Drug Information Response Center Questions

A Brief Review of the Recent Fungal Meningitis Outbreak

Meningitis is a serious condition associated with significant morbidity and mortality. Recently, an outbreak in the United States was identified, linked to contaminated injections of methylprednisolone acetate (MPA) solution originating from a compounding pharmacy, the New England Compounding Center (NECC), in Framingham, MA.1 Of note, a similar outbreak of fungal meningitis associated with contaminated steroid injections occurred in 2002.2 The identification of the recent outbreak began on September 18, 2012, when the Tennessee Department of Health was notified of a culture-confirmed case of Aspergillus fumigatus meningitis. As more cases were identified, the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) became involved in the investigation. As of November 11, 2012, a total of 438 cases of fungal meningitis or stroke secondary to presumed fungal meningitis had been confirmed by the CDC, with 32 deaths.3 Cases have been reported in 19 states with the bulk occurring in Michigan (128 cases), Tennessee (81 cases), Indiana (52 cases), and Virginia (50 cases). A total of 23 states received injections from the contaminated lots, which were recalled by the NECC on September 26, 2012, followed by a recall of all compounded products from the NECC on October 6. On October 23, the Massachusetts State Board of Pharmacy permanently revoked NECC’s license.4 An investigation by the FDA of NECC found 83/321 vials of an affected lot of MPA contained "greenish black foreign matter," and an additional 17/321 vials of that same lot to contain "white filamentous material."5 When 50 vials from this lot were tested, 100% showed "viable microbial growth." Though the index case of fungal meningitis was laboratory confirmed to be Aspergillus fumigatus, further testing by the CDC revealed the major causative pathogen to be Exserohilum rostratum with 75 confirmed cases as of November 2.3 Exserohilum rostratum, a brown-black mold, has been known to cause human disease. Several case reports and series have been published highlighting Exserohilum's ability to infect both healthy and immunocompromised individuals.6-10

Since the outbreak, the CDC has issued a definition for probable fungal meningitis.3 Patients must have received an epidural or paraspinal preservative free MPA injection and subsequently contracted: 1) meningitis of unknown etiology after May 21, 2012; or 2) had a posterior circulation stroke without documentation of a normal cerebrospinal fluid (CSF) profile. Associated signs and symptoms should include at least 1 of the following: fever, headache, stiff neck, or photophobia, in addition to an abnormal CSF profile (>5 white blood cells, regardless of glucose or protein). Other symptoms include weakness or numbness in any part of the body, slurred speech, and increased pain, tenderness or swelling at the injection site. Cases should be confirmed by the presence of a fungal pathogen in a culture of the blood or CSF.

A report of the index case of fungal meningitis was published recently.11 The patient, a man in his 50s, presented with symptoms including headache, neck pain, nausea, malaise, chills, fatigue, and decreased appetite. The patient received a course of antibiotic therapy and was discharged. The patient presented again with headache and lower back pain, as well as having incomprehensible speech. A lumbar puncture revealed a protein level of 319 mg/dL, glucose concentration of 2 mg/dL, and a white blood cell count of 4,422 cells/mm3. After antibiotics were reinitiated, the patient demonstrated improvement until hospital day 6, at which point increased somnolence, staring spells, and a transient right facial droop were observed. Liposomal amphotericin B was then added. Cultures of CSF were reported to contain Aspergillus fumigatus the following day, and voriconazole was initiated. On hospital day 11, the patient became unresponsive with seizure activity and was intubated and started on mechanical ventilation. Intraventricular hemorrhage, subarachnoid hemorrhage, and worsening hydrocephalus were detected by computerized tomography, and cerebral angiographic imaging suggested a mycotic aneurysm. On day 15, magnetic resonance imaging exposed additional cerebellar and cerebral infarcts. Life support was removed and the patient expired on hospital day 22. Another case report of a patient who received a contaminated MPA injection details a similar disease course, resulting in death on hospital day 10.12

Per the CDC, the greatest risk of contracting fungal meningitis is within the first 6 weeks after injection of the contaminated product.3 As the recall date for the affected lots was September 26, 2012, this period ended on November 7. However, there is potential for further cases to develop. A negative fungal culture or polymerase chain reaction based on a sample from the central nervous system (CNS) does not exclude infection. Empiric therapy should be initiated after the collection of a CSF sample for both fungal and other normal pathogens, including bacteria and viruses, based on the patient’s etiology. It is important to note that the current outbreak of fungal meningitis in not contagious. Prophylactic treatment is not recommended in patients without symptoms who received an epidural or paraspinal injection. Clinicians have an option to conduct a lumbar puncture to check for evidence of meningitis.

In response to the outbreak, the CDC issued interim treatment guidance for CNS infections associated with the injection of tainted MPA.3 The recommended therapy for fungal meningitis is voriconazole, possibly with the addition of liposomal amphotericin B depending on severity and patient response. This recommendation coincides with the Infectious Diseases Society of America (IDSA) guidelines for the treatment of aspergillosis of the CNS.13 Itraconazole or posaconazole may be used in patients unable to tolerate or refractory to voriconazole. There are few data supporting echinocandins (caspofungin, micafungin, anidulafungin) as single agents or in combination with voriconazole for aspergillosis infections of the CNS. Voriconazole is preferred because it is active against brown-black molds, Aspergillus, and has good penetration across the blood-brain-barrier, with concentrations approximately 50% of those found in plasma. In order to ensure adequate concentrations are reached, voriconazole should be administered at a dosage of 6 mg/kg every 12 hours, preferably by intravenous (IV) route.3 Because voriconazole is metabolized through the liver, and there is significant interpatient variability, a trough level should be drawn 5 days after initiation of therapy and weekly thereafter, targeting a level of 2-5mcg/mL. Voriconazole is also available in a tablet formulation, and patients may be transitioned to this once they are clinically stable or improving. In patients who exhibit severe cases of fungal meningitis or are deteriorating despite antifungal therapy, providers should consider adding liposomal amphotericin B. The preferred formulation is AmBisome®, given at 5-6 mg/kg IV daily. Doses as high as 7.5 mg/kg daily may be considered in patients who are not improving. Intrathecal amphotericin B should be avoided. Prolonged therapy is likely necessary to fully cure the infection. A minimum of 3 months of therapy is recommended, and possibly longer in patients with underlying immunosuppression, more severe disease, or disease involving the bone.

Adverse effects associated with voriconazole therapy include transient visual disturbances, hepatotoxicity (elevated alkaline phosphatase, serum bilirubin, and aminotransferase enzyme levels), rash, fever, chills, and headache.13,14 Voriconazole is a potent inhibitor and substrate of cytochrome P450 (CYP) enzymes, including CYP3A4, CYP2C9, and CYP2C19. Dose adjustments or alternatives may be necessary in patients taking drugs that are metabolized by or induce these enzymes. Adverse effects of amphotericin B include infusion-related reactions (fever, chills, nausea, vomiting, arthralgia, myalgia), dose-limiting nephrotoxicity (azotemia, elevated creatinine, potassium wasting, renal tubular acidosis), hypotension, diarrhea, and elevated liver enzymes.13,15

Regarding the 2002 outbreak of fungal meningitis, preservative free MPA injections from a compounding pharmacy led to cases of meningitis, resulting in 1 death.2 The causative pathogen during this outbreak was found to be Exophiala (Wangiella) dermatitidis, a brown-black mold related to E. rostratum, which responded to treatment with voriconazole.16 Cases from the outbreak in 2002 continued to appear over 6 months. Based on this precedent, the currently recommended treatment should be effective, though patients who received injections from the affected lots of MPA should continue to be vigilant for symptoms of meningitis.

The current outbreak of fungal meningitis associated with contaminated MPA injections from the NECC indicates the importance of maintain sterility when compounding injectable medications.17 Patients who received injections from the 3 identified lots should continue to be vigilant for symptoms. It is imperative that providers begin antifungal treatment empirically in patients with probable fungal meningitis, and can optionally perform a lumbar puncture in patients without symptoms. Voriconazole is the treatment of choice, and liposomal amphotericin B may be added if needed. Though the compounded products have been recalled, cases may continue to appear through March of 2013.

References:

  1. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy - United States, 2012. MMWR. Morbidity and mortality weekly report. Oct 19 2012;61:839-842.
  2. Perfect JR. Iatrogenic Fungal Meningitis: Tragedy Repeated. Annals of Internal Medicine. 2012.
  3. Multistate Fungal Meningitis Outbreak Investigation. Centers for Disease Control and Prevention 2012; http://www.cdc.gov/hai/outbreaks/meningitis.html. Accessed November 11, 2012.
  4. Remarks of Governor Deval L. Patrick. Executive Office of Health and Human Services 2012; http://www.mass.gov/eohhs/docs/dph/quality/boards/necc/remark-governor-p.... Accessed November 11, 2012.
  5. Multistate outbreak of fungal meningitis and other infections. Food and Drug Administration 2012; http://www.fda.gov/Drugs/DrugSafety/FungalMeningitis/default.htm. Accessed November 11, 2012.
  6. Adam RD, Paquin ML, Petersen EA, et al. Phaeohyphomycosis caused by the fungal genera Bipolaris and Exserohilum. A report of 9 cases and review of the literature. Medicine. Jul 1986;65(4):203-217.
  7. Anandi V, George JA, Thomas R, Brahmadathan KN, John TJ. Phaeohyphomycosis of the eye caused by Exserohilum rostratum in India. Mycoses. Nov-Dec 1991;34(11-12):489-491.
  8. Aquino VM, Norvell JM, Krisher K, Mustafa MM. Fatal disseminated infection due to Exserohilum rostratum in a patient with aplastic anemia: case report and review. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Jan 1995;20(1):176-178.
  9. Bhigjee AI, Parmanand V, Hoosen AA, Roux L, Bill PL. Disseminated Exserohilum infection. The Journal of infection. May 1993;26(3):336-337.
  10. Burges GE, Walls CT, Maize JC. Subcutaneous phaeohyphomycosis caused by Exserohilum rostratum in an immunocompetent host. Archives of dermatology. Oct 1987;123(10):1346-1350.
  11. Pettit AC, Kropski JA, Castilho JL, et al. The Index Case for the Fungal Meningitis Outbreak in the United States. The New England Journal of Medicine. Oct 19 2012.
  12. Lyons JL, Gireesh ED, Trivedi JB, et al. Fatal Exserohilum Meningitis and Central Nervous System Vasculitis after Cervical Epidural Methylprednisolone Injection. Annals of Internal Medicine. 2012.
  13. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Feb 1 2008;46(3):327-360.
  14. Voriconazole (Vfend) prescribing information. Pfizer Inc. New York, NY. 2011; http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021266s035,0212.... Accessed November 13, 2012.
  15. Amphotericin B liposome (AmBisome) prescribing information. Gilead Sciences, Inc. San Dimas, CA. 2012; http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050740s021lbl.pdf. Accessed November 13, 2012.
  16. Richardson MD, Warnock DW. Fungal infection : diagnosis and management. 4th ed. Chichester, West Sussex, UK: Wiley-Blackwell; 2012.
  17. Alcorn T. Meningitis outbreak reveals gaps in US drug regulation. Lancet. Nov 3 2012;380(9853):1543-1544.

 

Use of Metformin as Adjunctive Chemotherapy in Patients with Cancer

The American Diabetes Association (ADA) issued a consensus report in 2010 addressing diabetes and cancer.1 In this review, metformin was noted to have numerous effects on cancer, specifically breast cancer cell lines. In laboratory experiments, metformin inhibited cell proliferation and caused partial cell cycle arrest in some cancer cells. Metformin activates adenosine-monophosphate (AMP)-activated protein kinase (AMPK), which in turn inhibits growth of cancer cells because it inhibits protein synthesis. Studies in mice injected with lung carcinoma cells showed the antineoplastic effect of metformin was greater in subjects on a high-energy diet than those on a control diet, as measured by tumor size.2 This indicates the insulin lowering action of metformin may play a role in its anti-cancer actions.

A review by Rattan et al delves into the mechanism by which metformin slows tumor growth.6 As previously noted, metformin activates AMPK, which leads to downstream effects including inhibition of the mammalian target of rapamycin (mTOR), activation of p53 and p21 (both of which result in cell cycle arrest), inhibition of sterol and lipid synthesis pathways, and a systemic effect that reduces circulating levels of growth factors such as insulin, leptin, and insulin-like growth factor (IGF). In vitro studies have shown metformin to inhibit the growth of numerous types of cancer cells, including glioma, breast, pancreatic, colon, renal, ovarian, endometrial, lung, and prostate. Metformin may also be effective against metastasis. There are currently 2 theories on how metastases arise: either by epithelial to mesenchymal transition or via cancer stem cells. Metformin has been shown in vitro to inhibit both of these, via similar mechanisms as described before. These antineoplastic properties have made metformin the subject of numerous trials, though many are still in their early stages.

Per the ADA consensus report, several observational studies show that patients with diabetes, when treated with metformin compared to other agents, such as sulfonylureas and insulin, have a lower risk of cancer or cancer mortality.1 These observational studies, however, are likely confounded; the patients taking metformin were generally healthier and had a shorter history of diabetes than those on other antidiabetic therapies. The ADA notes that associations of specific antidiabetic agents with cancer risk are likely confounded by other factors, including body weight, hyperglycemia, hyperinsulinemia, drug indication, and the complexity of diabetes, though early evidence suggests metformin is associated with a lower risk of cancer compared to other therapies, such as sulfonylureas and insulin. Further research is needed to clarify the role of metformin and cancer risk.

A meta-analysis by Noto et al examined cancer risk in patients with diabetes taking metformin.3 They included studies involving patients with type 2 diabetes who received metformin, both randomized controlled trials (RCTs) with ≥ 1 year of follow-up and observation studies of any duration. Pooled risk ratios (RRs) were used for cancer incidence and cancer mortality. Ten studies (2 RCTs, 6 cohort studies, 2 case-control studies) including 21,195 patients met criteria and were selected to evaluate cancer incidence while 6 studies (4 cohort studies, 2 RCTs) including 210,892 patients were used to evaluate cancer mortality. The RR for all-cancer incidence was 0.68 (95% confidence interval [CI] 0.53 to 0.88) and 0.66 (95% CI 0.49 to 0.88) for cancer mortality. Significant risk reductions were found for colorectum (RR 0.68, 95% CI 0.53 to 0.88), liver (RR 0.20, 95% CI 0.07 to 0.59), and lung cancer (RR 0.67, 95% CI 0.45 to 0.99). The authors noted that there were significant differences among the types of studies. Evaluating heterogeneity among the different study types, significant variation was observed among the observational cohort studies but not the RCTs or case-control studies. In addition, the RCTs showed no benefit of metformin on cancer incidence and cancer mortality, while the observational studies demonstrated otherwise. Interestingly, the duration of the observational studies was not reported.

Another meta-analysis examined cancer mortality associated with metformin and other therapies.4,5 Stevens et al evaluated RCTs of minimum duration 1 year in which ≥500 patients without preexisting cancer were given metformin. Thirteen trials were included in the analysis, comprising 66,447 person-years of follow-up. The pooled RR for all-cause mortality was 0.99 (95% CI 0.83 to 1.17). Of note, not all trials included in the meta-analysis were specifically designed to evaluate cancer mortality. Also, though the authors only included trials of 1 year or more, this is a relatively short time period to evaluate patients for cancer mortality.

Jiralerspong et al investigated the role of metformin in early-stage breast cancer patients receiving neoadjuvant chemotherapy.7 Patients with diabetes taking metformin were compared to patients with diabetes not taking metformin and patients without diabetes. The primary endpoint was the effect of metformin on growth of tumor cells, as measured by pathologic complete response (pCR). pCR was significantly higher in patients with diabetes taking metformin (n=68) compared to those not taking metformin (n=87), at 24% vs. 8%, respectively (p=0.007). Interestingly, patients with diabetes taking metformin had a higher pCR than patients without diabetes (n=2,374), though not significantly (24% vs 16%, p= 0.10) In this study, a multivariate logistic regression model found that metformin was independently predictive of pCR (odds ratio 2.95, 95% CI 1.07 to 8.17) after adjustment for age, stage of cancer, body mass index, diabetes, grade, receptor status, and neoadjuvant taxane use.

In contrast, Bayraktar et al examined metformin use in patients receiving adjuvant chemotherapy for triple negative breast cancer.8 This study also evaluated patients with diabetes receiving metformin, not receiving metformin, and patients without diabetes. Outcomes were distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). There were 63 patients with diabetes receiving metformin, 67 patients with diabetes not receiving metformin, and 1,318 patients without diabetes. At a median follow-up of 62 months, there were no significant differences in DMFS, RFS, and OS among the 3 groups. Patients with diabetes who did not receive metformin and patients without diabetes had a higher risk of distant metastases, with hazard ratios (HR) of 1.63 (95% CI 0.87 to 3.06) and 1.62 (95% CI 0.97 to 2.71), respectively.

Hadad et al conducted a trial of metformin in women without diabetes receiving neoadjuvant chemotherapy for breast cancer.9 The study consisted of a pilot in which all patients were given metformin at 500mg daily for 1 week followed by 1,000mg twice daily for another week leading up to surgery. In a follow up trial, patients were randomized to receive metformin in this regimen or no drug for 2 weeks prior to surgery. The primary endpoint was expression of Ki67, which is a marker for tumor growth, measured prior to metformin initiation and at time of operation. Ki67 was detected in significantly fewer cells in the metformin group compared to the control for both the pilot and study groups (p=0.041 and 0.027, respectively), suggesting a reduction in tumor growth. Based on these results the authors concluded metformin may have antiproliferative effects in women with breast cancer. This trial was important because it demonstrated the effects of metformin even in patients without diabetes, though it did not measure clinical endpoints.

In conclusion, metformin has been proposed to inhibit tumor growth via a number of mechanisms. In observational studies of patients with diabetes, metformin use has been associated with lower incidence of cancer as well as cancer mortality. In RCTs, however, this finding has not been duplicated. Studies examining metformin as an addition to neoadjuvant chemotherapy in patients with diabetes have had mixed results. In patients with breast cancer without diabetes, metformin use was associated with a secondary marker of tumor growth, though no clinical endpoints were examined. There are numerous studies currently ongoing to further elucidate the role of metformin in various types of cancer, and though it appears to be promising, there is little evidence examining clinical outcomes to support its use currently.6

References:

  1. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes care. Jul 2010;33(7):1674-1685.
  2. Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocrine-related cancer. Sep 2008;15(3):833-839.
  3. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PloS one. 2012;7(3):e33411.
  4. Stevens RJ, Ali R, Bankhead CR, et al. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia. Oct 2012;55(10):2593-2603.
  5. Stevens RJ, Ali R, Bankhead CR, et al. Erratum to: Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia. Oct 18 2012.
  6. Rattan R, Ali Fehmi R, Munkarah A. Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. Journal of oncology. 2012;2012:928127.
  7. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jul 10 2009;27(20):3297-3302.
  8. Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer. Mar 1 2012;118(5):1202-1211.
  9. Hadad S, Iwamoto T, Jordan L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast cancer research and treatment. Aug 2011;128(3):783-794.

 

Glyburide vs. Glipizide: Which is superior?

Both glyburide and glipizide are second generation sulfonylureas. The drugs have slightly different pharmacokinetic characteristics.1,2 Although both are dosed once or twice daily, time to onset of the drug and duration of effect are slightly longer for glyburide (nonmicronized formulation), as is the serum half-life.3 These parameters may be seen in Table 1. Despite these differences, administration for both drugs is recommended approximately 30 minutes prior to a meal. Of note, absorption of glyburide is not affected by food intake, while absorption of glipizide is delayed by food. Both drugs are renally excreted (glyburide 50%, glipizide 80-85%); thus, conservative dosing with potential dosage adjustment is recommended for patients with renal insufficiency.

Table 1. characteristics of glipizide and glyburide.1,2
Drug Approximate equivalent dose (mg) Serum t1/2(h) Onset (h) Duration (h)
Glyburide-nonmicronized 5 10 2-4 16-24
Glyburide-micronized 3 ~4 1 12-24
Glipizide 10 2-4 1-3 10-24
t1/2 = half-life

Regarding clinical efficacy, glyburide is more potent than glipizide,4 as evidenced by the fact that comparatively lower doses may be used to control hyperglycemia; however, the maximum effects attainable with glyburide are similar to those of glipizide as well as other sulfonylureas. Compared to glyburide, glipizide may produce a faster blood glucose-lowering effect and is eliminated more rapidly, suggesting a potential for lower risk of hypoglycemia. However, a difference in the risk for hypoglycemia between these 2 drugs has not been clearly substantiated.

Several trials have been conducted involving glyburide and glipizide, few with direct comparisons; additionally, most of the available literature is not recent. In 2000, Kitabchi et al performed a trial in which they compared the effectiveness and relative potency of glyburide and glipizide over a 15-month period in patients with type 2 diabetes mellitus (T2DM) who were unresponsive to lifestyle modifications.5 Their assessments included quarterly fasting blood glucose (FBG) and 2-h post-prandial glucose (PPG, after a standardized meal), and quarterly glycosylated hemoglobin (A1c). A total of 18 patients were randomized to receive glyburide, initial dose 2.5 to 5 mg once daily, or glipizide, initial dose 5 mg once daily. Dosages were increased every 2 weeks until fasting levels <140 mg/dL or 2-h PPG <200 mg/dL were achieved. Dosages were decreased with the occurrence of hypoglycemic episodes.

Patients in both groups experienced significant reductions in FBG, 2-h PPG, and A1c over the study period.5 Differences between the groups in FBG and 2-h PPG were significant at 6 months, with lower values observed in the glipizide group (FBG: -42.08 mg/dL, p=0.021; 2-h PPG: -52.08 mg/dL, p=0.033); however, over the 15-month period, there were no significant differences between groups for these parameters. Regarding adverse events, there were 101 complaints of hypoglycemia in the glipizide group and 110 in the glyburide group – this difference was not statistically significant. All episodes were characterized as mild or moderate; neither group reported severe hypoglycemia. The investigators concluded that both drugs are effective in controlling hyperglycemia in patients with T2DM.

In a similar study, Birkeland et al evaluated differences among glipizide, glyburide, and placebo in glycemic control and insulin secretion in patients with T2DM over a 15-month period.6 A total of 46 patients were included in this study. The investigators observed a comparable reduction in A1c levels in the groups treated with sulfonylureas, relative to placebo, throughout the study period. Both sulfonylureas were found to reduce postprandial glucose levels and increase fasting and postprandial insulin levels compared to placebo. Birkeland et al concluded that glyburide and glipizide were effective in achievement and maintenance of glycemic reduction and insulin secretion over a 15-month period.

In another study, Sami et al compared the effects of glipizide and glyburide on metabolic parameters including FBG and A1c in patients withT2DM who had manifested failure to first generation sulfonylurea therapy.7 Patients had been receiving either chlorpropamide or tolazamide and were switched at the discretion of the physician to either glyburide 20 mg daily or glipizide 40 mg daily, both administered in 2 divided doses. Patients were monitored every 2 months for a total of 6 months. There were 55 patients included, of mean age 63 years (43 to 73 years) and with a mean duration of diabetes of 8 years (5 to 15 years). No significant changes were observed in FBG and A1c for the 29 patients on glipizide (FBG: 209 ± 31 mg/dL vs. 211 ± 34 mg/dL; A1c: 12.3 ± 2.1% vs. 11.7 ± 1.8%, p>0.05 for both) and 26 patients on glyburide (FBG: 180 ± 16 mg/dL vs. 184 ± 20 mg/dL; A1c: 11.2 ± 1.6% vs. 11.0 ± 1.5%, p>0.05 for both) over the study period. Although the investigators did not statistically analyze differences between the 2 treatment groups (i.e., glipizide vs. glyburide), they concluded that treatment with both agents was comparable and not superior to treatment with the first-generation sulfonylureas in this study.

Rosenstock et al compared the efficacy and safety of glyburide and glipizide in elderly patients with well-controlled T2DM.8 Patients >65 years of age with stable T2DM on a sulfonylurea for >3 months prior to enrollment were included. At baseline, patients were subjected to a washout phase, after which they were randomized to receive glyburide 1.25 or 1.5 mg/d or glipizide 2.5 or 5 mg/d. Dosages were titrated over a 4- to 8-week period and maintenance doses then administered for a total of 4 months. Drug efficacy was assessed using FBG and A1c levels. A total of 139 patients were included in the study. Most patients in both treatment groups attained satisfactory glycemic control with no significant differences between groups in FBG or A1c at any time during the study. At the study endpoint, mean doses of glyburide and glipizide were 8.5 mg/d and 15.4 mg/d, respectively. Both regimens were determined to be well-tolerated with low incidences of hypoglycemia.

Of note, several guidelines are available addressing the management of patients with T2DM, including those of the American Diabetes Association, American Association of Clinical Endocrinologists, and the National Institute for Health and Clinical Excellence.9-12 Recommendations for preferential use of glipizide or glyburide were not found in any of these guidelines.

In summary, while there are pharmacologic differences between glipizide and glyburide, there does not appear to be a clear consensus that 1 drug is superior to the other.

References:

  1. Facts and Comparisons® [Internet database]. St. Louis, MO: Wolters Kluwer Health. Updated periodically.
  2. Micronase® [package insert]. New York, NY: Pharmacia and Upjohn Company; 2010.
  3. Glucotrol® [package insert]. New York, NY: Roerig; 2010.
  4. Micromedex® [Internet database]. Greenwood Village, CO: Thomson Reuters Healthcare. Updated periodically.
  5. Kitabchi AE, Kaminska E, Fisher JN, et al. Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus. Am J Med Sci. 2000;319(3):143-148.
  6. Birkeland KI, Furuseth K, Melander A, Mowinckel P, Vaaler S. Long-term randomized placebo-controlled double-blind therapeutic comparison of glipizide and glyburide. Glycemic control and insulin secretion during 15 months. Diabetes Care. 1994;17(1):45-49.
  7. Sami T, Kabadi UM, Moshiri S. The effect on metabolic control of second-generation sulfonylurea drugs in patients with NIDDM after secondary failure to first-generation agents. J Fam Pract. 1996;43(4):370-374.
  8. Rosenstock J, Corrao PJ, Goldberg RB, Kilo C. Diabetes control in the elderly: a randomized, comparative study of glyburide versus glipizide in non-insulin-dependent diabetes mellitus. Clin Ther. 1993;15(6):1031-1040.
  9. American Diabetes Association. Standards of medical care in diabetes – 2012. Diabetes Care. 2012;35(Suppl 1):S11-S63.
  10. American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. https://www.aace.com/files/glycemic-control-algorithm-ppt.pdf. Accessed September 17, 2012.
  11. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(Suppl 2):1-53.
  12. The National Collaborating Center for Chronic Conditions. Type 2 Diabetes: National Clinical Guideline for Management in Primary and Secondary Care (Update). http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf. Accessed September 17, 2012.

What are the relative benefits of the various inhaled corticosteroids for pediatric asthma?

Inhaled corticosteroids (ICS) play an integral part to the management of asthma in pediatric patients. In 2007, the National Heart Lung and Blood Institute (NHLBI) issued guidelines for the diagnosis and management of asthma in which they assert that initiation of low-dose ICS as a long-term control therapy may significantly reduce overall symptom burden and frequency of asthma exacerbations in pediatric patients.1 Recommendations are categorized by patient age (0 to 4 years, 5 to 11 years, and >e; years); however, overall, the NHLBI states that ICS are the preferred therapy for initial long-term control in children of all ages. These drugs have been shown to consistently control and prevent asthma symptoms, reverse airflow obstruction, improve quality of life, and decrease the number and severity of asthma exacerbations.2 Additionally, ICS are deemed to be generally safe, especially when given at low doses, even for extended periods.1 Of note, while ICS are effective in controlling symptoms, their administration will not alter the underlying disease progression or severity, as demonstrated by worsening of symptoms and airway responsiveness when treatment is withdrawn.

Several ICS are commercially available. In their 2007 guidelines, the NHLBI outlines then-available ICS with estimated comparative daily dosages in children under 11 years of age.1 This information may be seen in Table 1. These doses were based largely on the results of then-available comparative trials. The NHLBI cautions that the preparations are not absolutely interchangeable on a mcg or per puff basis. Also, different delivery devices may offer greater or lesser amounts of drug to the airways, affecting the dose.

Table 1. Comparative Daily Dosages for Inhaled Corticosteroids in Children Aged 0 to 11 Years.1
Drug Low Daily Dose Medium Daily Dose High Daily Dose
Child 0-4 Child 5-11 Child 0-4 Child 5-11 Child 0-4 Child 5-11

Beclomethasone HFA
(40 or 80 mcg/puff)

 NA 80-160 mcg NA >160-320 mcg NA >320 mcg
Budesonide DPI
(90, 180, or 200 mcg/inhalation)		 NA 180-400 mcg NA >400-800 mcg NA >800 mcg
Budesonide inhaled (suspension for nebulization) 0.25-0.5 mg 0.5 mg >0.5-1.0 mg 1.0 mg >1.0 mg 2.0 mg
Ciclesonide3,4*
(80 or 160 mcg/puff)		 NA NA
(80-160 mcg)		 NA NA
(>160-320 mcg)		 NA NA
(>320 mcg)
Flunisolide
(250 mcg/puff)		 NA 500-750 mcg NA 1,000-1,250 mcg NA >1,250 mcg
Flunisolide
(80 mcg/puff)		 NA 160 mcg NA 320 mcg NA ≥640 mcg
Fluticasone HFA
(44, 110, or 220 mcg/puff)		 176 mcg 88-176 mcg NA >176-352 mcg >352 mcg >352 mcg
Fluticasone DPI
(50, 100, or 250 mcg/inhalation)		 NA 100-200 mcg NA >200-400 mcg NA >400 mcg
Mometasone DPI (200 mcg/inhalation) NA NA NA NA NA NA

Triamcinolone acetonide**
(75 mcg/puff)

 NA 300-600 mcg NA >600-900 mcg NA ≥900 mcg
HFA=hydrofluoroalkane; NA=not approved; DPI=dry powder inhaler
*Not included in NHLBI Guideline recommendations. Doses suggested are for off-label usage.
**No longer available

For children aged 12 years and older, the NHLBI recommends the same comparative daily dosages of ICS as for adult patients.1 These recommendations may be seen in Table 2.

Table 2. Comparative Daily Dosages for Inhaled Corticosteroids in Adults and Children ≥12 Years.1
Drug Low Daily Dose Medium Daily Dose High Daily Dose

Beclomethasone HFA

(40 or 80 mcg/puff)

 80-240 mcg >240-480 mcg >480 mcg

Budesonide DPI        

(90, 180, or 200 mcg/inhalation)

 180-600 mcg >600-1200 mcg >1200 mcg

Ciclesonide HFA3,4*

(80 or 160 mcg/puff)

 160-320 mcg >320-640 mcg >640 mcg

Flunisolide (250 mcg/puff)
 

Flunisolide HFA (80 mcg/puff)

500-1,000 mcg
 

320 mcg

>1,000-2,000 mcg

 

>320-640 mcg

>2,000 mcg

 

>640 mcg

Fluticasone HFA
(44, 110, or 220 mcg/puff)

Fluticasone DPI
(50, 100, or 250 mcg/inhalation)

88-264 mcg

 

100-300 mcg

>264-440 mcg

 

>300-500 mcg

>440 mcg

 

>500 mcg

Mometasone DPI     

(200 mcg/inhalation)

 200 mcg

400 mcg

 >400 mcg

Triamcinolone acetonide**

(75 mcg/puff)

 300-750 mcg >750-1,500 mcg >1500 mcg
HFA=hydrofluoroalkane; DPI=dry powder inhaler
*Not included in NHLBI Guideline recommendations
**No longer available

An ICS was approved by the Food and Drug Administration (FDA) in 2006: ciclesonide (Alvesco®).5 Available as a metered dose inhaler with either 80 mcg/puff or 160 mcg/puff, ciclesonide is approved for maintenance treatment of asthma in adults and pediatric patients aged 12 years and older.  While not included in the NHLBI guidelines, comparative dosing of the drug has been suggested and is incorporated in Tables 1 and 2.   

Based on the recommendations of the NHLBI, it appears that while the ICS differ in potency and dosage form, they do not differ in efficacy.1 From a search of the literature, several comparative clinical trials and clinical reviews were identified that discuss potential clinical differences among available ICS. In 2009, Kelly provided an update to his previous publication comparing ICS in which the author reviews pharmacokinetic and pharmacodynamic differences among the ICS and their comparative doses.3 In this review, the author asserts that ICS potency and efficacy are slightly disparate concepts, with potency defined by the binding affinity at the glucocorticoid receptor and efficacy measured through various clinical endpoints (e.g., improvement in baseline lung function and reduction of asthma exacerbations), represented by the therapeutic index. While the potency determines efficacy of specific doses, differences in efficacy of medications may be overcome by administering comparative or equipotent doses.

In a more recent review, Stoloff and Kelly compared ciclesonide with older ICS in terms of pharmacokinetic and pharmacodynamic characteristics as well as efficacy.4 While the newer ICS was developed to improve the therapeutic index, the authors assert that the therapeutic index narrows with increasing doses for all ICS. Ciclesonide was found to be similarly efficacious to fluticasone and mometasone in equipotent doses with a potentially improved therapeutic index, but the authors report that further data are needed to assess its systemic effects.

As stated in the NHLBI guidelines, the ICS in general are purported to be safe, particularly at low doses.1 The Expert Panel concluded that benefits from ICS may plateau at low doses, but increasing the ICS dose in children with more severe asthma may be associated with further benefits and reduction in the risk of exacerbations. There is a concern for an increase in the risk of systemic effects with increasing ICS doses, though. The NHLBI asserts that the clinical significance of these effects is unclear.

Per a review by Murphy, studies of selected ICS have shown mixed results regarding effects of the ICS on growth velocity, one of the major concerns with ICS use in children.6 When used at approved doses for 1 year, for example, neither mometasone nor flunisolide was found to significantly reduce growth velocity compared to placebo or a non-ICS asthma medication. In contrast, in a study comparing budesonide (dry powder inhaler) to placebo, over a follow-up period of 4 to 6 years, a statistically significant difference in growth of 1.1 cm was observed. Whether this result is clinically significant is questionable. Regarding suppression of the hypothalamic-pituitary-adrenal (HPA) axis, another major concern with ICS use, no significant issues have been noted with any of the currently available ICS when used at approved doses.

In addition to safety and efficacy, adherence is another issue of concern. Murphy states in his review that several factors may affect adherence to ICS, including behavioral and treatment-related issues.6 Among the latter, ease of administration and frequency of dosing are cited as possible factors. Thus, it is worth noting that the available ICS differ in frequency of dosing and administration technique. Most ICS require twice daily administration, except budesonide (which may be administered once daily after a maintenance dose is achieved) and mometasone. Budesonide, fluticasone, and mometasone are available as dry powder inhalers which require a minimum peak inspiratory flow rate but do not require a spacer. In contrast, a spacer is recommended for the ICS available as metered dose inhalers, but there is no minimum required peak inspiratory flow rate. There are other notable differences among the dosage forms, including the availability of a dose counter and necessity to prime the delivery device before use, that may affect adherence.

In summary, ICS are recommended as the preferred agents for long-term control of asthma in pediatric patients and are generally viewed as safe. Among the agents, there appear to be differences in potency, but these may be overcome with dose conversion or comparative dosing. Adherence-related issues should be noted, however, as these may factor into the relative benefits of ICS therapy.

References:

  1. National Heart Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. Full report 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed May 10, 2012.
  2. Rachelfsky G. Inhaled corticosteroids and asthma control in children: assessing impairment and risk. Pediatrics. 2009;123(1):353-366.
  3. Kelly HW. Comparison of inhaled corticosteroids: an update. Ann Pharmacother. 2009;43(3):519-527.
  4. Stoloff SW, Kelly HW. Updates on the use of inhaled corticosteroids in asthma. Curr Opin Allergy Clin Immunol. 2011;11(4):337-344.
  5. Alvesco [package insert]. Marlborough, MA: Sunovion Pharmaceuticals, Inc.; 2011.
  6. Murphy KR. Adherence to inhaled corticosteroids: comparison of available therapies. Pulm Pharmacol Ther. 2010;23(5):384-388.

 

What is the statin of choice in patients infected with human immunodeficiency virus (HIV) taking protease inhibitors?

Several sources assert that there is a potential for drug-drug interactions between protease inhibitors (PIs) and lipid-lowering therapies, particularly the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins.1-3 In a recent drug safety communication, the Food and Drug Administration (FDA) states that concomitant use of PIs and certain statins may raise blood levels of the statins, increasing the risk for myopathy.4 There does not appear to be a clear consensus regarding a statin of choice in patients infected with human immunodeficiency virus (HIV) who are taking PIs.

The potential for drug interactions between statins and PIs may be explained by their pharmacokinetic characteristics.1 Most of the statins undergo extensive hepatic metabolism by cytochrome P450 (CYP) 3A4.5 A summary of statin pharmacokinetic characteristics may be seen in Table 1. All of the PIs are metabolized by CYP enzymes, primarily CYP 3A4, and have either inducing or inhibitory effects. Additionally, however, it has been proposed that there may be multiple mechanisms of drug interactions involved, based on differences in the degree to which statin concentrations are changed when co-administered with the PIs.6

Table 1. Pharmacokinetic Characteristics of Available Statins.7-13
Statin Absorption Distribution Metabolism Elimination
Atorvastatin 14% ≥98% protein bound CYP 3A4, extensive T1/2 14 h; biliary excretion, <2% in urine
Fluvastatin 24% 98% protein bound CYP 2C9 and 3A4, extensive T1/2 <3 h; 90% fecal, 5% in urine
Lovastatin <5% >95% protein bound CYP 3A4, extensive T1/2 3-4 h; 83% fecal, 10% in urine
Pitavastatin 51% >99% protein bound CYP 2C9, marginal T1/2 12 h; 79% fecal, 15% in urine
Pravastatin 34%;
17% absolute bioavailability		 50% protein bound Sulfation, extensive T1/2 77 h; 70% fecal, 20% in urine
Rosuvastatin 20% 88% protein bound CYP 2C9, minor T1/2 19 h; 90% fecal
Simvastatin <5% 95% protein bound CYP 3A4, extensive T1/2 not specified; 60% fecal, 13% in urine
CYP=cytochrome P450; T1/2=half life

The National Institutes of Health (NIH) issue guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents in which they list medications that should not be used with PIs.14 This list was last updated in October of 2011 and may be found on page 134 of the document. Of note, the PIs include amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Information from these guidelines on interactions between each statin and the PIs is summarized in Table 2.

Table 2. Data on Interactions between Statins and PIs.14
Statin PI Effect on PI or Statin Dosing and Clinical Recommendations
Atorvastatin All PIs Darunavir/r + atorvastatin 10 mg similar to using atorvastatin 40 mg alone
Fosamprenavir ± ritonavir increased atorvastatin AUC by 130-153%
Lopinavir/r increased atorvastatin AUC by 488%
Saquinavir/r increased atorvastatin AUC by 79%
Tipranavir/r increased atorvastatin AUC by 836%		 Use lowest possible starting dose with careful monitoring for toxicities or consider other statins with less potential for interaction
Lovastatin All PIs Significant increase in lovastatin expected Contraindicated. Do NOT administer.
Pitavastatin Atazanavir Pitavastatin AUC increased by 31%, Cmax by 60%; no significant effect on atazanavir No dosage adjustment needed for atazanavir without ritonavir
All ritonavir-boosted PIs Pitavastatin AUC may be increased Do NOT co-administer due to possible increase in pitavastatin concentration and risk of rhabdomyolysis.
Pravastatin Darunavir/r Pravastatin AUC increased by 81% Use lowest possible starting dose with careful monitoring.
Lopinavir/r Pravastatin AUC increased by 33% No dosage adjustment necessary.
Saquinavir/r Pravastatin AUC decreased by 47-50% No dosage adjustment necessary.
Rosuvastatin Atazanavir/r Rosuvastatin AUC increased by 213%, Cmax by 600% Use lowest possible starting dose with careful monitoring or consider other statins with less potential for interaction.
Darunavir/r, Fosamprenavir
± ritonavir, Saquinavir/r		 Rosuvastatin AUC may increase
Lopinavir/r Rosuvastatin AUC increased by 108%, Cmax by 366%
Tipranavir/r Rosuvastatin AUC increased by 26%, Cmax by 123%
Simvastatin All PIs Significant increase in simvastatin;
Saquinavir/r 400 mg/400 mg twice daily increased simvastatin AUC by 3059%		 Contraindicated. Do NOT administer.
PI=protease inhibitor; PI/r=PI boosted with ritonavir; AUC=area under the curve; Cmax=maximum concentration

The NIH guidelines suggest that use of lovastatin, pitavastatin, and simvastatin are contraindicated with most PIs.14 As alternatives, they state that pravastatin and fluvastatin have the least potential for drug-drug interactions with the PIs, except for pravastatin and darunavir boosted with ritonavir. Atorvastatin and rosuvastatin may also be used with caution, starting at the lowest possible dosage and titrating based on lipid levels and tolerability.

In addition to the NIH, the Infectious Diseases Society of America (IDSA) put forth guidelines for the management of dyslipidemia in HIV-infected patients, in which they address use of statins.15 In patients taking PIs, the IDSA recommends starting with low doses of statins and titrating upward while carefully monitoring the patient’s virologic status and development of liver or skeletal muscle toxicities. The statins they recommend and initial doses include pravastatin 20-40 mg daily or atorvastatin 10 mg daily. Fluvastatin 20-40 mg daily is suggested as an alternative. Simvastatin and lovastatin are not recommended. The IDSA notes that these recommendations are based on a small number of studies involving HIV-infected patients taking PIs that had been published to date. Of note, these guidelines were published in 2003, at which time rosuvastatin and pitavastatin were not available.

In February of 2012, the FDA required labeling changes of all statins, including removal of routine monitoring of liver enzymes from the safety section.16 Healthcare providers are advised to perform liver function tests prior to initiation of statin therapy and as clinically indicated. The prescribing information for lovastatin in particular has been extensively revised to include new contraindications and dose limitations. In the revised label, the manufacturer clearly states that the combination of protease inhibitors with lovastatin is contraindicated.17

From a search of the literature, there are few studies evaluating the comparative efficacy and safety of statins in patients infected with HIV. Also of note, while there are studies of the reduction in cardiovascular risk associated with statin use in non-HIV infected patients, such studies in HIV-infected patients are lacking. Most evaluate changes in low density lipoprotein cholesterol (LDL-c).18 For example, Aslangul et al recently conducted a trial which compared the LDL-lowering effect of pravastatin and rosuvastatin in HIV-infected patients taking a ritonavir boosted PI for at least 2 months.19 Patients with exposure to a statin or fibrate within 2 months of enrollment were excluded. Patients were randomized to receive either rosuvastatin 10 mg daily or pravastatin 40 mg daily for 45 days. The primary endpoint was percent change in LDL-c from baseline to study endpoint. A total of 83 patients participated of which 41 received rosuvastatin and 42 received pravastatin. At baseline, the median LDL-c was 4.93 mmol/L (190 mg/dL); by the study endpoint, the investigators observed a median reduction in LDL-c of 37% in the rosuvastatin group vs. 19% for the pravastatin group. Changes in serum creatinine, liver transaminases, creatine phosphokinase, and proteinuria were also documented; these were not significantly different between groups although the values were not specified. No renal, hepatic, or musculoskeletal adverse events were reported. The authors concluded that rosuvastatin was more effective than pravastatin in lowering LDL-c in patients taking PIs and that both statins were well-tolerated.

Calza et al performed an open-label study in which they compared the cholesterol lowering effects of rosuvastatin, pravastatin, and atorvastatin in HIV-infected patients who had PI-associated hypercholesterolemia.20 Patients included in the study had been taking a stable PI-based regimen for at least 12 months prior to enrollment. Patients were randomized to receive rosuvastatin 10 mg daily, pravastatin 20 mg daily, or atorvastatin 10 mg daily. The primary endpoint was decrease in LDL-c and total cholesterol from baseline to 12 months. A total of 85 patients completed the study, 26 in the rosuvastatin group, 31 in the pravastatin group, and 28 in the atorvastatin group. All patients were taking ritonavir-boosted PIs. Mean decreases in total cholesterol from baseline to the study endpoint were appreciated in all treatment groups; however, the reductions were significantly greater in the rosuvastatin group compared to the pravastatin group (25.2% vs. 17.6%, p=0.01) and compared to the atorvastatin group (25.2% vs. 19.8%, p=0.03). Mean LDL-c levels were also significantly reduced in the rosuvastatin group compared to the pravastatin and atorvastatin groups (26.3% [rosuvastatin] vs. 18.1% [pravastatin], p=0.04, and 26.3% vs. 20.3% [atorvastatin], p=0.02). Commonly reported adverse events included nausea, dyspepsia, and diarrhea, and these occurred at similar incidences among the treatment groups. There were no reports of myopathy or hepatotoxicity. The authors concluded that all statins used in the study were effective in lowering LDL and total cholesterol levels in patients taking PIs and were well-tolerated. Among the statins used, rosuvastatin demonstrated the greatest cholesterol-lowering effect.

It is important to note that while the literature suggests that pravastatin carries the lowest potential for drug interactions, use of pravastatin is not without risks. Mikhail et al described a case in which an HIV-infected patient who had been taking atazanavir boosted with ritonavir, emtricitabine, and tenofovir developed rhabdomyolysis 4 months after increasing his pravastatin dose.21 He had been virologically stable on this regimen and had been taking pravastatin 40 mg as well for 18 months. The dose of pravastatin was increased to 80 mg daily in an effort to attain his LDL goal of <100 mg/dL. The patient had symptoms consistent with myopathy beginning shortly after the dose increase and the resulting rhabdomyolysis resolved within 10 days of pravastatin discontinuation.

In a recent review, Martinez et al state that it may be beneficial to initiate a statin with high potency and low risk of clinically significant drug interactions, and to administer the statin at higher doses than used in HIV-uninfected patients.18 They justify the latter recommendation based on data indicating a lower efficacy of lipid-lowering therapies in general in patients infected with HIV compared to that reported in uninfected patients. Statins of higher potency include atorvastatin and rosuvastatin, both of which may be safe to use in HIV-infected patients. While the authors state that pravastatin may be associated with the least amount of drug interactions compared to the other statins, it is of low potency. Similarly, fluvastatin may have a low potential for drug interactions but is also of low potency.

Jimenez-Nacher et al also suggest that while interactions may occur with atorvastatin and PIs, the effect of CYP 3A4 inhibition is more modest compared to that of simvastatin or lovastatin; thus, atorvastatin may be a viable treatment option.22 Regarding rosuvastatin, Jimenez-Nacher et al state that the drug may compete with PIs for uptake in the liver and lead to an increase in plasma concentrations of rosuvastatin but decreases in liver concentrations, possibly diminishing the efficacy of the statin.

In summary, based on the current literature, no one statin appears to be clearly superior in the management of dyslipidemia in HIV-infected patients taking PIs. There is agreement on the recommendation to avoid use of simvastatin or lovastatin based on a higher propensity to interact with the PIs. Healthcare providers should closely monitor HIV-infected patients who are taking statins and be conservative with the dosing, both at initiation and with titration.

References:

  1. Struble KA, Piscitelli SC. Drug interactions with antiretrovirals for HIV infection. In: Piscitelli SC, Rodvold KA. Drug Interactions in Infectious Diseases. 2nd ed. Totowa, NJ: Humana Press; 2005:112-123.
  2. Tatro DS, ed. Drug Interaction Facts 2010. St. Louis, MO: Wolters Kluwer Health; 2010:208.
  3. HIV Drug Interactions. University of Liverpool and eMedFusion. http://www.hiv-druginteractions.org/. Accessed February 16, 2012.
  4. Statins and HIV or Hepatitis C Drugs: Drug Safety Communication – Interaction Increases Risk of Muscle Injury. Food and Drug Administration. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm. Accessed March 13, 2012.
  5. Facts and Comparisons® [Internet database]. St. Louis, MO: Wolters Kluwer Health. Updated periodically.
  6. Josephson F. Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition. J Intern Med. 2010;268(6):530-539.
  7. Lipitor [package insert]. New York, NY: Parke-Davis; 2009.
  8. Lescol and Lescol XL [package insert]. East Hanover, NJ: Novartis; 2006.
  9. Mevacor [package insert]. Whitehouse Station, NJ: Merck & Co Inc.; 2008.
  10. Altoprev [package insert]. Atlanta, GA: Sciele Pharma Inc.; 2006.
  11. Pravachol [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
  12. Crestor [package insert]. Wilmington, DE: AstraZeneca; 2009.
  13. Zocor [package insert]. Whitehouse Station, NJ: Merck & Co Inc.; 2011.
  14. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed February 16, 2012.
  15. Dube MP, Stein JH, Aberg JA et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trial Group. Clin Infect Dis. 2003;37(5):613-627.
  16. Statin Drugs – Drug Safety Communication: Class Labeling Change. Food and Drug Administration. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm293670.htm. Accessed March 13, 2012.
  17. Drugs@FDA. Mevacor Tracked Changes Label. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019643s085-trackedchangeslbl.pdf. Accessed March 13, 2012.
  18. Martinez E, Leyes P, Ros E. Effectiveness of lipid-lowering therapy in HIV patients. Curr Opin HIV AIDS. 2008;3(3):240-246.
  19. Aslangul E, Assoumou L, Bittar R, et al. Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial. AIDS. 2010;24(1):77-83.
  20. Calza L, Manfredi R, Colangeli V, Pocaterra D, Pavoni M, Chiodo F. Rosuvastatin, pravastatin, and atorvastatin for the treatment of hypercholesterolemia in HIV-infected patients receiving protease inhibitors. Curr HIV Res. 2008;6(6):572-578.
  21. Mikhail N, Iskander E, Cope D. Rhabdomyolysis in an HIV-infected patient on anti-retroviral therapy precipitated by high-dose pravastatin. Curr Drug Saf. 2009;4(2):121-122.
  22. Jimenez-Nacher I, Alvarez E, Morello J, Rodriguez-Novoa S, de Andres S, Soriano V. Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients. Expert Opin Drug Metab Toxicol. 2011;7(4):457-477.

 

Should Metformin Be Used in Patients with Kidney Disease?

Background

In 2009, the American Diabetes Association (ADA) recommended initiation of metformin in combination with lifestyle changes for type 2 diabetes mellitus (T2DM) at the time of diagnosis.1  This was based on the level of glycemic control achieved, little association with weight gain or hypoglycemia, generally low level of adverse effects, high level of acceptance, and relatively low cost of the drug. The ADA continues to recommend metformin as first-line therapy, unless contraindicated, in the most recent update of their guidelines.2  Prescribers are advised to initiate metformin at a dose of 500 mg daily and titrate up to the maximum tolerated dose or 2000 mg (immediate or extended-release) per day.3  Of note, although the manufacturer asserts a maximum dosage of 2550 mg per day for the immediate-release formulation, little clinical benefit has been demonstrated at doses exceeding 2000 mg per day. A second oral antidiabetic agent is recommended only if metformin monotherapy at the maximum tolerated dose is not effective in achieving or maintaining the goal A1C over 3 to 6 months.2  Additionally, the ADA recommends initiation of metformin for prevention of T2DM in patients with impaired glucose tolerance, impaired fasting glucose, or an A1C of 5.7 to 6.4%, particularly those with a body mass index >35 kg/m2 or under 60 years of age, and in women with a history of gestational diabetes mellitus.

The National Institute for Health and Clinical Excellence (NICE), an organization based in the United Kingdom, recently issued an update of their guidelines on the management of type 2 diabetes.4  The NICE also recommends metformin as a first-line therapy in patients whose blood glucose is inadequately controlled with lifestyle modifications. Additionally, they recommend reviewing the dose of metformin if serum creatinine (Scr) levels exceed 130 mcmol/L (1.5 mg/dL) or the estimated glomerular filtration rate (eGFR) falls below 45 mL/min/1.73 m2 and discontinuing metformin if Scr levels exceed 150 mcmol/L (1.7 mg/dL) or the eGFR falls below 30 mL/min/1.73 m2.  The NICE advocates prescribing metformin with caution in patients who are at risk for acute renal dysfunction.

Contraindications to metformin use include renal impairment, defined by the manufacturer as Scr levels exceeding 1.4 mg/dL in females and 1.5 mg/dL in males or abnormal creatinine clearance, as well as metabolic acidosis.3  It has been proposed that usage of metformin in patients with renal impairment may lead to an increased risk of lactic acidosis due to decreased renal clearance of the drug. Lactic acidosis is a rare metabolic adverse event with a documented incidence of 0.03 cases per 1000 patient-years, but it is potentially fatal in up to 50% of cases. Per the manufacturer, the risk of lactic acidosis increases with degree of renal function impairment and patient age, and the risk may be significantly reduced through regular monitoring of renal function and use of the minimum effective dose.

Literature Evaluation

While there are concerns for an increased risk of lactic acidosis in patients with renal impairment, there is no evidence from which a causal relationship can be established.5  Per Lalau,6 the idea of a threshold Scr for continuation or cessation of metformin therapy is undesirable as it suggests that metformin should be either given at the usual dose or “not at all.” This may lead to underutilization of metformin in patients who could significantly benefit from therapy. Lalau also suggests that the threshold is inappropriate as metformin-associated lactic acidosis has been shown to occur more often in patients with acute kidney failure, as opposed to chronic kidney failure.

In a review of contraindications to metformin, Holstein and Stumvoll state that lactic acidosis is a non-specific consequence of a variety of disorders, characterized by serum pH <7.25 and elevated lactate levels (>5 mmol/L).7  They note that data from some prospective studies and a meta-analysis suggest that metformin may be used safely in patients with chronic renal impairment. Moreover, they assert based on several studies performed in the U.S. and abroad that the incidence of lactic acidosis was comparable in patients with T2DM without metformin therapy and those in patients receiving metformin (9.7 vs. 5 to 9 cases per 100,000 patient-years, respectively). This observation casts some doubt onto whether metformin use itself plays a causal role in the development of lactic acidosis.

Few studies have been published evaluating the safety of metformin in patients with mild renal impairment. Connolly and Kesson conducted a case-control study of the adverse effects associated with metformin use in patients with T2DM and either normal or elevated Scr (>120 mcmol/L or 1.4 mg/dL).8  They identified a total of 17 patients with elevated Scr and 24 controls (age-matched, normal Scr) who had been taking metformin for ≥6 months. The primary endpoint was the difference in plasma lactate levels between groups, using lactate levels from age-matched healthy volunteers as a reference. The mean age among groups was similar (60.7 vs. 66.5 years, normal vs. elevated Scr; p=non-significant [NS]), as well as the metformin doses (1846 mg vs. 1717 mg, normal vs. elevated Scr; p=NS) and duration of diabetes (6.5 ± 5.3 years vs. 10.6 ± 8.2 years, normal vs. elevated Scr; p=NS). The mean Scr was 101.7 mcmol/L (1.2 mg/dL) in the normal group vs. 132.2 mcmol/L (1.5 mg/dL) in the elevated group (p<0.00001). Baseline use of metformin was significantly longer in patients with elevated Scr compared to those with normal Scr (3.0 ± 2.9 years vs. 6.3 ± 5.4 years; p<0.02). However, there was no significant difference observed among groups in the plasma lactate levels (2.64 vs. 2.3 vs. 1.7 mmol/L; normal vs. elevated Scr vs. reference value; p=NS for normal vs. elevated Scr). Connolly and Kesson concluded that while plasma lactate levels were elevated in patients with diabetes vs. healthy volunteers, there was no association between the mild renal impairment and elevated lactate levels.

Rachmani et al performed a prospective cohort study in which they sought to evaluate the safety of continued use of metformin in patients who had been taking metformin and developed a contraindication.9  They included patients aged 40 to 75 years with an Scr of 132 to 220 mcmol/L (1.5 to 2.5 mg/dL) and chronic heart failure, abnormal liver function, chronic obstructive pulmonary disease, and/or acute coronary syndromes. A total of 393 patients were randomized to either stop metformin (n=198) or continue therapy (n=195) and were followed for 4 years. Of note, all patients included had an elevated Scr. Primary endpoints included differences between groups in lactic acid and various micro/macrovascular complications. In the group who discontinued metformin, lactic acid levels increased from 1.50 to 1.63 mmol/L (p<0.01). Similarly, lactic acid levels increased in the group continuing metformin, from 1.50 to 1.66 mmol/L (p<0.01); however, the difference between groups was not statistically significant. The Scr values increased in both groups, as well, from 161 to 186 mcmol/L (1.8 to 2.1 mg/dL) in the group that discontinued therapy and 163 to 179 mcmol/L (1.8 to 2.0 mg/dL) in the group that continued therapy. However, the difference between groups was also not significant and, despite the elevated Scr, none of the patients continuing metformin therapy developed lactic acidosis. No statistically significant differences were observed in the number of cardiovascular events or cardiovascular mortality between groups. The authors concluded that metformin may be relatively safe in patients with mild renal impairment, and possibly in patients with other current contraindications to metformin.

More recently, Lim et al conducted a cross-sectional study of patients with diabetes who had been taking metformin for ≥1 month, comparing fasting plasma lactate levels in those with normal renal function and those with renal impairment.10  A total of 97 patients were included and stratified by total daily metformin dose and GFR. For the latter analysis, patients were categorized according to GFR levels of <60 (n=39), 60 to 90 (n=34), and >90 mL/min/1.73 m2 (n=24). The mean fasting plasma lactate levels were 1.7, 1.8, and 1.8 mmol/L, respectively (p=0.757). When further categorized according to total daily metformin dose, no statistically significant differences were observed in the fasting plasma lactate levels. The authors concluded that there was no association between level of renal impairment and fasting plasma lactate levels in these patients.

While there are few studies investigating the safety of metformin use in patients with mild renal impairment, the available data, in conjunction with the presence of conflicting data regarding the causality of metformin use alone and lactic acidosis, suggest that this therapy may be appropriate.5-10  Limitations to current studies include the small number of patients involved and their demographics, length of metformin treatment and follow-up methods, as well as differences in estimates of renal function and definitions of renal impairment.8-10  The appropriateness and accuracy of parameters such as Scr for measurement of renal function and frequency of monitoring should be evaluated.

Clinical Implications

It may be recommended that prescribers consider the individual patient’s renal function in concert with other factors that may predispose the patient to the development of lactic acidosis when choosing to initiate or continue metformin therapy. Consideration of the nature of renal dysfunction is also warranted, as the development of lactic acidosis has been shown to occur more often in acute rather than chronic renal failure.

Of note, metformin-associated lactic acidosis is characterized generally by elevated plasma metformin levels (>5 mcg/mL) in the setting of decreased serum pH and elevated lactate levels and may be accompanied by abdominal pain, nausea, vomiting, malaise, myalgia, and dizziness.3,11  More severe symptoms include confusion, hypothermia, respiratory insufficiency and hypotension. Patients and care-givers should be instructed to notify their healthcare providers should these symptoms arise. Metformin-associated lactic acidosis may be managed through hemodialysis, which will filter metformin at a clearance of up to 170 mL/min, and general supportive measures.3

As recommended in the NICE guidelines, prescribers should consider refraining from metformin therapy in patients with Scr levels exceeding 1.7 mg/dL or an eGFR below 30 mL/min/1.73 m2.4  While metformin should not be used in patients with acute kidney failure or severe kidney dysfunction, mild renal impairment alone may be insufficient cause to discontinue or avoid metformin use. Metformin use in the setting of stable chronic kidney disease may be both safe and effective.

References:

  1. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203.
  2. American Diabetes Association. Standards of medical care in diabetes – 2012. Diabetes Care. 2012;35(Suppl 1):S11-S63.
  3. Glucophage and Glucophage XR [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2009.
  4. National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes – an update of NICE clinical guidelines E, F, G, and H. Available at: http://www.nice.org.uk/nicemedia/pdf/CG66NICEGuideline.pdf. Accessed February 14, 2012.
  5. Philbrick AM, Ernst ME, McDanel DL, Ross MB, Moores KG. Metformin use in renal dysfunction: is a serum creatinine threshold appropriate? Am J Health Syst Pharm. 2009;66(22):2017-2023.
  6. Lalau JD. Lactic acidosis induced by metformin: incidence, management, and prevention. Drug Saf. 2010;33(9):727-740.
  7. Holstein A, Stumvoll M. Contraindications can damage your health – is metformin a case in point? Diabetologia. 2005;48(12):2454-2459.
  8. Connolly V, Kesson CM. Metformin treatment in NIDDM patients with mild renal impairment. Postgrad Med J. 1996;72(848):352-354.
  9. Rachmani R, Slavachevski I, Levi Z, Zadok B, Kedar Y, Ravid M. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002;13(7):428-433.
  10. Lim VC, Sum CF, Chan ES, Yeoh LY, Lee YM, Lim SC. Lactate levels in Asian patients with type 2 diabetes mellitus on metformin and its association with dose of metformin and renal function. Int J Clin Pract. 2007;61(11):1829-1833.
  11. Bosse GM. Antidiabetics and hypoglycemics. In: Flomenbaum N, Goldfrank L, Hoffman R, et al. Goldfrank’s Toxicologic Emergencies. 8th ed. New York, NY: McGraw-Hill;2006:759-760.

Could lisinopril cause angiodema after 1 year?

Are angiotensin receptor blockers (ARBs) safe in patients with angiotensin-converting enzyme (ACE) inhibitor-induced angiodema?

Angioedema, characterized by swelling of the mouth, face, and extremities, is a well-documented adverse reaction of ACE inhibitors, occurring at an incidence of 0.1 to 1%.1  Per the manufacturer, black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-black patients (incidence not stated); this is corroborated by the results of a retrospective review by Brown et al in which blacks were found to have a 5-fold higher incidence of angioedema than whites.2 Patients with ACE inhibitor-induced angioedema have also been described as older (age not specified) and without a history of other allergies.3  Per a consult found on Micromedex, the earliest reported onset of angioedema after initiation of an ACE inhibitor is 4 hours, and the latest onset is 7 years, with duration of symptoms ranging from 5 to 24 hours (with therapy), up to 72 hours (without therapy).1  The cases appear to occur more commonly during the first week of therapy.  However, a search of the literature revealed multiple case reports/reviews describing late-onset angioedema.  Ricketti et al described a 52 year old male who they diagnosed with type I hereditary angioedema (HAE), an autosomal disorder characterized by low levels of active C1 esterase inhibitor (C1-INH), “unmasked” after 7 years of treatment with lisinopril.4 The patient had been taking other medications, including simvastatin, ezetimibe, amlodipine, lansoprazole, and valdecoxib; none were thought to significantly interact with ACE inhibitors or C1-INH pathways.  Lisinopril was discontinued and the patient was observed to be symptom-free at the time of publication (24 months).   Pillans et al conducted a retrospective review of 116 reports of angioedema and urticaria associated with ACE inhibitors including captopril, enalapril, and lisinopril.5 Of these, 68 reports involved angioedema alone, 37 involved urticaria alone, and 11 involved both.  There were 47 reactions with documented occurrence between 3 weeks and 4 years after ACE inhibitor initiation.

Regarding management of ACE inhibitor-associated angioedema, immediate discontinuation of the offending agent is recommended.1 Antihistamines may be useful to relieve symptoms but are not always essential.  Administration of epinephrine is recommended in patients with respiratory distress.

As this reaction is considered to be a class effect, therapy with an agent from an alternative class of antihypertensives is recommended.  There is controversy surrounding the issue of initiation of an ARB in patients with a history of ACE inhibitor-associated angioedema.  Based on the speculation that this reaction is caused by bradykinin accumulation, substitution with an ARB may seem reasonable.6 However, several articles have been published suggesting possible cross-reactivity of ACE inhibitors and ARBs.  In a review on the tolerability of ARBs,7 a study was identified in which 19 patients experienced angioedema (18 receiving losartan, 1 receiving valsartan); of these, 6 (32%) had a history of ACE inhibitor-induced angioedema.  In the same review, findings from an overview of the Food and Drug Administration’s (FDA) Adverse Event Reportings System (AERS) revealed a total of 851 and 6642 cases of angioedema reported, attributed to ARBs and ACE inhibitors, respectively, indicating that angioedema is more commonly seen with use of ACE inhibitors.  The number of patients experiencing cross-reactivity was not reported.  Of note, a case series and clinical study of safe substitution of an ARB in patients with confirmed ACE inhibitor-induced angioedema were also described in this review.

More recently, Haymore et al conducted a meta-analysis assessing the risk of angioedema associated with ARB use in patients with ACE inhibitor-induced angioedema.8 The study included 1 randomized controlled trial and 2 retrospective cohorts describing confirmed and suspected cases of angioedema.   The risk of developing confirmed angioedema associated with an ARB in these patients was determined to be 3.5% (95% CI: 0 to 9.2%).  For suspected cases, the risk was determined to be 9.4% (95% CI: 1.6 to 17%).  The results of this study were updated in a letter by the investigators,9 in which they combined data from the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular disease (TRANSCEND) trial.10 Including this data, the risk for developing angioedema with ARB use was determined to be 1.5% for confirmed cases (95% CI: 0 to 5.1%) and 2.5% for suspected cases (95% CI: 0 to 6.6%).  The authors concluded that there is a risk for development of angioedema with ARB use in patients with history ACE inhibitor-associated angioedema, but the incidence is low.9

In summary, while usage of an alternative class of antihypertensives is advised in patients with suspected ACE inhibitor-associated angioedema, ARBs should be used with caution.

References:

  1. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically.
  2. Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther. 1996;60(1):8-13.
  3. Bingham CO. An overview of angioedema: Clinical features, diagnosis, and management. In: UpToDate, Feldweg AM (Ed), UpToDate, Waltham, MA, 2011.
  4. Ricketti AJ, Cleri DJ, Ramos-Bonner LS, Vernaleo JR. Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment. Ann Allergy Asthma Immunol. 2007;98(4):397-401.
  5. Pillans PI, Coulter DM, Black P. Angioedema and urticaria with angiotensin converting enzyme inhibitors. Eur J Clin Pharmacol. 1996;51(2):123-126.
  6. Gavras I, Gavras H. Are patients who develop angioedema with ACE inhibition at risk of the same problem with AT1 receptor blockers? Arch Intern Med. 2003;163(2):240-241.
  7. Tolerability and quality of life in ARB-treated patients. Am J Manag Care. 2005;11(13 Suppl):S392-S394.
  8. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495-499.
  9. Haymore BR, DeZee KJ. Use of angiotensin receptor blockers after angioedema with an angiotensin-converting enzyme inhibitor. Ann Allergy Asthma Immunol. 2009;103(1):83-84.
  10. Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet. 2008;372(9644):1174-1183.

Does aspirin use have an increased benefit in patients with ischemic heart disease (IHD) taking angiotensin-converting enzyme (ACE) inhibitors?

In theory, based on their mechanisms of action, it has been proposed that concomitant use of aspirin may interfere with the efficacy of ACE inhibitors.1  Angiotensin-converting enzyme inhibitors are thought to be efficacious in treatment of patients with IHD in part due to their effects on kinins.  Specifically, ACE inhibitor use is associated with increased kinin levels, which may be mediated by the release of vasodilator prostaglandins.  Aspirin is known to inhibit prostaglandin synthesis and therefore thought to interfere with ACE inhibitor efficacy.  In fact, a cursory search of several databases for interactions between aspirin and ACE inhibitors (e.g., enalapril), including Micromedex,2 Clinical Pharmacology,3 and Facts and Comparisons,4 corroborates this, classifying the drug interactions as mild4 to moderate2,3 in severity, with substantial documentation.

A search of the literature revealed several studies addressing this interaction and possible decrease in ACE inhibitor efficacy.  In a review, Park summarizes that the data from these studies are conflicting and there are several limitations to the studies cited.5 For example, she cites a study in which 18 patients with chronic, stable but severe heart failure with mean left ventricular ejection fraction (LVEF) of 23.9% were given enalapril prior to, concomitantly, or the day after a 350 mg dose of aspirin.  The investigators found that co-administration of enalapril on the day of or day after aspirin was associated with a negative hemodynamic effect.  Park notes the limited external validity of this study and other similar studies based on their small population, endpoints, and short duration.  She includes the results of larger scale trials such as the Studies of Left Ventricular Dysfunction (SOLVD) trials, which demonstrated a reduction in benefit of enalapril among patients taking aspirin (as observed by an absolute decrease in mortality of 9% in patients taking enalapril alone compared to an absolute increase in mortality of 4% in patients taking both enalapril and aspirin6), and the Heart Outcomes Prevention Evaluation (HOPE) study, which did not reveal any negative interactions between ramipril and aspirin.7 She notes that these, too, are limited in their clinical application, the former lacking data on dosage and duration of therapy with aspirin, and the latter excluding patients with reduced systolic function.5-7  Based on these findings, Park recommends that clinicians take into consideration the severity of heart failure when placing patients with IHD and on an ACE inhibitor on aspirin therapy, stating that the more severe the heart failure, the greater likelihood of an observable interaction between aspirin and ACE inhibitor.5

Therefore, although inconclusive, it appears that concomitant use of aspirin with ACE inhibitor therapy may lead to decreased ACE inhibitor efficacy.  No studies were found suggesting that the use of aspirin would potentiate the effects of ACE inhibitor therapy in patients with IHD.

References:

  1. Colucci WS. ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use. In: UpToDate, Yeon SB (Ed), UpToDate, Waltham, MA, 2011.
  2. Micromedex® Healthcare Series [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically.
  3. Clinical Pharmacology® [Internet database]. Tampa, FL: Elsevier / Gold Standard. Updated periodically.
  4. Facts and Comparisons® [Internet database]. St. Louis, MO: Wolters Kluwer Health. Updated periodically.
  5. Park MH. Should aspirin be used with angiotensin-converting enzyme inhibitors in patients with chronic heart failure? Congest Heart Fail. 2003;9(4):206-211.
  6. Massie BM, Teerlink JR. Interaction between aspirin and angiotensin-converting enzyme inhibitors: real or imagined. Am J Med. 2000;109(5):431-433.
  7. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.  Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):145-153.

What is the exact mechanism behind the use of angiotensin-converting enzyme (ACE) inhibitors in patients with ischemic heart disease (IHD)?

Ischemic heart disease is a condition primarily caused by the formation of atherosclerotic plaques in the coronary vasculature, leading to imbalance of oxygen supply and demand, and initially manifests as chronic stable angina.  Per Hurst’s The Heart, angina usually occurs in patients with coronary artery disease (CAD) affecting ≥1 of the large epicardial arteries.1 The goals of therapy are to alter the underlying process of atherosclerosis and provide symptomatic relief using medications such as nitrates, beta blockers, calcium channel blockers, and ranolazine.  Angiotensin-converting enzyme inhibitors are recommended for patients with CAD and diabetes mellitus and/or left ventricular systolic dysfunction.  The basis for this recommendation was likely derived from the results of a meta-analysis conducted by Shekelle et al, in which the investigators determined estimates of mortality for different subgroups of patients from 12 randomized clinical trials of ACE inhibitors and beta blockers.2 The ACE inhibitors have consistently demonstrated significant reductions in both morbidity and mortality, with benefits observed in patients with all severities of symptomatic heart failure as well as patients with asymptomatic left ventricular dysfunction.

The mechanism of action of ACE inhibitors in heart failure/IHD is unclear, although several have been proposed.3 One hypothesis is that ACE inhibitors may modulate myocyte responses to the intracardiac renin-angiotensin system.  It is thought that there may be enhanced activity of ACE within the myocardium, and an increase in ACE binding sites has been observed in patients with advanced heart failure.  Another proposed mechanism is through reduction of sympathetic nervous activity, which is known to be increased in patients with heart failure.  A third mechanism is an increase in kinins (e.g., bradykinin) associated with ACE inhibitor use.  Bradykinins have been shown to cause vasodilation with the release of endothelial nitric oxide.  Angiotensin-converting enzyme inhibitors may also normalize nitric oxide synthase expression and inhibit the release of endothelin, a vasoconstrictor.  In addition to these, other effects attributed to ACE inhibitors that may lead to improvements in patients with IHD are possible alterations/reduction of proinflammatory cytokine levels, alteration of hypercoagulable states through reduction of fibrinogen and von Willebrand factor and improvement of fibrinolytic factors.

A search of the literature revealed numerous articles discussing the aforementioned possible mechanisms.  Examples of these include reviews by Rosenson,4 Dai and Kloner,5 Probstfield and O’Brien,6 and Hammoud et al.7

In summary, it appears that there are strong data to support the use of ACE inhibitors in patients with IHD, but there is no clear consensus regarding the mechanism(s) of action.  Likely, the benefits of ACE inhibitors are related to not 1 but several possible mechanisms.

References:

  1. O’Rourke RA, O’Gara P, Douglas JS Jr.  Diagnosis and management of patients with chronic ischemic heart disease. In: Fuster V, O’Rourke R, Walsh R, Poole-Wilson P, eds. Hurst’s The Heart.  12th ed. New York, NY: McGraw-Hill; 2008. http://www.r2library.com/contents/content_resource_frame.aspx?ResourceID=887&Library=Medicine. Accessed May 24, 2011.
  2. Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status. J Am Coll Cardiol. 2003;41(9):1529-1538.
  3. Hennekens CH, Cannon CP. Secondary prevention of cardiovascular disease: risk factor reduction. In: UpToDate, Saperia GM (Ed), UpToDate, Waltham, MA, 2011.
  4. Rosenson RS. Modulating atherosclerosis through inhibition or blockade of angiotensin. Clin Cardiol. 2003;26(7):305-311.
  5. Dai W, Kloner RA. Potential role of renin-angiotensin system blockade for preventing myocardial ischemia/reperfusion injury and remodeling after myocardial infarction. Postgrad Med. 2011;123(2):49-55.
  6. Probstfield JL, O’Brien KD. Progression of cardiovascular damage: the role of renin-angiotensin system blockade. Am J Cardiol. 2010;105(1 suppl):10A-20A.
  7. Hammoud RA, Vaccari CS, Nagamia SH, Khan BV. Regulation of the renin-angiotensin system in coronary atherosclerosis: a review of the literature. Vasc Health Risk Manag. 2007;3(6):937-945.

Does an increase in metformin dosage lead to an increased risk of lactic acidosis?

Lactic acidosis is a well-documented side effect of metformin, occurring rarely but potentially fatal in up to 50% of cases, and it is thought to occur due to decreased renal clearance of the drug.1 Per the manufacturer, the risk of lactic acidosis increases with degree of renal function impairment and patient age, and the risk may be significantly reduced through regular monitoring of renal function and use of the minimum effective dose.2 (Of note, other risk factors that have been proposed in the literature include concurrent liver disease, alcohol abuse, heart failure, and a history of lactic acidosis).  Although this suggests that lactic acidosis may be a dose-related side effect, the literature concerning this is conflicting.  The reports that describe a potential dose-related effect of metformin are toxicologic, involving patients who have overdosed on metformin.  For example, Al-Makadma and Riad describe the development of lactic acidosis in a patient who had ingested 40-45 g of metformin in a suicide attempt.3 They allude to other, similar cases detailing metformin-associated lactic acidosis with metformin overdoses ranging from 25 g to 100 g.

With regard to therapeutic doses, few studies have been published addressing the possibility of lactic acidosis as a dose-related side effect of metformin.  Lim et al conducted a cross-sectional study of Asian patients with type 2 diabetes mellitus (T2DM) with or without renal impairment, assessing for an association between fasting plasma lactate levels, total daily dose of metformin, and glomerular filtration rate (GFR).4 There were 97 patients in their study with a mean age of 58.8 years; the mean fasting plasma lactate level was 1.8 mmol/L.  (Of note, the manufacturer defines lactic acidosis as plasma lactate >5 mmol/L and decreased blood pH).2 The mean fasting plasma lactate levels for patients taking metformin ≤1000 mg/d, 1001-2000 mg/d, and >2000 mg/d were 1.7 mmol/L, 1.6 mmol/L, and 2.1 mmol/L, respectively (p=0.119).4 The levels for patients with GFR <60, 60-90, and >90 ml/min/1.73m2 were 1.7 mmol/L, 1.8 mmol/L, and 1.8 mmol/L, respectively (p=0.757).  The authors determined that there was no significant correlation between total daily metformin dose, GFR, and plasma lactate levels in these patients.

In a similar study, Van Berlo-van de Laar et al investigated the incidence and correlation of lactic acidosis with metformin serum concentrations.5 A total of 16 cases of metformin-associated lactic acidosis (defined as arterial pH<7.35 and lactate>5 mmol/L) were identified, 11 of which had risk factors for lactic acidosis in their medical history (e.g., heart failure, COPD), and 13 with renal failure.  Metformin doses ranged from 850 to 2550 mg/d, and serum concentrations from 0.4 to 44 mg/L.  Interestingly, the patients who survived the metformin-associated lactic acidosis had a higher metformin serum concentration compared to those who did not survive (18.9 mg/L vs. 2.9 mg/L, p=0.006).  Based on these results, the authors determined that the incidence and outcome of lactic acidosis is dependent on severity of the underlying disease, rather than the level of metformin.  While serum metformin levels are not routinely drawn nor recommended in clinical practice, it may be suggested that they are correlated with metformin dose.

In summary, at this time, evidence for metformin-associated lactic acidosis as a dose-related side effect is available in the toxicology literature.  However, literature supporting lactic acidosis as a dose-related effect at therapeutic doses was not found.

References:

  1. Micromedex® Healthcare Series [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically.
  2. Glucophage, Glucophage XR [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.
  3. Al-Makadma YS, Riad T. Successful management of high-dose metformin intoxication. Role of vasopressin in the management of severe lactic acidosis. Middle East J Anesthesiol. 2010;20(6):873-875.
  4. Lim VCC, Sum CF, Chan ESY, Yeoh LY, Lee YM, Lim SC. Lactate levels in Asian patients with type 2 diabetes mellitus on metformin and its association with dose of metformin and renal function. Int J Clin Pract. 2007;61(11):1829-1833.
  5. Van Berlo-van de Laar IRF, Vermeij CG, Doorenbos CJ. Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. J Clin Pharm Ther. 2011;36(3):376-382.

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