September 2011 FAQs
September 2011 FAQs
What is the place in therapy of linagliptin for type 2 diabetes?
What is the place in therapy of linagliptin for type 2 diabetes?
The Centers for Disease Control and Prevention estimated that in 2010, 10% of adults aged 20 years and older and 26.9% of adults older than age 65 had diabetes in the United States.1 Diabetes was the seventh leading cause of death in the United States in 2007. Diabetes is the leading cause of new cases of blindness, kidney failure, and lower limb amputations.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer medication class used to treat type 2 diabetes. There are currently 3 agents available: sitagliptin, saxagliptin, and linagliptin. Linagliptin is the most recently approved agent, which has led to questions regarding the place in therapy of this drug compared to the other 2 agents. Although the American Diabetes Association (ADA) 2009 guidelines for treatment of type 2 diabetes do not recommend DPP-4 inhibitors due to their less established evidence, greater cost, and less effective glucose reduction compared to other agents, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) endorses the use of DPP-4 inhibitors alone or in combination with metformin.2,3
Overall, the DPP-4 inhibitors are less effective in lowering plasma glucose than other agents, with reductions in A1C ranging from 0.4% to 0.7% for linagliptin compared to 1.5% to 2% with metformin.4 The risk of hypoglycemia is less with DPP-4 inhibitors compared to other antidiabetic agents. In terms of adverse effects, DPP-4 inhibitors are weight neutral, unlike sulfonylureas and thiazolidinediones (TZD) which often result in weight gain. The DPP-4 inhibitors also have fewer gastrointestinal side effects compared with glucagon-like peptide-1 (GLP-1) agonists or metformin.
Linagliptin has several differences compared to the other currently available DPP-4 inhibitors.5 It has the longest terminal half-life (up to 184 hours) and less renal excretion than the other DPP-4 inhibitors, avoiding the need for dose adjustments in patients with renal impairment. Linagliptin is the most potent inhibitor of DPP-4 in vitro and has the highest selectivity for DPP-4; however, it is unclear whether this is relevant in clinical practice. In a preclinical animal study, linagliptin had beneficial effects on wound healing by reducing polymorphonuclear neutrophils, a biomarker of inflammation.6 To date, no other DPP-4 inhibitors have been shown to promote wound healing, so this may be a unique effect of linagliptin.5
Clinical studies with linagliptin
In a randomized, placebo-controlled, multicenter trial, linagliptin 5 mg once daily was evaluated in 503 patients (18 to 80 years of age) with type 2 diabetes.7 Patients could be treatment-naïve or could have previously received a single antidiabetic agent. Treatment-naïve patients had to have an A1C between 6.5% and 9%, and previously-treated patients had to have an A1C of 7% to 10%. Patients who received a TZD, GLP-1 agonist, or insulin within the prior 3 months were excluded. Prior to starting the 24-week trial, patients receiving other antidiabetic agents went through a 6-week washout period, of which the last 2 weeks were also a placebo run-in period. The primary endpoint was change in A1C from baseline and secondary endpoints included the percentage of patients at target A1C, A1C reduction of at least 0.5%, and change in fasting plasma glucose and 2-hour postprandial glucose from baseline. At baseline, the mean A1C was 8% in both groups. After 24 weeks, the mean change in A1C with linagliptin was -0.44% from baseline, with a difference from placebo of -0.69% (95% confidence interval [CI] -0.85 to -0.53, p<0.001). Patients with higher baseline A1C levels (>9%) experienced a placebo-corrected reduction of -0.86% from baseline, which was larger than the reduction in patients with baseline A1C of 7% to 8%. The percentages of patients at target A1C after 24 weeks were 25.2% with linagliptin and 11.6% with placebo. Fasting and postprandial glucose concentrations were also improved with linagliptin. Linagliptin was well-tolerated; adverse events were similar to the placebo group. One patient in each group experienced hypoglycemia.
Two trials have evaluated the efficacy and safety of combination therapy with linagliptin and metformin.8,9 For both trials, the primary endpoint was change in A1C from baseline and secondary endpoints were change in fasting glucose concentrations, proportion of patients achieving goal A1C (<7% and <6.5%), and the proportion of patients with an A1C decrease of at least 0.5%. The first trial, by Forst and colleagues, compared safety and efficacy of linagliptin combined with metformin therapy in a randomized, 12-week, placebo-controlled, double-blinded, multicenter trial in 333 patients.8 Patients on metformin monotherapy at baseline had to have an A1C level of 7.5% to 10% (definition of inadequate glycemic control). For patients who were on metformin and one other antidiabetic agent the baseline A1C level had to be 7% to 9%. Patients who had received a TZD within 6 months or insulin within 3 months were excluded. The antidiabetic agent other than metformin was discontinued during a 6-week washout period, in which the last 2 weeks was an open-label, placebo run-in phase. All patients continued metformin therapy and were randomized to one of 5 parallel groups: linagliptin 1, 5, or 10 mg, placebo, and open-label glimepiride. At baseline, the overall mean A1C was 8.3%. The trial resulted in placebo-corrected reductions in A1C of -0.4%, -0.73%, -0.67%, and -0.93% in the 1, 5, and 10 mg linagliptin groups and the glimepiride group, respectively (p-values not reported). All 3 doses of linagliptin had statistically significant reductions compared to placebo (p<0.01 for the 1 mg group; p<0.0001 for the 5 and 10 mg groups; p-values vs. glimepiride were not reported). All secondary endpoints were also improved with the addition of linagliptin therapy. Fifteen percent of the linagliptin 1 and 5 mg groups and 21% of the linagliptin 10 mg group achieved goal A1C <7% compared to 1 patient receiving placebo (p-values not reported). Similarly, 3% of patients in the linagliptin 1 and 5 mg groups and 8% of patients in the linagliptin 10 mg group achieved goal A1C <6.5% (p-values not reported). The proportion of patients in the glimepiride group that achieved goal A1C was not reported. Adverse events occurred at a similar frequency in all groups and there were no hypoglycemic events in any group except for 3 patients (5%) receiving glimepiride.
In the second study, Taskinen et al compared the safety and efficacy of linagliptin as add-on therapy with metformin in a randomized, double-blind, placebo-controlled, 24-week, multicenter trial in 701 patients.9 All patients were on metformin doses of at least 1500 mg daily and could have been receiving no more than a single additional antidiabetic agent before the trial. Use of a TZD, GLP-1 agonist or insulin within 3 months excluded the patient from participating in the trial. Patients had to have a baseline A1C of 7% to 10% to participate and were randomized to either 5 mg linagliptin or placebo in addition to continuing their prior metformin dose. At baseline, the mean A1C was 8.08%. After 24 weeks, linagliptin lowered A1C levels by 0.64% compared to placebo (95% CI for difference, -0.78 to -0.5, p<0.0001 vs. placebo). More patients receiving linagliptin (26%) successfully achieved a target A1C of <7% compared to the placebo group (9%), and a similar trend was seen for the goal A1C of <6.5% (10% vs. 2%, respectively). Linagliptin was more effective than placebo for all secondary endpoints. Safety and tolerability were comparable in the linagliptin and placebo groups, with only 8 patients (5 placebo, 3 linagliptin) reporting hypoglycemic events.
A recent randomized, placebo-controlled, double-blind, 24-week, multicenter trial in 1058 patients with type 2 diabetes evaluated the addition of linagliptin 5 mg daily to combination therapy with metformin and a sulfonylurea.10 Doses of the metformin (≥1500 mg daily) and the sulfonylurea (maximum tolerated dose) had to be stable for 10 weeks before the study and during the entire study period. Patients receiving a TZD, GLP-1 agonist, or insulin within 3 months were excluded. At baseline, patients had to have an A1C between 7% and 10%; the mean A1C was 8.14% in the linagliptin group and 8.15% in the placebo group. The primary endpoint, placebo-adjusted change in A1C from baseline to 24 weeks in the linagliptin group, was -0.62% (95% CI -0.73 to -0.5, p<0.0001). Secondary endpoints included the proportion of patients achieving A1C <6.5% and <7%, A1C reduction of ≥0.5%, changes in fasting glucose, and use of rescue medication. More patients receiving linagliptin than placebo achieved an A1C <7% (29.2% vs. 8.1%, p<0.0001); the proportion of patients achieving A1C <6.5% was not reported. Linagliptin was superior to placebo for all other secondary endpoints. Hypoglycemia occurred more frequently with linagliptin than placebo (22.7% vs. 14.8%, p=0.0083), but severe hypoglycemia was more common with placebo (4.8% vs. 2.7% with linagliptin).
Linagliptin monotherapy resulted in a reduction in A1C of 0.44% from baseline and 25% of patients reached the target A1C level with this agent. 7 These modest results are not sufficient to justify the use of linagliptin monotherapy in patients with inadequate glycemic control. When linagliptin was added to metformin or metformin with a sulfonylurea, similar A1C reductions were seen (-0.4% to ‑0.7%).8-10 It is unclear why more patients achieved goal A1C in the study by Taskinen et al compared to the study by Forst et al (26% vs. 15% to 21%, respectively). The duration of the studies was not sufficient to evaluate the long-term effects of linagliptin, an important consideration in light of the chronic nature of diabetes treatment.7-10 Comparative data with linagliptin are lacking; however, the study by Forst et al that compared linagliptin to glimepiride as add-on therapy with metformin found a numerically greater response with glimepiride.8 This difference was not statistically evaluated. In addition to the lack of comparative data, linagliptin has not been evaluated for its effects on risk of mortality or myocardial infarction, time to dialysis, or other clinically meaningful diabetes-related endpoints.
Based on the available data, linagliptin use should be limited to adjunctive therapy with metformin or combination therapy with metformin and a sulfonylurea, which is consistent with the AACE/ACE clinical practice guidelines. The possibility that certain populations (such as those with renal dysfunction or those with higher baseline A1C levels) may particularly benefit from linagliptin requires further study. In addition, the potential benefits of linagliptin on wound healing should be investigated further since lower extremity wounds are common in patients with diabetes. Comparative clinical trials conducted over a longer time period will help to better define linagliptin's place in therapy in relation to the efficacy and safety of other available agents for treatment of type 2 diabetes.
- National Diabetes Fact Sheet, 2011. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed July 26, 2011.
- 2. Rodbard HW, Jellinger PS, Davidson JA. et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540-559.
- Nathan DM, Buse JB, Davidson MB, et al. American Diabetes Association, European Association for Study of Diabetes. 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.
- Linagliptin (Tradjenta)–a new DPP-4 inhibitor for type 2 diabetes. Med Lett Drugs Ther. 2011;53(1367):49-50.
- Gerich J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res Clin Pract. 2010;90(2):131-140.
- Linke A, Frank S, Mark M, Klein T. The DPP-4 inhibitor linagliptin (BI 1356) improves wound healing in ob/ob mice. In: Proceedings from the American Diabetes Association 69th Scientific Sessions; June 5-9, 2009; New Orleans, LA. Abstract 596-P.
- Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13(3):258-267.
- Forst T, Uhlig-Laske B, Graefe-Mody U, et al. Lingliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med. 2010;27(12):1409-1419.
- Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13(1):65-74.
- Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011 Jul 22 [Epub ahead of print].
Soojin Jun, PharmD candidate, 2013
What is rilpivirine?
What is rilpivirine?
Infectious Disease Fellow
Rilpivirine (Edurant) is a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI).1 It received approval by the US Food and Drug Administration (FDA) on May 20, 2011 to be used in combination with other active antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve individuals. Rilpivirine is also available as part of a single-tablet combination with emtricitabine and tenofovir disoproxil (Complera), approved by the FDA on August 10, 2011.2
Both the current US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents and the International AIDS Society-USA panel recommend efavirenz-based regimens as one of the preferred options for initial therapy for treatment-naïve patients due to improved virologic outcomes, low pill burden, and minimal toxicities.3-5 However, use of efavirenz may be limited by its central nervous system (CNS) adverse effects (usually transient) and teratogenicity.4 Another important limitation of efavirenz is its low genetic barrier to resistance in which non-compliance can lead to a single point mutation in the reverse transcriptase enzyme.3 This confers high-level resistance within the NNRTI class. Point mutations that alter the allosteric binding sites of the reverse transcriptase inhibitors prevent binding of first generation NNRTIs to the enzyme, and subsequent inhibition of cDNA elongation does not occur, allowing the virus to replicate. The second-generation NNRTI agent etravirine is able to bind to different allosteric pockets on the reverse transcriptase enzyme. It has a higher genetic barrier to resistance than first-generation NNRTIs, as well as less likelihood to develop cross-resistance within the NNRTI class. These characteristics make etravirine an attractive agent as salvage therapy for patients who are treatment-experienced and have developed resistance to multiple agents. However, unlike etravirine, rilpivirine has been studied in treatment-naïve patients and showed promising results for efficacy and tolerability, although virologic failure was greater than expected.
Rilpivirine is available as an oral tablet containing 27.5 mg of rilpivirine hydrochloride equivalent to 25 mg rilpivirine.1 It is given once daily with a meal that is preferably >500 kcal and high-fat, as concentrations of rilpivirine were approximately 40% to 50% lower when taken in a fasted condition or with a protein-rich shake. No dosage adjustment is recommended in patients with mild or moderate hepatic impairment, and the drug has not been studied in severe impairment. No dosage adjustment is recommended for patients with mild or moderate renal impairment. Severe renal impairment may increase rilpivirine concentrations, so it should be used with caution in this patient population. At supratherapeutic doses (75 mg daily and 300 mg daily), rilpivirine has been shown to prolong the QTc interval and should be used with caution when administering medications associated with torsades de pointes.
Rilpivirine is metabolized by the cytochrome P450 3A system.1 Patients taking potent inducers of this enzyme system may have reduced plasma concentrations of rilpivirine and should avoid co-administration. Examples of medications to avoid are the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin, and the antimycobacterials, rifabutin, rifampin, and rifapentine, as well as dexamethasone. Absorption of rilpivirine is also pH-dependent. Co-administration of rilpivirine and proton pump inhibitors is not recommended. Antacids can decrease plasma concentrations of rilpivirine and should be taken 2 hours before or at least 4 hours after rilpivirine. Histamine (H2)-receptor antagonists should be taken 12 hours prior to rilpivirine or 4 hours after.
Clinical efficacy and safety
Three published clinical trials evaluated the efficacy and safety of rilpivirine.6-8 The study by Pozniak et al presents both 48- and 96-week analyses of a large phase IIb randomized, multicenter, dose-finding study in treatment-naïve HIV-1 infected individuals.6 The trial evaluated safety, efficacy, and tolerability of rilpivirine in 368 patients. They were randomized 1:1:1:1 to receive rilpivirine 25, 75, or 150 mg, or open-label efavirenz 600 mg daily as a control. A nucleoside reverse transcriptase inhibitor (NRTI) backbone of zidovudine/lamivudine or tenofovir disoproxil fumarate/emtricitabine was selected by investigators to complete the regimen. Treatment with other NNRTIs, protease inhibitors, fusion inhibitors, or interacting cytochrome P450 3A4 drugs was not permitted. The primary endpoint was to assess rilpivirine dose-efficacy relationships at 48 weeks, measured as the proportion of patients with a viral load <50 copies/mL. Secondary endpoints included efficacy over 96 weeks (measured as viral load <50 copies/mL and <400 copies/mL), CD4 count changes, safety, immunologic response, pharmacokinetics, and resistance analyses.
At 48 weeks the proportion of patients with a viral load <50 copies/mL was similar between the rilpivirine dosing regimens: 79.6%, 80%, and 76.9% for the 25, 75, and 150 mg doses respectively, which was similar to the efavirenz group (80.9%).6 By week 96, the proportion of patients with viral loads <50 copies/mL was 76.3%, 71%, 71.4%, respectively, and 70.8% in the efavirenz group. No p-values were reported for the 48- or 96-week data. By week 96, mean increases in CD4 cell counts among the rilpivirine doses were 145.8, 172, and 158.9 cells/µL for the 25, 75, and 150 mg daily doses, respectively. CD4 counts in efavirenz-treated patients increased by a mean of 159.8 cells/ µL. Virologic failure was not statistically different between groups at either 48 or 96 weeks: mean of 8.2% for rilpivirine groups and 7.9% for efavirenz group after 96 weeks. The doses of rilpivirine were generally safe and well-tolerated. The most common grade 2 to 4 adverse effects included nausea and dizziness in all 3 groups as well as with efavirenz, and abnormal dreams in the rilpivirine 75 mg and efavirenz groups. The proportion of patients who discontinued treatment due to adverse events was 11.5% of those treated with rilpivirine as compared to 9% of those treated with efavirenz. The results at 96 weeks in this trial support the efficacy of rilpivirine in terms of virologic suppression, immunologic response, and safety.
Two rilpivirine phase III double-blind, double-dummy, randomized, 96-week studies were published in July 2011.7,8 The ECHO and THRIVE trials examined the noninferiority of rilpivirine 25 mg once daily to efavirenz 600 mg once daily. Both studies assessed the medications in combination with 2 NRTIs. The ECHO trial included a dual NRTI regimen of tenofovir disoproxil fumarate/emtricitabine while THRIVE included either the dual NRTI regimens of tenofovir disoproxil fumarate/emtricitabine, or zidovudine/lamivudine, or abacavir/lamivudine. Both trials used the same definition for response (viral load <50 copies/mL) and for virologic failure (no response or response with subsequent rebound before 48 weeks).
The ECHO trial found rilpivirine to be noninferior to efavirenz, with 83% of patients in both groups having a response at week 48.7 However, there was a greater number of virologic failures based on efficacy in the rilpivirine group compared to efavirenz (11% vs. 4%), as well as based on the resistance analysis (13% vs. 6%). Similar to the ECHO trial, the THRIVE trial found rilpivirine to be noninferior to efavirenz with 86% of patients in the rilpivirine group and 82% of patients in the efavirenz group achieving a response at week 48.8 No difference in response was noted based on NRTI background therapy. Virologic failure was proportionally greater with rilpivirine (7%) than efavirenz (5%), and increased slightly in both groups when defined by the resistance analysis (8% vs. 6%). Both trials had patients self-report their adherence to medication.7,8 Similar responses were seen between groups based on adherence, and response was less as adherence declined.
Resistance analysis of the virologic failures from the phase III trials showed the emergence of resistance, either genotypic or phenotypic, to be greater in the rilpivirine arm (41%) than the efavirenz arm (25%).1 Additionally, emergence of resistance to the dual NRTI regimens was greater in patients who experienced virologic failure in the rilpivirine arm, 48%, compared to 15% in the efavirenz arm. Virologic failure and the development of resistance was greater in patients who had a baseline viral load of >100,000 copies/mL. Cross-resistance to NRTIs was observed in patients resistant to rilpivirine. Eighty-nine percent of patients who experienced virologic failure with rilpivirine demonstrated cross-resistance to etravirine and efavirenz, and 63% were resistant to nevirapine. In the efavirenz arm, none of the patients who experienced virologic failure and efavirenz resistance developed resistance to etravirine. In both trials, the mutation seen most frequently among those with virologic failure in the rilpivirine groups was E138K/G (36%) and for efavirenz, K103N (32%).
The most common adverse drug reactions with rilpivirine (incidence >2%) included depression, insomnia, headache and rash.1 In the ECHO trial, discontinuation rates due to adverse events were 2% in the rilpivirine arm and 7% in the efavirenz arm.7 Findings were similar in the THRIVE trial.8 Overall adverse events rates were similar between groups, occurring in approximately 90% of patients in both groups in both trials.7,8 The frequency of grade 2 adverse events was the same in both trials for both groups and significantly less with rilpivirine (16% vs. 31% with efavirenz, p<0.0001). Of these, rash was most common and also occurred less frequently with rilpivirine than efavirenz. The incidence of neurologic events was lower with rilpivirine than efavirenz in both the ECHO (16% vs. 37%, p<0.0001) and THRIVE trials (18% vs. 39%, p<0.0001). The incidence of psychiatric events was also lower with rilpivirine than efavirenz in the ECHO trial (15% vs. 25%. p=0.0006) and the THRIVE trial (15% vs. 20%, p=0.09), although the difference was not statistically significant in the latter.
Rilpivirine is a promising option for NNRTI-based antiretroviral regimens in treatment-naïve patients. It is as efficacious as the first-line NNRTI agent, efavirenz, and less likely to cause rash and CNS events. Rilpivirine is pregnancy category B, unlike efavirenz which is pregnancy category D, so rilpivirine may be be an option for use in pregnant patients; however no data are currently available.1 Important considerations with the limited data available are the rates of virologic failures and development of resistance to the NNRTI class with the use of rilpivirine, which were higher than with efavirenz. Among those with virologic failure with rilpivirine, a majority also developed resistance to etravirine. Virologic failure while taking rilpivirine would likely preclude the use of any other NNRTI class agent (both first and second generations) as a secondary treatment option. This is not the case with virologic failure for patients taking efavirenz, as viral susceptibility to etravirine is usually maintained, and etravirine is indicated as salvage therapy for those who fail efavirenz.4 Nearly half of patients who had virologic failure on rilpivirine also developed resistance to one or more NNRTIs. A possible contributing factor to virologic failure and resistance may be related to adherence and the administration of the drug. Absorption of rilpivirine decreases significantly if not taken with a relatively large or high-fat meal. This requirement may be difficult for patients to achieve, resulting in suboptimal concentrations and development of resistance. Among treatment-naïve patients, rilpivirine may be a better choice for patients with lower baseline viral loads (<100,000 copies/mL). Current guidelines do not address the use of rilpivirine due to its recent approval; however, approval of rilpivirine provides an alternative NNRTI for patients who may not be candidates for efavirenz-based regimens due to its side effect profile.
1. Edurant [package insert]. Raritan, NJ: Tibotec, Inc.; 2011.
2. Complera [package insert]. Foster City, CA: Gilead Sciences; 2011.
3. Adams J, Patel N, Mankaryous N, Tadros M, Miller CD. Nonnucleoside reverse transcriptase inhibitor resistance and the role of the second-generation agents. Ann Pharmacother. 2010;44(1):157-165.
4. Panel on Antiretroviral Guidelines for Adults and Adolescents Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents Department of Health and Human Services. January 10, 2011;1-139 Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed June 12, 2011.
5. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection. JAMA. 2010;304(3):321-333.
6. Pozniak AL, Morales-Ramirez J, Katabira E, et al. Efficacy and safety of TMC278 in antiretroviral-naïve HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010;24(1):55-65.
7. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naïve adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246.
8. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378(9787):229-237.
Melinda Soriano, PharmD
Does varenicline (Chantix) increase the risk of cardiovascular events in patients with cardiovascular disease?
Does varenicline (Chantix) increase the risk of cardiovascular events in patients with cardiovascular disease?
Each year, approximately 20% of deaths in the United States are attributed to smoking.1 Smoking is a modifiable risk factor for many diseases and has a huge impact on a person's quality of life and the rate of disease progression. Cigarette smoking and tobacco use increase the risk of cardiovascular disease (CVD) that may result in myocardial infarction (MI), stroke, and even death.2 The risk for respiratory diseases is also amplified and may include asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), and emphysema. These often may result in lung cancers and other malignancies.
In 2006, the US Food and Drug Administration (FDA) approved varenicline (Chantix)-a partial agonist at the a4b2 nicotinic acetylcholine receptor that acts to block the mesolimbic dopamine pathway usually associated with nicotine stimulation.3 This is also known as the "reward pathway." Normal stimulation of this pathway results in dopamine release, which provides the smoker with a positive feeling leading to the continuous desire to stimulate this pathway. Without it, cravings and symptoms of withdrawal are experienced. Varenicline competes with nicotine and prevents nicotine from binding to this receptor site. The site continues to be stimulated by varenicline, and the negative symptoms associated with withdrawal are still present. However, the intensity of the symptoms is greatly reduced. The dosing for varenicline is based on a gradual increase to minimize side effects. Initially, it is recommended to start with 0.5 mg once daily for the first 3 days and then increase to twice daily for the next 4 days. On day 8, 1 mg twice a day is recommended, and treatment should be continued at this dose. According to previous labeling, patients were permitted to continue smoking only during the first week of use with varenicline.
Per the 2008 guidelines from the US Public Health Services, nicotine replacement therapy (gum, patches, lozenges, inhalers, nasal spray), bupropion SR (Zyban), and varenicline are all recommended as first-line therapy for smoking cessation.4 There is no distinction in the guidelines recommending the use of one medication over another; however, it does caution use in specific patient populations (e.g., adolescents, pregnant women). Counseling has also been associated with high abstinence rates for smokers trying to quit, especially when in combination with medication.
Although varenicline has been shown to have higher abstinence success rates when compared to bupropion SR, an oral antidepressant approved for smoking cessation, the benefits of use must be weighed against the risks.3 Patients with pre-existing mental illnesses and CVD were excluded from initial clinical trials; therefore, the effects of varenicline were not studied in this patient population. Varenicline carries a boxed warning describing possible psychological adverse effects, including depression and suicide ideation, regardless of psychiatric history.5 Because of this warning, a Risk Evaluation and Mitigation Strategy (REMS) was implemented for varenicline, which requires that a medication guide be dispensed to every patient, advising of potential risks.
On June 16, 2011, the FDA announced concern over varenicline and the possibility that it may contribute to an increased incidence of cardiovascular-specific adverse events in smokers with already diagnosed and established CVD.6 The following is a summary of the available literature with an emphasis on cardiovascular events.
A multicenter, randomized, double-blind, placebo-controlled trial was conducted to determine the efficacy and safety of varenicline in smokers with cardiovascular disease.7 There were 714 patients with stable cardiovascular disease enrolled in the trial. Participants were randomized into 2 groups: one group received 1 mg of varenicline twice daily and the other received placebo twice daily; both received smoking cessation counseling for 12 weeks. The primary endpoint of the trial was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12, which signified successful smoking cessation with the use of varenicline. The results of the trial showed a statistically significant increase in the number of individuals who were able to quit smoking with varenicline (47% abstinence rate) when compared to placebo (13.9% abstinence rate), which demonstrated that varenicline is effective for smoking cessation. However, the trial did look at the occurrence of cardiovascular events and deaths separately, and these incidences were reviewed by an independent committee.
Due to the lack of statistically significant increases in mortality, cardiovascular events, or hemodynamic events in the varenicline group when compared to placebo, the authors concluded that there is no increased cardiovascular risk for patients with stable CVD when using varenicline, suggesting its apparent safety in this population.7 These results should be looked at cautiously. Smokers who were included had stable CVD, and any smokers with a history of a recent MI or unstable CVD, uncontrolled blood pressure, or other coexisting disease states such as COPD and/or diabetes, were excluded. The trial was relatively small and statistically underpowered based on number of events seen (a power of 80% was not met to test secondary endpoints of safety with 703 patients [700 initially needed]). Therefore, no definite conclusions can be made about the safety of varenicline in the population that was included since it was not representative of all patients with CVD, including acute and unstable patients.
More recently, a meta-analysis was conducted by Singh and colleagues to evaluate whether or not there is a risk of serious adverse cardiovascular events associated with the use of varenicline.8 Data were included from 14 double-blinded, controlled trials containing a total of 8,216 randomized individuals, to show the effects of varenicline on cardiovascular events. Only 1 of the 14 trials included in the meta-analysis predefined the specific cardiovascular events that would be monitored throughout the trial, allowing for each event to be classified based on severity. It is also important to note that this analysis included both cigarette smokers and people who used smokeless tobacco and may or may not have had a history of CVD. The primary outcome was arrhythmic or ischemic cardiovascular adverse effects. Adverse cardiovascular events that fell into this category included the incidence of MI, unstable angina, coronary artery disease, stroke, transient ischemic stroke, coronary revascularization, heart failure, and sudden or cardiovascular-related death. The secondary outcome was all-cause mortality.
Dosing for varenicline varied between trials, ranging from 0.3 mg daily to 1 mg twice daily.8 All treatment arms were collapsed into one for comparison of the overall results between trials. Also, not taken into account was the fact that 3 of the trials compared varenicline to bupropion SR and placebo, and 1 trial compared varenicline with nicotine transdermal patch. Duration of the trials ranged from 7 weeks to 52 weeks.
The results of all of the individual trials included in the meta-analysis showed that there was a 72% increase in the relative risk for serious adverse cardiovascular events in patients who received varenicline when compared to placebo.8 However, the absolute increase in the incidence was 0.24% (1.06% incidence of cardiovascular events in the varenicline groups vs. 0.82% incidence in the placebo group). The number of cardiovascular events that were recorded in a majority of the trials and overall in the meta-analysis were not statistically significant. The authors concluded that due to the fact that varenicline was approved prior to obtaining a complete and thorough safety profile, physicians should be cautious in prescribing the agent, especially in patients with already established CVD. Larger and more inclusive trials must be conducted to obtain that necessary information.
The potential for cardiovascular events in tobacco users who use varenicline is still a point of controversy. In June of 2011, the FDA issued a safety announcement which stated that varenicline may be associated with a small increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease. As a result of this warning, many physicians are questioning whether or not to recommend varenicline as a first-line agent for smoking cessation in patients with and without CVD. The FDA is continuing to evaluate the safety of this medication and is requiring that Pfizer, the manufacturer of Chantix, conduct a large combined meta-analysis so that a consensus may be reached regarding the cardiovascular risk. On July 22, 2011, the FDA updated the warning label for varenicline to includes information on the safety of varenicline in patients with stable CVD; the proven effectiveness of varenicline in patients with COPD when compared to placebo; and alternative directions for appropriate use.9,10 Patients may continue to smoke on varenicline up until day 35 of treatment with no additional adverse effects. Previously, patients were instructed to set their quit date 7 days after initiating therapy.
Physicians must be diligent when prescribing varenicline and must weigh the benefits of use against any potential risks.6 Varenicline has been shown to have a 2-fold increase in abstinence rates in patients wanting to quit smoking. This is significant since cigarette smoking and tobacco use has been shown to directly contribute to the progression of CVD.9,10 It is also important that patients read the provided medication guide for varenicline and inform their physician if they experience any worsening of cardiovascular symptoms. Pharmacists must be available to counsel patients and answer any questions that they may have. Varenicline is currently still recommended as first-line therapy, but should only be used in specific patient populations (adults without a psychiatric or cardiovascular history) until more conclusive data are available in regards to a possible increase in cardiovascular risk.
- Centers for Disease Control and Prevention. Adult cigarette smoking in the United States: current estimate. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm . Accessed August 24, 2011.
- Doering PL, Kennedy WK, Boothby LA. Substance-related disorders: alcohol, nicotine, and caffeine. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008:1089-1095.
- Varenicline: drug information. UpToDate. http://www.uptodate.com/contents/varenicline-drug-information?source=search_result&selectedTitle=1~17 . Accessed July 26, 2011.
- Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. U.S. Department of Health and Human Services, Public Health Services. http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf. Accessed August 24, 2011.
- Chantix [package insert]. New York, NY: Pfizer Inc; 2009.
- Food and Drug Administration. FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease. http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm. Accessed August 24, 2011.
- Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121(2):221-229.
- Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ. 2011 Jul 4. [Epub ahead of print]
- Food and Drug Administration. FDA Drug Safety Communication: Chantix (varenicline) drug label now contains updated efficacy and safety information. http://www.fda.gov/Drugs/DrugSafety/ucm264436.htm. Accessed August 24, 2011.
- Food and Drug Administration. FDA Drug Safety Podcast for Healthcare Professionals: Chantix (varenicline) drug label now contains updated efficacy and safety information. http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm266365.htm . Accessed August 4, 2011.
Lauren Tramutola, PharmD candidate, 2012