre-prandial, post-prandial, and any time the patient identifies symptoms of hypo- or hyperglycemia. All meals should begin with intake of water or non-sugary drinks and contain a balance of carbohydrates, protein and fat. Exercise should not be increased during fasting periods and if participating in strenuous activity, hydration and consumption of carbohydrates should be stressed. All patients should be educated on recognizing signs and symptoms of hypoglycemia and the importance of breaking the fast if needed to treat hypoglycemia.

Non-Insulin Medication Adjustment:

Hypoglycemia risk as well as effect on glycemic control during fasting periods must be considered to ensure safe and effective therapy. Most non-insulin diabetes therapies, with the exception of sulfonylureas, carry a low hypoglycemic risk and do not require adjustment in patients participating in 8-12 hour daily fasts. Sulfonylureas, however, carry a moderate to high hypoglycemia risk. When possible, a second generation agent should be used. In patients who receive a sulfonylurea once daily, the full dose should be taken with the post-fast meal. If the diabetes is well controlled, it is appropriate to decrease the dose during the fasting period. In patients who receive twice daily dosing, the total daily dose should be continued and split equally between the two meals. If the patient’s diabetes is well controlled, the dose taken with the pre-fast meal in the morning should be decreased.^5,6

Another strategy to avoid hypoglycemia that has been evaluated is to switch from a sulfonylurea to an agent with a lower hypoglycemia risk. In a study by Wan Seman et al., 110 patients receiving metformin and a sulfonylurea who fasted during Ramadan were randomized to continue their current therapy or switch to a combination of dapagliflozin and metformin therapy. Six weeks after the switch and at the end of the fast, the rate of hypoglycemia was 19.2% in the sulfonylurea group compared to 3.4% in the dapagliflozin group (p=0.008). There was no significant difference in change in A1c between the two groups from baseline to 10 to 12 weeks of therapy (p= 0.174). The authors concluded that switching from a sulfonylurea to dapagliflozin decreased hypoglycemic events through Ramadan without compensating glycemic control. Although effective in reducing hypoglycemia, cost and the general impracticality of switching solely during fasting periods should be considered. ⁷

Insulin Adjustments

Adjustments to insulin regimens vary based on the pre-fasting insulin regimen. In general, both basal and bolus regimens should be reviewed. The recommendations for these adjustments are largely based on data from those participating in a fast for Ramadan. Therefore, the adjustments recommended in Table 2 are based on those who eat a meal before sunrise, fast during the day, and have a meal after sunset. Ideally, those with diabetes will still be in contact with their providers to report their blood glucose log. Hypoglycemia, should still be managed with a 10-20% reduction in the insulin dose.

Conclusion

It is important that healthcare practitioners inquire about fasting practices while taking into consideration that various definitions and interpretations of a fast exist among different people. Characteristics of the fast, patient’s history, and the hypoglycemic profiles of the medications should be considered when assessing therapy. In patients participating in frequent, prolonged fasts, attention should be paid to medications that already have a higher risk of hypoglycemia such as sulfonylureas and insulin. There is data to suggest that short-term switches to oral agents with a low hypoglycemic profile, such as an SGLT-2 inhibitor might be an appropriate consideration. It may also be more practical to consider such a switch for the long-term, rather than the short-term. The practitioner should adjust insulin regimens to take into account the prolonged fast in the day based on the patients plans for a fast and agreement to continue to routinely check the blood glucose. Finally, this dialogue with the patient is crucial to avoid potentially life-threatening complications from unsafe fasting practices and should not be dependent on the patient initiating the conversation.

References

1. Cryer PE, Davis SN. Hypoglycemia. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; http://accesspharmacy.mhmedical.com/content.aspx?bookid=2129& sectionid=192288656.
2. Lessan N, Hannoun Z, Hasan H, et al. Glucose excursions and glycaemic control during Ramadan fasting in diabetic patients: Insights from continuous glucose monitoring (CGM). Diabetes Metab. 2015;41:28–36.
3. Bravis V, Hui E, Salih S et al. European implications of the READ (Ramadan focused Education and Awareness in Diabetes) programme [Abstract]. Diabetologia 2008; 51(Suppl.): S454.
4. Ali M, Adams A, Hossain MA, et al. Primary care providers’ knowledge and practices of diabetes management during Ramadan. J Prim Care Community Health. 2016;7:33-7.
5. International Diabetes Federation and the DAR International Alliance. Diabetes and Ramadan: Practical Guidelines. Brussels, Belgium: International Diabetes Federation, 2016. www.idf.org/guidelines/diabetes-in-ramadan and www.daralliance.org
6. Al-Arouj M, Assad-Khalil S, Buse J, et al. Recommendations for Management of Diabetes During Ramadan Update 2010. Diabetes Care. 2010; 33(8): 1895-1902.
7. Wan Seman WJ, Kori N, Rajoo S, et al. Switching from sulfonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia. Diabetes Obes Metab. 2016;18(6):628-32.

Author: Angelou Song, PharmD Candidate 2021-UMKC School of Pharmacy

Mentor: Barb Kasper, PharmD, BCACP; Clinical Assistant Professor-UMKC School of Pharmacy

Introduction

The U.S. Food and Drug Administration (FDA) approved oral semaglutide tablets (Rybelsus^®) in September 2019.¹ Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist analog and the first oral agent developed in the drug class. Oral semaglutide is indicated to lower A1C in patients with Type II Diabetes (T2DM).  According to the American Diabetes Association’s recommendations for pharmacological therapy, GLP-1 receptor agonists are used when A1c levels are over 1.5% above the glycemic target, as one of the agents for dual combination therapy. Also, GLP-1 receptor agonists are indicated when A1c levels are above target despite using two or three anti-hyperglycemic agents. Injectable GLP-1 receptor agonists with proven cardiovascular disease benefits (semaglutide, dulaglutide, liraglutide) are recommended to patients with established atherosclerotic cardiovascular disease (ASCVD), high ASCVD risk, chronic kidney disease or heart failure.²

Mechanism of Action

GLP-1 is an incretin peptide hormone that is released by enteroendocrine L cells in the gastrointestinal tract. GLP-1 is secreted in response to eating or an increase in glucose levels to stimulate insulin from pancreatic β-cells and lower glucagon secretion from pancreatic α-cells. GLP-1 receptor agonists lower postprandial blood glucose levels and delay postprandial gastric emptying. In addition to glucose lowering effects, GLP-1 receptor agonists also promote satiety, eventually leading to decreased body weight.³

Oral Drug Delivery System

Until oral semaglutide was developed, GLP-1 agents were only available as injectables, because the compounds undergo proteolytic degradation in the stomach. Oral semaglutide is formulated with sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) to increase its absorption and efficacy in the stomach. SNAC is the intestinal permeation enhancer for oral delivery of macromolecules.⁴ SNAC allows semaglutide to accumulate in the cells and changes membrane permeability by interacting with the cell lipid membrane. SNAC converts oligomer forms of GLP-1 analogs into monomer forms, which increases absorption. Degradation of semaglutide occurs in an acidic environment and SNAC also works as a local buffer to protect from degradation and increase absorption.⁵

Dosage and Administration

The starting dose of oral semaglutide is 3 mg once daily for 30 days. The 3 mg dose is for initiation of therapy and minimization of gastrointestinal adverse effects, rather than glycemic control.  If tolerated, oral semaglutide is titrated up to 7 mg daily for at least 30 days. If additional glycemic control is needed, the dose may be titrated to a maximum of 14 mg daily.  Oral semaglutide is best absorbed on an empty stomach, at least 30 minutes before the first food, beverage, or other oral medication intake of the day. Additionally, the medication must be taken with less than 4 ounces of plain water only.   The manufacturer recommends eating 30 to 60 minutes after the dose.⁶

Literature reviews regarding efficacy and safety

A phase II, randomized, placebo-controlled trial was conducted to compare different dosages of oral semaglutide with placebo in 632 patients with T2DM and insufficient glycemic control. Oral semaglutide 2.5 mg, 5 mg, 10 mg, 20 mg, standard escalation of 40 mg, slow escalation of 40 mg, fast escalation of 40 mg, once weekly subcutaneous semaglutide 1 mg and oral placebo were compared with appropriate titration for 26 weeks. The primary endpoint was a change in A1c level from baseline to week 26. Oral semaglutide at 20 mg and standard escalation of 40 mg were not significantly different than subcutaneous semaglutide. More gastrointestinal adverse reactions were reported with oral semaglutide but fewer adverse reactions were reported when patients began on a low dose. The authors concluded that oral semaglutide is more effective at controlling glucose levels than a placebo over 26 weeks. Findings from this trial supported phase III trials.⁷ 

The Peptide Innovation for Early Diabetes Treatment (PIONEER) trials included a series of phase III trials conducted to establish the efficacy and safety of oral semaglutide.⁸ According to the PIONEER 1 trial, the average decrease in A1c was 0.9% for 7 mg and 1.1% for 14 mg. The mean weight loss was 0.9 kg and 2.3 kg for the 7 mg and 14 mg doses, respectively. ⁹

Safety

The most common side effects of oral semaglutide are nausea (20%), abdominal pain (11%), diarrhea (10%), decreased appetite (9%), vomiting (8%) and constipation (5%) for 14 mg. These adverse reactions are less severe with appropriate and slow dose titration. For severe adverse reactions, pancreatitis and diabetic retinopathy complications may happen. Oral semaglutide has a black box warning for risk of thyroid C-cell tumors. Oral semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 1.⁶

Comparison between oral and subcutaneous semaglutide

The two forms of semaglutide have not been studied against each other. Data were analyzed in Table 2 from individual studies to compare between oral and subcutaneous semaglutide by A1c level, amount of weight loss, side effects, cost and dosage.

Conclusion

Oral semaglutide is the first oral GLP-1 receptor agonist approved by the FDA.1 The PIONEER trials demonstrated the efficacy and safety of the agent versus placebo and active comparator agents.⁸ The oral formulation provides a more convenient dosage form and broadens options available within the GLP-1 drug class.

References

1. FDA approves first oral GLP-1 treatment for type 2 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes. Accessed January 5th, 2020.
2. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standard Medical Care in Diabetes - 2020. https://care.diabetesjournals.org/content/43/Supplement_1/S98 Published January 2020. Accessed January 12th, 2020.
3. Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr. 2017 August;30(3):202-210. doi: 10.2337/ds16-0026.
4. Twarog C, Fattah S, Heade J et al. Intestinal permeation enhancers for oral delivery of macromolecules: A comparison between salcaprozate sodium (SNAC) and sodium caprate (C10). Pharmaceutics. 2019 Feb 13;11(2). doi: 10.3390/pharmaceutics11020078.
5. Buckley ST, Bækdal TA, Vegge A, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467).  doi: 10.1126/scitranslmed.aar7047.
6. Rybelsus (semaglutide tablets) [package insert]. Plainsboro, NJ; Novo Nodisk, Inc; Published September 2019. https://www.novo-pi.com/rybelsus.pdf. Accessed January 5th, 2020
7. Davies M, Pieber TR, Hartoft-Nielsen ML, et al. 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
8. A quick guide to the PIONEER trials. Medicine Matters website. https://diabetes.medicinematters.com/semaglutide/cardiovascular-outcomes/a-quick-guide-to-the-pioneer-trials/16877792. Accessed January 5th, 2020
9. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONNER 1: Randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019 Sep; 42(9): 1724-1732. Doi:10.2337/dc19-0749
10. Rodbard HW, Rosenstock J, Canani LH, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019 Dec; 42(12): 2272-2281. Doi:10.2337/dc19-0883
11. 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. JAMA. 2019; 321(15):1466-1480. doi:10.1001/jama.2019.2942
12. 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 Diabetes Endocrinol. 2019 July; 394(10192): 39-50. Doi: 10.1016/S0140-6736(19)31271-1
13. 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 June; 7(7): 515-527. doi: 10.1016/S2213-8587(19)30192-5
14. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; 381:841-851. doi: 10.1056/NEJMoa1901118
15. 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 June; 7(7):528-539. doi: 10.1016/S2213-8587(19)30194-9.
16. Zinman B, Aroda VR, Buse JB, et al. Efficacy, safety and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial. Diabetes Care. 2019 Dec; 42(12): 2262-2271. Doi:10.2337/dc19-0898
17. Dose-response, safety and efficacy of oral semaglutide versus placebo and versus liraglutide, all as monotherapy in Japanese subjects with type 2 diabetes (PIONEER 9). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03018028. Accessed January 5th, 2020
18. Safety and efficacy and oral semaglutide versus dulaglutide both in combination with one OAD (oral antidiabetic drug) in Japanese subjects with type 2 diabetes (PIONEER 10). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03015220. Accessed January 5th, 2020.
19. Sorli C, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomized, placebo-controlled, parallel-group, multinational, multicenter phase 3a trial. Lancet Diabetes Endocrinol. 2017 Apr;5(4):251-260. doi: 10.1016/S2213-8587(17)30013-X
20. Ozempic (semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk, Inc; Revised December 2019. https://www.novo-pi.com/ozempic.pdf. Accessed January 5th, 2020
21. IBM Micromedex® RED BOOK®. IBM Micromedex®. https://www-micromedexsolutionscom.proxy.library.umkc.edu/micromedex2/librarian/PFDefaultActionId/redbook.ModifyRedBookSearch. Accessed January 12th, 2020

By: Diari Gilliam, PharmD Candidate 2020 and Rachel Wolfe, PharmD, BCCCP

Diabetes is a metabolic disorder characterized by hyperglycemia due to impaired insulin secretion, insulin action, or a combination of both.1 In the United States, it is a frequently encountered disease state with an estimated incidence of 30.3 million in 2015.² While it is well known that chronic hyperglycemia is associated with poor long term outcomes, such as retinopathy, nephropathy, and neuropathy, acute hyperglycemia in the surgical setting has also been associated with poor outcomes. Acute hyperglycemia in the surgical setting may precipitate surgical site infections, impaired wound healing, cardiovascular events, and even death.^3-4 Due to the potential for these complications, perioperative glycemic control is essential.

The various transitions of care throughout the surgical continuum of care put patients at risk for sub-optimal perioperative glycemic control. A different team of providers will care for patients as they transition through the pre-admission, preoperative, intraoperative, recovery, and postoperative phases of care. Any miscommunication or omission of information concerning diabetic status or insulin use may result in perioperative hypo- or hyperglycemic events. This poses a significant threat to surgical outcomes and can be especially harmful in those with type 1 diabetes as they need a continuous exogenous source of insulin at all times. This article will provide a brief overview of the importance of perioperative glycemic control throughout the surgical continuum of care.

Diabetic patients are at an increased risk for hyperglycemia in the perioperative period due to the metabolic stress induced by surgery and anesthesia. Both alter the balance of glucose production and utilization due to the increased secretion of counterregulatory hormones such as catecholamines, cortisol, glucagon, and growth hormone.⁵ The collective effect of this imbalance results in increased lipolysis, gluconeogenesis, glycogenolysis, and simultaneously reduced insulin secretion.⁵ Increased glucose production coupled with insulin resistance creates a perfect storm for hyperglycemia and its associated complications.  According to a study in patients undergoing abdominal surgery, insulin resistance persists for at least 5 days postoperatively.⁶ Therefore, it is important to develop an interprofessional approach to address glycemic control that can withstand the challenges of the multitude of care transitions inherent to the surgical environment.

When possible, preoperative optimization of a patient with diabetes should begin in the surgeon’s office and/or in the preoperative assessment clinic. Patients should be screened for indicators of uncontrolled diabetes such as hemoglobin A1c > 8.5%, hypoglycemic episodes (<70 mg/dL), or hyperglycemic episodes (>299 mg/dL).⁷ Additional indicators requiring selective attention would be outpatient use of concentrated insulin and insulin pump therapy, as these modalities are commonly associated with medication errors or suboptimal management within healthcare facilities.⁷ If patients present with any of these indicators, it is advisable to refer them to an endocrinologist for adequate optimization of their disease state and antidiabetic regimen prior to surgery and to create and communicate a management plan for the surgical continuum of care. For those who do not require further evaluation, explicit instructions should be given on how to take their antidiabetic medications the day prior to and the day of surgery (Table 1). Insulin-based regimens require the most modifications prior to surgery. Based on the type of insulin, different modifications may be necessary. For example, rapid and short-acting insulin should only be held on the day of surgery secondary to the restricted oral intake.⁷ Patients with insulin pumps should consult with their endocrinologist to discuss pump programming for surgery or make plans to disconnect on the day of surgery.⁷ It is important to note that if the insulin pump is disconnected at any time, there must be a plan in place to immediately provide another form of continuous insulin therapy for these patients. If patients undergo surgery with a connected infusion pump, they should be assessed preoperatively for their capacity to manage the pump after surgery.⁸ It is important to refer to institution policy regarding personal infusion pumps as not every institution allows their use.

Studies have shown that intraoperative hyperglycemia may play a role in postoperative complications such as infections, myocardial infarctions, and neurological and pulmonary dysfunction.³ A study on intensive intraoperative insulin therapy revealed that maintaining intraoperative glycemic targets between 80 mg/dL and 100 mg/dL is also associated with poor outcomes.⁹ While we lack nationwide consensus, recommendations from various organizations can be used to guide perioperative glucose targets (Table 2). To best achieve these targets, intraoperative management of hyperglycemia may require a continuous insulin infusion or subcutaneous rapid-acting insulin with monitoring every one to two hours. Intravenous push doses of short-acting insulin should be avoided when possible due to its short duration of action.

In the postoperative setting, patients often recover from anesthesia in the post-anesthesia care unit (PACU). Therapy in the PACU is influenced by the patient’s adherence to recommended adjustments to their home anti-diabetic regimen prior to surgery as well as the pre-and intra-operative regimen, making a thorough handoff essential. Obtaining a blood glucose value when the patient is admitted to and discharged from the PACU assists in determining the next steps of glycemic control.⁸ In this setting, various modalities may be utilized. Insulin drips can be titrated, insulin pumps may continue at a basal rate, and subcutaneous doses of intermediate- or short-acting insulin can be administered as necessary. Blood glucose monitoring in the PACU should mimic monitoring established on the inpatient divisions. Although the monitoring requirements may differ based on institution-specific and patient-specific factors, blood glucose is typically assessed every hour for continuous intravenous insulin infusions and approximately every four hours for subcutaneous insulin therapy. PACU glycemic control also addresses the therapeutic response to agents given perioperatively that may affect blood glucose. For example, studies have shown that dexamethasone, which may be administered to some patients pre- or intra-operatively to prevent postoperative nausea and vomiting or reduce inflammation, can increase the risk of postoperative hyperglycemia.^14-16 In order to avoid acute hyperglycemia, clinicians may consider prescribing a dose of an intermediate-acting insulin in patients that receive greater than 10 mg of dexamethasone.¹⁴ Before discharging patients from the PACU and transitioning them to the next level of care, their history of perioperative glycemic control and diabetic status should be communicated to the next healthcare provider and any present family members. Patients being discharged to home should be instructed to monitor their blood glucose frequently while fasting or during times of minimal oral intake. Their home regimen may be re-initiated when they resume their normal diet.

In conclusion, perioperative glycemic control is essential to prevent poor outcomes in diabetic patients undergoing surgery. Institution specific protocols that foster multidisciplinary communication among various phases of care can streamline clinical decisions and communication. It is imperative that both the patient and the providers communicate effectively to achieve the best possible outcomes before, during, and after surgery.

1. Sudhakaran S, Surani SR. Guidelines for Perioperative Management of the Diabetic Patient. Surg Res Pract. 2015;2015:284063. doi:10.1155/2015/284063
2. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Department of Health and Hu- man Services; 2017.
3. Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010;33(8):1783-8.
4. Mcmurry JF. Wound healing with diabetes mellitus. Better glucose control for better wound healing in diabetes. Surg Clin North Am. 1984;64(4):769-78.
5. Duggan EW, Carlson K, Umpierrez GE. Perioperative Hyperglycemia Management: An Update [published correction appears in Anesthesiology. 2018 Nov;129(5):1053]. Anesthesiology. 2017;126(3):547–560. doi:10.1097/ALN.0000000000001515
6. Thorell A, Efendic S, Gutniak M, Häggmark T, Ljungqvist O. Insulin resistance after abdominal surgery. Br J Surg. 1994;81(1):59-63.
7. Joshi GP, Chung F, Vann MA, et al. Society for Ambulatory Anesthesia consensus statement on perioperative blood glucose management in diabetic patients undergoing ambulatory surgery. Anesth Analg. 2010;111(6):1378-87.
8. Simha V, Shah P. Perioperative Glucose Control in Patients With Diabetes Undergoing Elective Surgery. JAMA. 2019;321(4):399-400.
9. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med. 2007;146(4):233-43.
10. Guillermo E. Umpierrez, Richard Hellman, Mary T. Korytkowski, Mikhail Kosiborod, Gregory A. Maynard, Victor M. Montori, Jane J. Seley, Greet Van den Berghe, Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Setting: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 1, 1 January 2012, Pages 16–38, https://doi.org/10.1210/jc.2011-2098
11. Lazar HL, Mcdonnell M, Chipkin SR, et al. The Society of Thoracic Surgeons practice guideline series: Blood glucose management during adult cardiac surgery. Ann Thorac Surg. 2009;87(2):663-9.
12. Ban KA, Minei JP, Laronga C, et al. American College of Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. J Am Coll Surg 2017;224:59-74.
13. Berrios-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg 2017;152:784-91.
14. O'Connell RS, Clinger BN, Donahue EE, Celi FS, Golladay GJ. Dexamethasone and postoperative hyperglycemia in diabetics undergoing elective hip or knee arthroplasty: a case control study in 238 patients. Patient Saf Surg. 2018;12:30. Published 2018 Nov 5. doi:10.1186/s13037-018-0178-9
15. Purushothaman AM, Pujari VS, Kadirehally NB, Bevinaguddaiah Y, Reddy PR. A prospective randomized study on the impact of low-dose dexamethasone on perioperative blood glucose concentrations in diabetics and nondiabetics. Saudi J Anaesth. 2018;12(2):198–203. doi:10.4103/sja.SJA_409_17
16. Pasternak JJ, Mcgregor DG, Lanier WL. Effect of single-dose dexamethasone on blood glucose concentration in patients undergoing craniotomy. J Neurosurg Anesthesiol. 2004;16(2):122-5.

Authors: Kathryn M. Holt, PharmD, BCPS, University of Missouri-Kansas City School of Pharmacy, Clinical Assistant Professor Meritas Health North Kansas City

Amanda M. Stahnke, PharmD, BCACP, University of Missouri-Kansas City School of Pharmacy, Clinical Associate Professor Kansas City VA Honor Annex

Diabetes mellitus remains one of the leading causes of chronic kidney disease (CKD) and occurs in 20-40% of people with diabetes.1 With the continued increase in prevalence of CKD in diabetes, limited pharmacologic therapies exist to assist in decreasing the development and progression outside of renin-angiotensin-aldosterone system (RAAS) agents.1-2 Recent clinical trials with sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) have demonstrated their potential role in this much needed area. SGLT2-Is currently available on the market include canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin. Despite the potentially blunted glucose lowering effect in patients with CKD, several proposed mechanisms regarding renal benefit exist: reduced intraglomerular pressure, renal tubular reabsorption and oxidative renal stress; and improved tubuloglomerular feedback.^1-5

Primary Outcome Data:

To date only canagliflozin has published primary literature regarding renal outcomes. CREDENCE enrolled 4401 patients and was published in June 2019. The trial included patients 30 years of age or older with type 2 diabetes (T2DM), a hemoglobin A1c (A1c) of 6.5-12%, and CKD (eGFR [estimated glomerular filtration rate] 30-90ml/min/1.73m²) with albuminuria (albumin-to-creatinine ratio [UACR] >300-5000mg/g). Patients were randomized in a 1:1 fashion to receive canagliflozin 100mg PO daily or matching placebo and had to be taking a RAAS agent (angiotensin converting enzyme inhibitor or angiotensin receptor blocker) for at least four weeks prior to entry in to the study. The majority of patients enrolled in the trial were Caucasian (66.6%), had baseline hypertension (HTN) (96.8%), and were male (66.1%). Average age and A1c at baseline were 63 and ~8.3%. An interim analysis resulted in sufficient number of primary outcome events, leading to the early termination of the trial at ~2.6 years. The primary composite outcome of end stage kidney disease (ESRD), including need for dialysis or eGFR <15ml/min/1.73m² for at least 30 days, kidney transplant; doubling of serum creatinine (SrCr) from baseline, and death from cardiovascular (CV) or renal disease occurred in 43.2 and 61.2 events per 1000 patient years in the canagliflozin and placebo groups respectively (HR 0.70, CI 0.59-0.82, P=0.00001, NNT 22). Doubling of SrCr from baseline and development of ESRD were also significantly different between groups (20.7 versus 33.8 events per 1000 patient years, HR 0.60, CI 0.48-0.76, P<0.001 and 20.4 versus 29.4 events per 1000 patient years, HR 0.68, CI 0.54-0.86, P=0.002). There were no statistically significant differences between subgroups in the trial though a trend favoring canagliflozin was seen in patients with lower eGFRs (30-<60ml/min/1.73m2) and higher baseline UACR (>1000mg/g). The results of CREDENCE support that SGLT2-Is may provide renal benefit, specifically in patients at high risk for CKD due to T2DM.⁶

Secondary Outcome Data:

Primary outcome data has yet to be published for the other SGLT2-Is; however, many of the cardiovascular outcomes trials (CVOTs) have included renal endpoints as secondary analyses. The CANVAS Program evaluated the effect of canagliflozin on the secondary outcome of progression of albuminuria (30% increase or change from normo- to micro- or micro- to macroalbuminuria) and included an exploratory composite outcome of need for dialysis or transplant, death from renal disease, and sustained 40% reduction in eGFR. Both the secondary and exploratory outcomes occurred less often in patients receiving canagliflozin versus placebo (HR 0.73, CI 0.67-0.79 for progression of albuminuria and HR 0.6, CI 0.47-0.77 for composite renal outcome), but due to sequential hypothesis testing and failure of the first secondary endpoint to meet statistical significance, statistical analysis was not completed on the renal secondary outcome.⁷

EMPA-REG OUTCOME assessed the impact of empagliflozin versus placebo on composite microvascular outcomes, which included incident or worsening nephropathy (progression to macroalbuminuria, doubling of SrCr with an eGFR ≤45ml/min/1.73m², initiation of renal replacement therapy or death from renal cause). The occurrence of nephropathy was lower in the empagliflozin group versus placebo (12.7 versus 18.8%, HR 0.61, CI 0.53-0.7, P<0.001). Additionally, all individual composite renal outcomes were found to be statistically significant favoring empagliflozin.⁵

DECLARE-TIMI 58, dapagliflozin CVOT, included analysis of new onset ESRD, death from renal or CV causes, and 40% sustained reduction in eGFR as a secondary composite endpoint. A lower incidence of the renal composite endpoint was seen in the dapagliflozin group versus placebo (4.3 versus 5.6%, HR 0.76, CI 0.67-0.87).⁸

Secondary outcomes in VERTIS-CV regarding renal effects of ertugliflozin include first event of renal death, dialysis or transplant, along with doubling of SrCr. The trial was expected to end late 2019 and results are pending.⁹

Based on CVOT and renal outcomes, The American Diabetes Association (ADA) now recommends SGLT2-Is (preferring agents with supporting data) as second line agents in many patients, including those with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), CKD, risk for hypoglycemia or those in which weight gain is a concern.² Though some are rare, adverse drug reactions (ADRs) seen with the use of SGLT2-Is include genital mycotic infections, hypovolemia, hypotension, diabetic ketoacidosis (DKA), Fournier’s gangrene, lower limb amputation and hyperkalemia (canagliflozin).^10-13 Acute kidney injury resulting from hypovolemia may be a concern in specific patient populations, such as those taking concomitant diuretics, but recent data did not support this association.⁶ Consideration to patient specific factors such as past medical history, baseline renal function, risk factors, and patient preference should be taken in to account when deciding to initiate an SGLT2-I.

SGLT2-Is are an exciting development in the treatment of T2DM and with growing evidence will likely become a mainstay in therapy to assist with decreasing the development and progression of CKD in this patient population. We anxiously await the publication of additional trials discussing the potential renal benefits of SGLT2-Is, including DAPA-CKD, EMPA-KIDNEY, and VERTIS-CV to solidify this important drug class’s place in therapy.

References:

1. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes 2020. Diabetes Care 2020;43(Suppl. 1):S135–S151. https://doi.org/10.2337/dc20-s011
2. American Diabetes Association. 2. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes 2020. Diabetes Care 2020;43(Suppl. 1):S98–S110. https://doi.org/10.2337/dc20-S009
3. Alicic RZ, Neumiller JJ, Johnson EJ, Dieter B, Tuttle KR. Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes 2019;68:248-257. https://doi.org/10.2337/dbi18-0007
4. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016;39(Suppl. 2):S165–S171. doi:10.2337/dcS15-3006
5. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-334. doi:10.1056/NEJMoa1515920
6. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306. doi:10.1056/NEJMoa1811744
7. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657. doi:10.1056/NEJMoa1611925
8. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-357. doi: 10.1056/NEJMoa1812389
9. Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the evaluation of ertugliflozin efficacy and safety cardiovascular outcomes trial. Am Heart J 2018;206:11-23. https://doi.org/10.1016/j.ahj.2018.08.016
10. Invokana [package insert]. Titusville, NJ: Janssen; 2019.
11. Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2018.
12. Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2019.
13. Steglatro [package insert]. Whitehouse Station, NJ: Merck; 2017.