Glenn Schulman, PharmD, MS, BCPS, BCACP, CGP

The National Institutes of Health (NIH) estimates that ovarian cancer (OC) will have accounted for 1.2% of new cases and 2.3% of all cancer deaths in the United States in 2020.

The most recent global statistics from 2018 show that OC is ranked eighth in cancer incidence rates for women, with more than 295,000 or 3.8% cases diagnosed in 2018.

There are no routine screenings for OC, which often results in delayed diagnosis beyond stage I and II, secondary to generalized vague symptoms.

 About 70% of the cases are diagnosed as advanced stage III or IV OC.

 The patients' 5-year survival rate varies greatly, depending on the stage at which they are initially diagnosed (FIGURE

). The CDC reported that new cases are 10.2 of 100,000, with 6.6 of 100,000 women succumbing to death annually.

Ovarian Cancer 5-year Relative Survival vs Diagnosis By Stage

Patients in developed countries have a higher rate of OC, with a peak incidence occurring between 55 and 64 years of age with a higher prevalence in Caucasian women.

 The most common type of OC is epithelial, which accounts for about 90% of all cases, and the remaining 10% are considered to be nonepithelial.

 About 20% of all OCs have been associated with an inherited gene mutation, eg, BRCA1, BRCA2, MLH1, MSH2. This malignancy has been linked to 1 of 3 hereditary patterns: ovarian cancer alone, ovarian cancer plus breast cancer, and ovarian cancer plus colon cancer.

 Women of Ashkenazi Jewish and Eastern European descent are more likely to be carriers of 

 gene mutations and therefore are at an increased risk of developing OC.

The National Comprehensive Cancer Network (NCCN) does not offer screening recommendations for ovarian cancer. Online table 1

 outlines common symptoms that might be produced by OC. If a patient is experiencing any of these signs or symptoms for greater than 2 weeks, diagnostic tests such as a CA-125 blood test, transvaginal ultrasound, or vaginal pelvic exam may be ordered to investigate the presence of OC.

 The staging of OC is determined postsurgically, which should be performed by a gynecologic oncologist and then examined microscopically by a pathologist.

Treatment options for OC include chemotherapy, hormone therapy, immunotherapy, radiation, surgery, and targeted therapy (Table 2

 The NCCN Clinical Practice Guidelines for OC recommend that the primary treatment consist of debulking surgery, plus systemic chemotherapy in most patients.

Clinicians use genetic testing to assess for specific gene mutations, such as 

, homologous-recombination deficiency, which will guide treatment decisions.

 This allows clinicians to prescribe a targeted therapy that includes poly-ADP ribose polymerase (PARP) inhibitors and/or vascular endothelial growth factor inhibitors.

Systemic immunotherapy enhances the activity of the immune system. Immune checkpoint inhibitors target key surface markers, eg, cytotoxic T-lymphocyte-associated protein 4, programmed cell death ligand, and programmed cell death protein 1.

Hormone therapy involves the use of hormones or hormone-blocking agents acting as anti-estrogen agents to suppress OC tumor growth. This type of therapy involves 3 classes of drugs: aromatase inhibitors, luteinizing-hormone-releasing hormone agonists, and tamoxifen. This mode of systemic therapy is rarely employed in epithelial OC but is more commonly used in refractory ovarian stromal tumors.

PARP inhibitors are vital in the treatment and maintenance of OC and may improve outcomes. Some recent clinical trials, ie, PAOLA-1/ENGOT-OV26, PRIMA/ENGOT-OV26, and SOLO-1, (Online table 3

Clinical trials evaluating combination products, eg, cediranib and olaparib, in patients that are considered to platinum-resistant and -sensitive, are showing promise. Cediranib, a VEGF inhibitor with olaparib, a PARP inhibitor, restricts blood supply to the area promoting apoptosis of the cancerous cells. Preliminary reports from the ICON 9 study demonstrate a significant improvement in progression-free survival.

OC negatively affects the lives of many women. It continues to remain one of the most lethal malignancies, despite continuing efforts and constant advances in treatments. The poor clinical outcomes associated with OC are attributable to chemotherapy resistance, its increased heterogeneity, and the ineffective tools for detecting the disease early in its course. New treatments are needed to enhance cure rates and provide long-term disease stability against platinum-resistance OC. Cellular and immune therapies combined with genetic testing and precision assays (biomarkers) are promising strategies that will inevitably lead to more favorable clinical outcomes. Accelerated research and novel approaches will also invariably spawn better therapeutic options to extend the life expectancy and improve the health of patients with OC.

1. United States cancer statistics data visualizations. Centers for Disease Control and Prevention. June 2020. Accessed March 7, 2021. https://www.cdc.gov/cancer/dataviz

2. Worldwide cancer data. World Cancer Research/American Institute for Cancer Research. Accessed February 14, 2021. https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data

3. Stages of ovarian cancer. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/staging/

4. Gaona-Luviano P, Medina-Gaona LA, Magana-Perez K. Epidemiology of ovarian cancer. 

5. Ovarian germ cell tumors treatment (PDQ)-health professional version. National Cancer Institute. Updated September 3, 2020. Accessed February 14, 2021. https://www.cancer.gov/types/ovarian/hp/ovarian-germ-cell-treatment-pdq

6. Risk factors. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/risk-factors/

7. Ovarian germ cell tumors treatment (PDQ)-patient version. National Cancer Institute. Updated January 8, 2021. Accessed February 14, 2021. https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq

8. About ovarian cancer. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/

9. Treatment. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/treatment/

10. Kaplan DA. Overview of the updated NCCN guidelines on ovarian cancer. Journal of Clinical Pathways. June 17, 2020. Accessed February 14, 2021. https://www.journalofclinicalpathways.com/overview-updated-nccn-guidelines-ovarian-cancer

11. Borella F, Ghisoni E, Giannone G, et al. Immune checkpoint inhibitors in epithelial ovarian cancer: an overview on efficacy and future perspectives. 

. 2020;10(3):146. doi:10.3390/diagnostics10030146

12. Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. 

. 2017;35(10):1103-1111. doi:10.1200/JCO.2016.71.0632

13. Shylasree TS, Richa B, Lavanya G, Gulia S. Molecular signatures of gynecological cancers: clinicians perspective. 

14. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. 

 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

15. Gonazlez-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. 

. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

16. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

17. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. 

. 2019;381(25):2403-2415. doi:10.1056/NEJMoa1909707

18. Clovis Oncology announces completion of target enrollment in the ATHENA trial, a phase 3 maintenance treatment study in front-line, newly-diagnosed advanced ovarian cancer. News release. Clovis Oncology. June 10, 2020. Accessed February 10, 2021. https://ir.clovisoncology.com/investors-and-news/news-releases/press-release-details/2020/Clovis-Oncology-Announces-Completion-of-Target-Enrollment-in-the-ATHENA-Trial-a-Phase-3-Maintenance-Treatment-Study-in-Front-line-Newly-Diagnosed-Advanced-Ovarian-Cancer/default.aspx

19. Mirza MR, Coleman RL, Gonzalez-Martin A, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. 

. 2020;31(9):1148-1159. doi:10.1016/j.annonc.2020.06.004

20. Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. 

. 2019;30(4):551-557. doi:10.1093/annonc/mdz018

21. Chandra A, Pius C, Nabeel M, et al. Ovarian cancer: current status and strategies for improving therapeutic outcomes. 

. 2019;8(16):7018-7031. doi:10.1002/cam4.2560

Articles

Guidelines typically recommend debulking surgery, plus systemic chemotherapy for most patients.

Explore Ovarian Cancer Treatments Through Clinical Trials

Abscesses (collections of pus) can occur in obscure places in the body, including the psoas muscle. The psoas (iliopsoas) muscle is part of the hip flexor muscles that connect the 12th thoracic and 5th lumbar vertebral spine. Anatomically, this muscle is very crucial because it is adjacent to some vital organs, including the vertebral spine (along with branching nerves), inferior vena cava, and kidneys. Because of the psoas muscle’s proximity to intraabdominal organs and the circulatory system, infection in the muscle can spread to these sites very quickly.

 Therefore, it is essential that this infection be diagnosed in an efficient and timely manner. However, this is often difficult because the clinical presentation consistently has the usual markers for infection, such as fever and back pain (~30% of cases).

 Other generalized symptoms include nausea, weight loss, and abdominal pain.

Because of the vague clinical presentation of a psoas infection, it can easily be misdiagnosed as diverticulosis, appendicitis, muscle strain, meralgia paresthetica, sciatica, pyelonephritis, septic arthritis of the hip, or abdominal aortic aneurysm.

 Definitive diagnosis is done via computed tomography (CT) scan of the abdomen.

The 2 classifications of psoas abscess are based on the etiology of the infection. Primary psoas abscess occurs due to hematologic spread of bacteria through the lymphatic system. Secondary psoas abscess indicates an alternate source of infection, such as the peritoneum or the spine. Lesions can arise from diverticulosis, Crohn’s disease, or appendicitis.

The bacteria found in psoas abscesses are determined by the source. In primary psoas abscesses, 

 Our review of the literature did not reveal why this is the case; however, it can be surmised that some type of skin trauma allows introduction of this bacteria into the body. For secondary infection, the type of bacteria depends on the original source of infection. For example, if the primary condition is diverticulitis, the probable pathogens in the psoas abscess would be gram-negative bacilli and/or anaerobes, such as 

The first step in treating this infection is incision and drainage; this improves the penetration the subsequent antibiotic. Often, culture results take 5 to 7 days; meanwhile, it is critical that empiric therapy be started. If there are no other sources of infection, the ideal empiric antibiotic regimen is one that adequately covers all 

 species, including methicillin-sensitive and methicillin-resistant agents. Because psoas abscesses are classified as severe purulent wound abscesses, intravenous (IV) therapy is initiated with vancomycin or linezolid. When culture results are obtained, reassess the appropriateness of antibiotic therapy and de-escalate as necessary. The duration of antibiotic therapy depends on the extensiveness and severity of the infection, as well as clinical improvement. Although the Infectious Diseases Society of America (IDSA) recommends 4 to 6 weeks of therapy for complicated bacteremia, treatment may be extended depending on clinical response.

. A 44-year-old African American man came to the emergency department with worsening abdominal pain that was sharp and excruciating. The patient’s other symptoms included fever, chills, nausea, vomiting, headache, and some left lower extremity paresthesia. See 

 for the patient’s vital signs and lab results at presentation. A CT scan of the abdomen and pelvis revealed diskitis between T12 and L1, as well as fragments and a bilateral psoas abscess measuring, from left to right, 15 mm × 18 mm and 12 mm × 8 mm, respectively. There was some mild impingement involving the S1 nerve root; the exiting nerve root was uninvolved.

Vancomycin was initiated empirically and continued when the patient was admitted. The Interventional Radiology Department aspirated the abscess and sent a sample for culture. Two-dimensional diagnostic imaging was used to ensure that there was no metastatic infection. Cultures revealed methicillin-resistant 

 (MRSA) bacteremia sensitive to vancomycin with an MIC of 2 mcg/ml, linezolid, and sulfamethoxazole-trimethoprim. The physician planned to continue IV vancomycin long term, for 12 weeks or longer, depending on the patient’s response. The infectious disease physician felt that oral antibiotics would not be able to penetrate the abscess.

The patient was continued on vancomycin for about 2 weeks until he developed a severe allergic reaction (red man syndrome?). His therapy was switched to daptomycin 925 mg IV daily, with an MIC of 0.5 mcg/ml, in addition to cefazolin 2 g IV every 8 hours for synergy. The patient’s creatine phosphokinase (CPK) level increased over 3 weeks to 367 U/L, and he started experiencing significant nausea. The patient was not taking a statin. More because of the adverse effect than the increase in the CPK level, the physician switched the patient to ceftaroline 600 mg IV every 12 hours. The CPK level began to decrease, and the patient had clinical signs of improvement within 2 weeks. He had a peripherally inserted central catheter line, and continued ceftaroline therapy. The patient was discharged home on oral sulfamethoxazole/trimethoprim and rifampin, with all subsequent cultures negative and the patient’s physical condition was still improving.

This case raises the following questions: was the severe reaction to vancomycin a true allergy or red man syndrome, which is easily treatable with diphenhydramine? Would the patient have been better able to tolerate daptomycin if the dose had just been decreased? According to the IDSA guidelines for treating MRSA infections, daptomycin can be given at 8 to 10 mg/kg for complicated MRSA bacteremia. However, considering this is a level B III recommendation (ie, from expert opinion and case reports), the dosing remains open for debate. It will never be truly known if this patient’s psoas abscess could have simply been treated with IV vancomycin. This article was meant to report on an actual patient and highlight differences in practice approaches. We are grateful for the opportunity to be involved in this patient’s care.

Jerry Barbee, Jr, PharmD, BCPS, CPh, is a clinical pharmacist at HCA West Florida Hospital. Glenn Schulman, PharmD, MS, BCPS, BCACP, CGP, is a clinical pharmacist at HCA West Florida Hospital. Alicia Patel is a 2017 PharmD candidate at the University of Florida.

Wong OF, Ho PL, Lam SK. Retrospective review of clinical presentations, microbiology, and outcomes of patients with psoas abscess. 

. 2013;19(5):416-423. doi: 10.12809/hkmj133793.

Chern CH, Hu SC, Kao WF, Tsai J, Yen D, Lee CH. Psoas abscess: making an early diagnosis in the ED. 

Shields D, Robinson P, Crowley TP. Iliopsoas abscess—a review and update on the literature. 

 2012;10(9):466-469. doi: 10.1016/j.ijsu.2012.08.016.

Adelekan MO, Taiwo SS, Onile BA. A review of psoas abscess. 

Ricci MA, Rose FB, Meyer KK. Pyogenic psoas abscess: worldwide variations in etiology. 

Krobot K, Yin D, Zhang Q, et al. Effect of inappropriate initial empiric antibiotic therapy on outcome of patients with community-acquired intra-abdominal infections requiring surgery. 

Liu C, Bayer A, Cosgrove SE, et al; Infectious Diseases Society of America. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant 

 2011;52(3):e18-e55. doi: 10.1093/cid/ciq146.

Alobaid AS, Hites M, Lipman J, Taccone FS, Roberts JA. Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: a structured review. 

2016;47(4):259-268. doi: 10.1016/j.ijantimicag.2016.01.009.

Abscesses can occur in obscure places in the body, including the psoas muscle.

Bilateral Psoas Abscess Treated with Multiple Antibiotic Regimens

Melanoma is responsible for approximately 1% of all skin cancers but is associated with the highest rate of deaths among patients with skin cancer.

 Surgical resection remains the main treatment for early cutaneous melanoma; however, excised melanomas that have high-risk features and lymph node involvement are associated with an increased risk of recurrent disease. Until recently, adjuvant high-dose interferon has been the only approved medication for stage 3 melanoma. The use of ipilimumab (Yervoy), a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, has been shown to significantly decrease the rate of cancer recurrence and may offer an alternative to high-dose interferon.

Melanoma is one of the most common and preventable cancers in the United States. This disease is notorious for being untreatable other than by complete cutaneous excision. According to the American Cancer Society, an estimated 76,380 new cases of invasive melanoma will be diagnosed in the United States in 2016.

 Excision is usually extremely effective but depends on early detection (at stage 1 or 2) prior to lymph node involvement.

Stage 3 melanoma is diagnosed through a sentinel lymph node biopsy or through biopsy of other forms of lymphatic regional metastases.

 In stage 4, patients have known systemic metastases in distant sites.

 Until recently, the use of adjuvant immunotherapy with high-dose interferon-alfa has been the only approved therapy for stage 3 melanoma.

 With the introduction of the new immunologic breakthrough pharmaceutical ipilimumab, patients with stage 3 or 4 melanoma may have a new treatment option that could put their disease in remission and allow them to live longer.

CP is an 80-year-old white man who presented to his dermatologist with an enlarging blister on his left forearm. He underwent a shave biopsy that showed nodular malignant melanoma with overlying ulceration, at least 4.1 mm in depth. The tumor was strongly positive for S100 (a calcium-binding protein that is a sensitive marker of melanocyte differentiation).

 The mitotic rate was up to 5 mitosis per high-power field, and the tumor was wild-type 

 (a gene that provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell’s nucleus).

CP was referred to an oncologist and a surgeon for excision of the melanoma and for a sentinel lymph node biopsy. Pathology showed a 1.5 × 1.2 × 0.8—cm tumor with a thickness of 8 mm and negative margins. The closest margin was 1.3 cm, and 1 of 6 lymph nodes examined was positive for micrometastatic disease. Positron emission tomography showed no metabolically active tumors or metastatic disease. However, the sentinel lymph node biopsy result was positive for metastatic disease. Therefore, the patient underwent lymph node dissection. The pathologist reported 2 positive lymph nodes of the 12 examined. The metastasis measured 0.4 cm.

CP’s final pathologic staging was stage 3B (T4a, N2, M0). He began treatment with ipilimumab on June 6, 2016, and received 4 treatments at 3-week intervals. He will continue to receive immunotherapy treatment once every 12 weeks beginning on week 24. CP tolerated the treatment well with minor adverse effects (AEs), such as itching, for which lotion was applied to keep the skin moist after treatments. Currently, CP is in remission and will continue to be screened on follow-up visits with his oncologist.

 has long been the standard for adjuvant treatment following disease resection in patients with melanoma.

 Although the use of interferon-alfa may help postpone melanoma recurrence, it has not been proved to increase patient survival rates. For interferon-alfa to be effective, high doses must be administered over the course of 1 year, which may lead to intolerable AEs, which commonly include fever, chills, aches, depression, exhaustion, and certain effects on the heart and the liver.

 The severity of these AEs varies among patients; however, many patients find this treatment to be intolerable and, therefore, stop treatment.

 is a human cytotoxic T-lymphocyte antigen 4 blocking antibody indicated for treating unresectable or metastatic melanoma and as adjuvant treatment for cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm after complete resection.

 In 2015, the FDA approved the use of ipilimumab as adjuvant treatment for patients with stage 3 melanoma.

 Ipilimumab is dosed as 3 mg/kg IV every 3 weeks for a maximum of 4 doses. Common AEs of ipilimumab include fatigue, rash, and diarrhea. Ipilimumab carries a black box warning for immune-mediated adverse reactions that could be severe or fatal.

 Although the AEs of ipilimumab may be severe, they are generally more well tolerated than those of interferon-alfa. Ipilimumab has shown promise by using the patient’s immune system to treat melanoma when the patient is not a candidate for surgery. The drug may also prevent melanoma recurrence after lymph node resection.

In the case of CP, the oncologist made an appropriate decision to use ipilimumab to treat stage 3B melanoma. By choosing ipilimumab as adjuvant therapy, the patient received 4 doses, resulting in minimal AEs.

Melanoma is an unrelenting disease with a poor prognosis. The pharmacologic treatment options have been limited in the past, but immunotherapy offers a glimmer of hope. Surgery is often unsuccessful and disfiguring and, with the addition of high-dose interferon-alfa, may decrease patients’ quality of life.

With the new and early use of immunotherapy, such as ipilimumab, the medical community is learning how to harness the patient’s immune system to improve clinical outcomes. In the case presented here, the patient’s initial outcome has been positive, with minimal AEs. The black box warnings and AEs of currently marketed agents suggest that continued research and development is needed. We are grateful to participate in these exciting, new drug innovations.

Jerry Barbee, Jr, PharmD, BCPS, CPh, is a clinical pharmacist at HCA West Florida Hospital. Hania Joudeh, BSPharm, is a clinical pharmacist at HCA West Florida Hospital. Glenn Schulman, PharmD, MS, BCPS, BCACP, CGP, is a clinical pharmacist at HCA West Florida Hospital. Jessica Hay is a 2017 PharmD candidate at the University of South Florida.

American Cancer Society. Key statistics for melanoma skin cancer. cancer.org website. cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. Accessed September 16, 2016.

American Cancer Society. Immunotherapy for melanoma skin cancer. cancer.org website. cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-treating-immunotherapy. Accessed September 16, 2016.

American Cancer Society. Cancer Facts & Figures 2016

 cancer.org website.  cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/index. Accessed September 16, 2016.

Geller A, Swetter S. Screening and early detection of melanoma. UpToDate.com website. uptodate.com/contents/screening-and-early-detection-of-melanoma?source=search_result&search=melanoma&selectedTitle=1~150. Accessed September 16, 2016.

American Joint Committee on Cancer. Melanoma of the skin. In: 

. 7th ed. New York, NY: Springer; 2010:325-344.

Blessing K, Sanders DS, Grant JJ. Comparison of immunohistochemical staining of the novel antibody melan-A with S100 protein and HMB-45 in malignant melanoma and melanoma variants. 

US National Library of Medicine. BRAF gene. Genetics Home Reference website. ghr.nlm.nih.gov/gene/BRAF. September 13, 2016. Accessed September 16, 2016.

Sosman JA. Adjuvant immunotherapy for melanoma. UpToDate.com website. uptodate.com/contents/adjuvant-immunotherapy-for-melanoma?source=search_result&search=melanoma&selectedTitle=27~150. Accessed September 16, 2016.

Yervoy [package insert]. Princeton, NJ: Bristol-Meyers Squibb; 2015.

FDA. FDA approves Yervoy to reduce the risk of melanoma returning after surgery [news release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469944.htm. Published October 28, 2015. Accessed September 16, 2016.

Case Report: Melanoma

Diabetes is a disease that affects a person’s life each day by having a negative effect on quality of life and creating a financial burden for patients and families.

 Diabetes occurs when the pancreas is incapable of producing the required amount of insulin or when the body does not use the insulin produced effectively (insulin resistance).

Most patients with diabetes are considered to be in one of the following categories

		Type 1 diabetes: characterized by lack of insulin production

		Type 2 diabetes: characterized by ineffective use of insulin by the body and lack of insulin secretion; combination therapy (oral and injectable medications) is often needed to achieve glycemic control and treat type 2 diabetes

In the United States, the number of Americans with diabetes is continuing to increase. This rise can be partly attributed to advances in health care that have increased the average life expectancy of patients.

The number of US adults with a diabetes diagnosis has quadrupled since 1980.

 If this trend continues, 1 in 3 Americans will have diabetes by 2050.

 In 2013, diabetes was the seventh leading cause of death in the United States, affecting more than 29.1 million Americans.

 Among these individuals, it is estimated that 8.1 million have not been given a diagnosis.

Diabetes is a chronic disease that can lead to macrovascular complications (eg, peripheral artery disease, stroke, myocardial infarction) and microvascular complications (eg, retinopathy, nephropathy, neuropathy) if left untreated. In 2012, the economic impact of diabetes in the United States was $245 billion.

 This economic impact will steadily increase as the number of Americans with diabetes continues to increase.

Diabetes is a metabolic disorder characterized by hyperglycemia resulting from lack of insulin secretion or action, or both.

 The kidneys are essential for helping maintain glucose balance. On average, the glomeruli filter 180 g of glucose every day through the glucose transporter proteins.

 The kidneys normally function to retrieve as much glucose as possible, which leaves urine almost completely free of glucose.

 Within the kidneys, the sodium-glucose cotransporter-2 (SGLT2) proteins help control glucose levels by actively transporting glucose against a concentration gradient. The SGLT2 proteins found in the proximal renal tubules reabsorb 90% of the glucose being filtered.

 Inhibition of these cotransporters allows lowering of insulin-independent glucose.

Table 1 lists the currently available SGLT2 inhibitors. On March 29, 2013, the FDA approved Invokana (canagliflozin) for the treatment of diabetes in adults. Canagliflozin was the first in a new class of medications called SGLT2 inhibitors, which inhibit renal proximal tubular glucose reabsorption. With this insulin-independent mechanism of action, SGLT2 inhibitors have a very low risk of causing hypoglycemia and are effective at lowering glycated hemoglobin. In addition, they have been shown to have several other favorable effects, including reduction of body weight and blood pressure.

 SGLT2 inhibition results in diuresis of 400 mL of fluid and 75 g of glucose per day, as well as a subsequent weight loss of 2.5 to 3.2 kg over 4 weeks, mainly because of reduced fat mass.

SGLT2 inhibitors are available as once-daily tablets, with their bioavailability ranging from 60% with empagliflozin to 78% with dapagliflozin. These drugs should be taken 30 minutes before the first meal of the day to maximize absorption. SGLT2 inhibitor dosing is optimized at a once-daily dose because these agents have a half-life of 10 to 13 hours.

The most common adverse effect (AE) of concern with SGLT2 inhibitor therapy is fungal infection of the genitourinary tract, which affects approximately 5% to 11% of patients; canagliflozin is most often associated with this AE.

 SGLT2 inhibitors have also been documented to cause serious urinary tract infections, including urosepsis and pyelonephritis.

The FDA has warned that the use of SGLT2 inhibitors can result in ketoacidosis, a serious condition in which the body produces high levels of blood acids called ketones. Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have symptoms of ketoacidosis, which include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.

 The FDA is also currently investigating whether the risk of leg and foot amputations is increased while taking canagliflozin. Patients are advised to notify their physician if they notice any new pain, tenderness, sores, ulcers, or infections in their lower extremities.

 SGLT2 inhibitors can also decrease blood pressure due to their volume-depleting diuretic effects, leading to AEs in some patients.

Baseline kidney function and serum potassium level should be determined at initiation of any SGLT2 inhibitor and monitored periodically thereafter for adverse changes. Patients with renal impairment may require a dose reduction, or SGLT2 inhibitors may be contraindicated in these patients (Table 2).

SGLT2 inhibitors have been quickly adopted into practice, and pharmacists are responsible for ensuring that these medications are used safely and effectively in patients. Since 2013, when the FDA approved canagliflozin as a first-in-class medication for treating diabetes, 5 new medications and combination treatments in this class have gained FDA approval. Each SGLT2 inhibitor is slightly different than the others, which should be considered in making the best choice for patients. As the market presence of these medications increases, pharmacists should be mindful of the long-term risks and benefits to patients in order to optimize treatment of diabetes. 

Jerry Barbee, Jr, PharmD, BCPS, CPh, is a clinical pharmacist at HCA West Florida Hospital. 

Glenn Schulman, PharmD, MS, BCPS, BCACP, CGP,

is a clinical pharmacist at HCA West Florida Hospital. Curtis Brashear is a 2016 PharmD candidate at Auburn University. Max Greenlee is a 2016 PharmD candidate at the University of Florida.

McCulloch DK. Overview of medical care in adults with diabetes mellitus. UpToDate.com website. uptodate.com/contents/overview-of-medical-care-in-adults-with-diabetes-mellitus?source=search_result&search=%22Overview+of+medical+care+in+adults+with+diabetes+mellitus%22&selectedTitle=1~1. U

Mar 9, 2016. Accessed December 15, 2015. 

2015 diabetes fact sheet. World Health Organization website.

Kishore P. Diabetes mellitus (DM). Merck Manual website. merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed April 29, 2016. 

Diabetes report card 2014. CDC website. cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf. Published 2015. Accessed April 29, 2016. 

American Diabetes Association. 2014 National Diabetes Statistics Report. ADA website. diabetes.org/diabetes-basics/statistics/. Accessed Dec. 5, 2015 

Triplitt CL, Repas T, Alvarez CA. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. 

Pharmacotherapy: A Pathophysiologic Approach

. 9th ed. New York, NY: McGraw-Hill Medical; 2014:1143-1190. 

. Type 2 sodium-glucose cotransporter (SGLT2) inhibitors: from familial renal glucosuria to the treatment of type 2 diabetes mellitus. 

doi: 10.3265/Nefrologia.pre2010.Sep.10494. 

Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. 

American Diabetes Association. Approaches to glycemic treatment. 

Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with SGLT2 inhibition. 

Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013. 

Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2014. 

Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015. 

FDA drug safety communication: labels to include warnings about too much acid in the blood and serious urinary tract infections. FDA website.

www.fda.gov/Drugs/DrugSafety/ucm475463.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Published December 4, 2015. Accessed December 4, 2015. 

		FDA Drug Safety Communication: interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet). FDA website. www.fda.gov/Drugs/DrugSafety/ucm500965.htm. Published May 18, 2016. Accessed June 25, 2016.

FDA approves Invokana to treat type 2 diabetes

www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm

Sarnoski-Brocavich S, Hilas O. Canagliflozin (Invokana), a novel oral agent for type-2 diabetes. 

Diabetes is a disease that affects a person's life each day by having a negative effect on quality of life and creating a financial burden for patients and families.