February 2016 FAQs

Do the insulin glargine products Basaglar and Lantus have similar safety and efficacy profiles?

The Food and Drug Administration (FDA) approved Basaglar, a new insulin glargine product, on December 16, 2015.¹ Basaglar is not considered a biosimilar to the original insulin glargine (Lantus); insulins are not approved as biologics in the United States so it was not eligible for approval via the biosimilar pathway. Basaglar has, however, been designated a follow-on product by the FDA.² It is the first insulin product to receive approval through this abbreviated pathway.¹

Despite its approval, Basaglar will not be available in the United States until December 2016 due to patent restrictions.³ Basaglar will be available as 100 units/mL pens and is approved for the treatment of type 2 diabetes in adults and the treatment of type 1 diabetes in adults and children, which are the same indications as Lantus.^4,5 Comparative pharmacokinetic and pharmacodynamic studies as well as clinical efficacy and safety studies are summarized below.

Pharmacokinetic/pharmacodynamic studies

Three single-center studies compared the pharmacokinetics and pharmacodynamics of Basaglar and Lantus.⁶ In these studies healthy subjects were randomized to a single dose (0.5 units/kg) of either Basaglar or Lantus then crossed-over to the other treatment. The treatment was repeated for a total of 2 doses of each drug. Pharmacokinetic and pharmacodynamic measurements were taken for 24 hours after the insulin dose and blood glucose concentrations were maintained with glucose infusions. There were 211 participants in the 3 studies. These studies found no difference in pharmacokinetic parameters with similar areas under the curve and maximum concentrations. Pharmacodynamic parameters were also similar.

Comparative literature

Safety and efficacy in type 1 diabetes

ELEMENT 1 was a randomized, open-label, 52-week, non-inferiority trial that compared Lantus and Basaglar in patients with type 1 diabetes who had been treated with once-daily basal insulin and mealtime insulin for at least 3 months.⁷ The primary outcome of the trial was change in hemoglobin A1c (HbA1c) from baseline to 24 weeks. All patients received mealtime insulin lispro in addition to the basal insulin. Patients included in the study had a type 1 diabetes diagnosis for at least 1 year, were 18 years of age or older, had a body mass index of ≤35 kg/m², and had a HbA1c of ≤11%. Patients receiving large insulin doses (≥1.5 units/kg) and those with severe hyperglycemic or hypoglycemic episodes within the previous 6 months were excluded. The prestudy insulin dose was continued as the initial study dose.

A total of 535 patients were enrolled in the study.⁷ The efficacy results are summarized in Table 1. Sixty-two percent of patients in each group experienced an adverse event with 6% of patients in the Basaglar group experiencing an adverse event deemed possibly related to the study drug compared with 5% in the Lantus group. The most common adverse events included nasopharyngitis, upper respiratory tract infection, hypoglycemia, and diarrhea. The authors concluded that Basaglar had similar safety and efficacy to Lantus when combined with insulin lispro in patients with type 1 diabetes.

 Table 1. Efficacy outcomes in patients with type 1 diabetes (ELEMENT 1).⁷

Safety and efficacy in type 2 diabetes

ELEMENT 2 was a randomized, double-blind, 24-week, non-inferiority trial that compared Lantus and Basaglar in patients with type 2 diabetes.⁸ Patients included in the study were receiving at least 2 oral antidiabetes medications at stable doses for 12 weeks, were 18 years of age or older, had a body mass index of ≤45 kg/m², and had HbA1c levels of ≥7% to ≤11%. Similar inclusion criteria were applied to patients receiving insulin glargine at screening except patients were allowed to enroll with HbA1c levels lower than 7%.  Patients receiving insulins other than insulin glargine within the prior 30 days, those who had received a basal-bolus regimen, and patients receiving large insulin doses (≥1.5 units/kg) were excluded. Patients who had more than 1 episode of severe hypoglycemia within the previous 6 months were also excluded. Insulin glargine was initiated at 10 units/day in insulin-naïve patients. Patients previously receiving insulin glargine continued their usual dose.

The primary outcome of the trial was change in HbA1c from baseline to 24 weeks.⁸ A total of 756 patients were enrolled in the study. The efficacy results are summarized in Table 2. Similar efficacy outcomes were seen in patients who were insulin-naïve at baseline compared with those who were being treated with insulin glargine. Overall, 52% of patients treated with Basaglar experienced an adverse event compared with 48% of Lantus-treated patients. Six percent of Lantus-treated patients had an adverse event deemed possibly related to the study drug compared with 7% of Basaglar-treated patients. The authors concluded that Basaglar had similar safety and efficacy to Lantus in patients with type 2 diabetes treated with oral antidiabetes agents.

Table 2. Efficacy outcomes in patients with type 2 diabetes (ELEMENT 2) at 24 weeks.⁸

Safety and efficacy in patients previously treated with insulin glargine

The safety and efficacy of Basaglar in patients who were previously treated with insulin glargine was evaluated.⁹ A total of 751 patients from ELEMENT 1 and ELEMENT 2 were included in the analysis. There were no significant differences between groups in HbA1c change from baseline in patients with type 1 or type 2 diabetes who had received insulin glargine prior to the trials. Hypoglycemia was also similar between groups and severe hypoglycemia occurred infrequently. Other adverse events related to the study drug occurred in 4% to 6% of patients with no significant difference between patients treated with Basaglar and Lantus.

Immunogenicity

A concern with biologic products is immunogenicity, and an analysis of the clinical trial data from ELEMENT 1 and ELEMENT 2 was done to evaluate the immunogenicity of Basaglar.¹⁰ In patients with type 1 diabetes, insulin antibodies were detected in 30.2% of patients treated with Basaglar compared with 33.7% of Lantus-treated patients at 24 weeks. Results at 52 weeks were similar (40.4% with Basaglar and 39.3% with Lantus). In patients with type 2 diabetes antibody levels were similar between groups (15.3% with Basaglar and 11% with Lantus). Insulin antibody levels did not affect clinical outcomes.

References

1. FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes. U.S. Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm. Accessed December 18, 2015.
2. Follow-on protein products: regulatory and scientific issues related to developing. U.S. Food and Drug Administration website. http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ucm085854.htm. Accessed December 21, 2015.
3. FDA Approves Basaglar® (insulin glargine injection), a long-acting insulin treatment. PR Newswire website. http://www.prnewswire.com/news-releases/fda-approves-basaglar-insulin-glargine-injection-a-long-acting-insulin-treatment-300194249.html. Accessed December 21, 2015.
4. Basaglar [package insert]. Indianapolis, IN: Lilly USA; 2015.
5. Lantus [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2015.
6. Linnebjerg H, Lam EC, Seger ME, et al. Comparison of the pharmacokinetics and pharmacodynamics of LY2963016 insulin glargine and EU- and US-approved versions of Lantus insulin Glargine in healthy subjects: three randomized euglycemic clamp studies. Diabetes Care. 2015;38(12):2226-2233.
7. Blevins TC, Dahl D, Rosenstock J, et al. Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study. Diabetes Obes Metab. 2015;17(8):726-733.
8. Rosenstock J, Hollander P, Bhargava A, et al. Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab. 2015;17(8):734-741.
9. Hadjiyianni I, Dahl D, Lacaya LB, Pollom RK, Chang CL, Ilag LL. The efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine [published online ahead of print January 7, 2016]. Diabetes Obes Metab. doi: 10.1111/dom.12628.
10. Ilag LL, Deeg MA, Costigan T, et al. Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus insulin glargine in patients with type 1 diabetes mellitus or type 2 diabetes mellitus [published online ahead of print October 5, 2015]. Diabetes Obes Metab. doi: 10.1111/dom.12584.

February 2016

The information presented is current as of January 13, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Should blood pressure goals be lowered based on recent evidence?

Introduction

It is well-established that lowering systolic blood pressure (SBP) results in numerous health benefits, including reduction in the risk for myocardial infarction, heart failure, stroke, and death.^1,2 However, there is still controversy over what blood pressure goal is ideal, with concern that “too low” is possible. This is known as the J-shaped curve phenomenon for blood pressure reduction, a theory that has existed since the 1970s.² According to the J-curve phenomenon, a reduction in blood pressure correlates linearly to a decrease in cardiovascular events and death until a certain reduction, at which point benefits cease and risk for these events increases again.^2,3 Hypotension and decreased organ perfusion may contribute to the upswing in cardiovascular events after a certain degree of blood pressure reduction.³ Individuals with lower blood pressure may also be sicker in general, confounding the phenomenon. The latter is seemingly plausible given that data exploring the J-curve phenomenon are mostly limited to post-hoc analyses and non-randomized and observational studies.²

The J-curve phenomenon has been studied in certain populations, including the elderly, and patients with diabetes, cerebrovascular disease, chronic kidney disease (CKD), and heart failure.^2,3 The optimal range for blood pressure may vary depending on the subgroup, and some individuals may be more sensitive to deleterious effects at higher and lower ends of the range than others in the same subgroup. The optimal blood pressure range may also vary for prevention of certain events (ie, the optimal range for prevention of stroke may differ from the optimal range for prevention of myocardial infarction). But the J-curve phenomenon is not seen in all studies, nor has it been seen in all subgroups; some studies only show that further blood pressure reduction is safe but does not provide additional benefit.² This document reviews the concept of lower blood pressure goals, with emphasis on the recently published SPRINT trial, along with a recent meta-analysis.

JNC 8 guidelines

The 2014 JNC 8 guidelines for management of high blood pressure recommend that for all people who are 18 to 60 years of age, the SBP goal should be <140 mmHg and the diastolic blood pressure (DBP) goal should be <90 mmHg.¹  The recommended goal for those aged ≥60 years is <150/90 mmHg. These goals for the elderly and patients with diabetes or CKD (who are included in the general population recommendation) are more relaxed than previous goals. Interestingly, the recommendation for a goal of SBP <140 mmHg in a general population is based only on expert opinion due to a lack of randomized controlled trials that compare this goal to a lower goal in this population. However, more concrete evidence exists for the recommendation of SBP <140 mmHg in patients with diabetes. Most notably, the ACCORD trial compared this SBP goal to a more intensive goal of <120 mmHg in patients with diabetes and found no benefit with intensive reduction.⁴ Similarly, evidence has shown no additional benefit with a BP goal <150/90 mmHg in a general population aged ≥60 years.¹ The lack of benefit with further blood pressure reduction and the limited evidence, rather than safety concerns, are the major reasons for the more relaxed goals in the JNC 8 guidelines. The evidence for safety concerns with greater blood pressure reductions is limited, so the guidelines did not consider this evidence when making their recommendations.

The SPRINT trial

Given the low level of evidence to support lack of additional benefit with more intensive blood pressure goals in a general population, investigators performed the SPRINT trial.⁵

The purpose of the SPRINT trial was to compare lowering SBP to a standard goal of <140 mmHg to a more intensive goal of <120 mmHg in a general patient population without diabetes but with increased risk for cardiovascular events. Increased cardiovascular risk was defined as at least one of the following: cardiovascular disease other than stroke, CKD, a Framingham 10-year risk of cardiovascular disease of 15% or more, or age ≥75 years. The SPRINT trial was open-label and used a similar treatment algorithm to the ACCORD trial for blood pressure reduction. Patients in the intensive group (n=4678) were given a 2- or 3-drug combination of a thiazide diuretic, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and/or a calcium channel blocker. Concomitant use of an ACEI and an ARB was not allowed. Patients in the standard group (n=4683) were initiated at randomization with one drug from the aforementioned drug options, and titrated if necessary. Titration goals for the standard group were 135 to 139 mmHg, and dosing was reduced if SBP was <135 mmHg on 2 consecutive visits. The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes. Secondary outcomes included the components of the primary composite.

The mean SBP after 1 year was 136.2 mmHg in the standard treatment group and 121.4 mmHg in the intensive treatment group.⁵ The trial was discontinued early after a median of 3.26 years due to a clear benefit in the intensive treatment group. Annual rates of the primary outcome in the intensive treatment and standard treatment groups were 1.65% and 2.19%, respectively, with a hazard ratio (HR) of 0.75 (95% confidence interval [CI] 0.64 to 0.89, p<0.001). Differences between groups for the primary outcome were noticeable after 1 year. Components of the primary outcome that were also significantly reduced with intensive treatment compared to standard treatment were heart failure (p=0.002), death from cardiovascular causes (p=0.005), and death from any cause (p=0.003). Differences between groups for death were noticeable after 2 years. The overall rate of serious adverse events was similar between groups, but hypotension occurred more frequently with intensive treatment (2.4% vs 1.4%, p=0.001), as did syncope (2.3% vs 1.4%, p=0.05), electrolyte abnormalities (3.1% vs 2.3%, p=0.02), and acute kidney injury or renal failure (4.1% vs 2.5%, p<0.001). The SPRINT trial showed no evidence of the J-curve phenomenon and also supported that reduction in SBP to a goal of <120 mmHg provides further benefit in a high-risk population without diabetes for the prevention of cardiovascular events and death.

In comparison to the ACCORD trial, the SPRINT trial was approximately twice the size and excluded patients with diabetes; ACCORD included only those patients.^4,5 While the ACCORD trial did not find significant differences in the primary outcome of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes between the intensive therapy and standard therapy groups, it did find a small but significantly greater reduction in stroke in the intensive therapy group (HR 0.59, 95% CI 0.39 to 0.89, p=0.01).⁴ The SPRINT trial did not find a difference in risk for stroke between groups. These differences between the ACCORD and SPRINT results support the theory that ideal blood pressure reductions may vary for subgroups, event types, and their combination.

Recent meta-analysis results

A meta-analysis on intensive blood pressure reduction was published around the same time as the SPRINT trial.⁶ It included 19 trials that compared more versus less intensive blood pressure lowering in hypertensive patients who had a high risk for cardiovascular disease and/or renal disease (n=44,989). This meta-analysis found that compared to less intensive regimens, more intensive regimens significantly decreased the risk for major cardiovascular events (relative risk [RR] 0.87, 95% CI 0.81 to 0.94, p<0.0001), myocardial infarction (RR 0.87, 95% CI 0.76 to 1.00, p=0.042), and stroke (RR 0.79, 95% CI 0.71 to 0.90, p<0.0001). No significant differences between the regimens were seen for outcomes of occurrence of heart failure, end-stage kidney disease, or death. The analysis also found that the beneficial effects were not dependent on baseline blood pressure. Adverse effects were inconsistently reported, but hypotension was found to occur more frequently with more intensive than less intensive regimens (p=0.015). These results differed from SPRINT in that more intensive regimens did not show additional benefit in decreasing death, but they did decrease the risk for stroke. Notably, the definitions of intensity varied among the studies. Some of the trials defined intensive regimens as SBP <140 to 150 mmHg and DBP <85 to 90 mmHg, while other intensive regimens were defined were defined as SBP <120 mmHg or even lower.

Conclusion

The most recent evidence suggests that more intensive blood pressure goals provide further cardiovascular benefit, with increased risk for hypotension.^4-6 No evidence for a J-curve phenomenon was seen, still leaving only low-level evidence to support this theory. The SPRINT trial is the first randomized controlled trial to assess intensive blood pressure goals in a high-risk patient population without diabetes, and it showed that an SBP goal of <120 mmHg provides further benefit in reducing cardiovascular events and death.⁵ This is in contrast to the 2010 ACCORD trial, which found no further benefit from intensive blood pressure reduction in patients with diabetes.⁴ The recent meta-analysis had some of the same findings as SPRINT, including further benefit with intensive blood pressure goals for protection from cardiovascular events, but not for death. Overall, there seems to be a further benefit with intensive blood pressure lowering in a general patient population and in those at high-risk for events, but more evidence is needed to further elucidate ideal blood pressure goals for specific patient subgroups and for prevention of specific event types, including death.

References

1. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
2. Moreira DM, Poffo MR, Miotto R, Matos Sde M, Ferreira AR, de Abreu-Silva EO. Revisiting the J-curve phenomenon. An old new concept? Curr Hypertens Rev. 2014;10(1):14-19.
3. Argulian E, Grossman E, Messerli FH. Misconceptions and facts about treating hypertension. Am J Med. 2015;128(5):450-455.
4. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
5. Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A Randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.
6. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2015 Nov 7. pii: S0140-6736(15)00805-3. doi: 10.1016/S0140-6736(15)00805-3. [Epub ahead of print].

February 2016

The information presented is current as of December 17, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Are proton pump inhibitors (PPIs) associated with negative outcomes in patients with cirrhosis?

Introduction

Chronic liver disease is the fourth leading cause of death in the United States among individuals between the ages of 45 and 54 years.¹ Cirrhosis, a subset of chronic liver disease, was responsible for over 30,000 deaths in 2010.² Spontaneous bacterial peritonitis (SBP), an acute infection of the ascitic fluid, is a potentially life-threatening complication of cirrhosis. Although the exact mechanism by which it occurs is not fully understood, factors such as bacterial overgrowth, increased intestinal permeability, and altered intestinal motility may play a role.³

Acid suppression therapy has recently been a topic of concern for patients with cirrhosis. Although the pathophysiology is not well understood, patients with cirrhosis are at an increased risk of peptic ulcers, with a prevalence of up to 21%.⁴ Many patients with cirrhosis receive gastric acid suppression therapy in order to decrease this risk, as well as to prevent complications in patients with a history of variceal or gastrointestinal bleeding. Despite their potential beneficial effects, acid suppression therapy with proton pump inhibitors (PPIs) or histamine H_2-receptor antagonists (H2RAs) has been associated with small intestine bacterial overgrowth and decreased gastric motility which are both considered risk factors for SBP.⁵

The 2012 update to the American Association for the Study of Liver Diseases (AASLD) Practice Guideline for the Management of Adult Patients with Ascites Due to Cirrhosis states that use of PPIs has been associated with an increased rate of SBP, and they recommend restricting the use of PPIs to data-supported indications including short-term treatment of gastroesophageal reflux disease (GERD), erosive esophagitis, gastric ulcers, duodenal ulcers, and hypersecretory conditions such as Zollinger-Ellison syndrome.^6-8 Based on more recent information, a review of the literature is warranted.

PPIs and SBP or other infections

Meta-analyses

Two recent meta-analyses on this topic have been published.⁹ A 2015 meta-analysis by Xu and colleagues pooled 17 observational studies (n=8204) that were published between 2008 and 2014. Studies with at least 20 subjects with cirrhosis were analyzed to evaluate the association between PPI use and the risk of SBP. The overall pooled data found a significant association between PPI use and risk of SBP, with an odds ratio (OR) of 2.17 (95% confidence interval [CI] 1.46 to 3.23, p<0.05). One limitation of this analysis was the high heterogeneity reported (I²=85.6%). The authors attributed this to the inclusion of conference abstracts in the analysis since abstracts likely have more heterogeneous characteristics and their methodology cannot be adequately assessed. Of the 17 studies, 3 evaluated PPI use and the overall risk of infection. When only these 3 studies were analyzed, PPI use was associated with an increased overall infection risk (OR 1.98, 95% CI 1.36 to 2.87, p<0.05).
 

An earlier meta-analysis from Deshpande et al in 2013 pooled 8 observational studies including 3815 patients with cirrhosis.¹⁰ Similar to Xu et al, this meta-analysis included studies that evaluated the risk of SBP associated with acid suppression therapy. One unique aspect of this analysis was the exclusion of studies that did not have a control group. Meta-analysis of the 8 studies found that the risk of SBP was significantly higher in patients on PPI therapy compared with those who were not on PPI therapy (OR 3.15, 95% CI 2.09 to 4.74, p<0.00001, I²=57%). When the meta-analysis was performed with only the 6 studies deemed to be of moderate to high quality, this association remained significant (OR 2.89, 95% CI 1.81 to 4.64, p<0.0001), with much less heterogeneity (I²=33%). The investigators also performed an analysis on patients taking H2RAs and found a significantly greater risk of developing SBP (OR 1.71, 95% CI 0.97 to 3.01, p=0.06) in those patients. These results suggest that acid suppression therapy in general, rather than PPI use specifically, may be a risk factor for the development of SBP.

Prospective Studies

Since 2012, 3 prospective studies have evaluated the association between PPI use and infection.^11-13 O’Leary et al prospectively collected data for 188 patients hospitalized with cirrhosis and infections. They found that patients who developed subsequent infections during the 6 months after hospital discharge had a higher rate of PPI use compared to patients who did not develop a subsequent infection (72.6% vs. 52.9%, p=0.006).¹¹ Additionally, both univariate logistic regression analysis and a multivariate stepwise regression model showed that PPI use was an independent predictor of developing a subsequent infection when model for end-stage liver disease (MELD) scores were included within the model. Similarly, a prospective study conducted by Merli et al in patients with cirrhosis found that PPI use was an independent predictor of any infection, including SBP (OR 2, 95% CI 1.2 to 3.2, p=0.008).¹² Unlike the most recent studies, an older prospective cohort study published in 2012 by van Vlerken et al found that despite rat models associating PPI use with significant bacterial overgrowth, there was not a significant increase in infection in human patients. ¹³ Although the human patients treated with PPI therapy had a higher incidence of infection, PPI therapy was not found to be an independent risk factor for development of bacterial infection upon multivariate regression analysis (hazard ratio [HR] 1.2, 95% CI 0.5 to 3.0, p=0.72).

Retrospective Studies

Eight retrospective studies that evaluated the association between PPI use and SBP have been published since 2012.^14-21 Of these studies, only 2 retrospective analyses concluded that there was no association between PPI use and SBP.^14,15 The first single-center analysis of 607 patients, 86% of which were on PPIs, evaluated patients presenting for a first paracentesis and found that the proportion of patients with SBP was not significantly different between patients receiving PPI therapy and those not receiving PPIs (19% vs. 17%; p=0.691).¹⁴ In a multivariate logistic regression analysis, investigators determined that PPI use, advanced age, hepatocellular carcinoma, history of variceal bleeding, varices, and MELD score were not associated with SBP on a first paracentesis. After adjusting for all confounders, PPI use was not associated with an increased risk of SBP. The investigators also found that PPI use was not an independent risk factor for mortality in patients with cirrhosis. The second study, published by de Vos et al in 2013, failed to show a significant association between PPI use and SBP upon multivariate regression analysis (p=0.1), despite PPIs being used more frequently in patients who developed SBP.¹⁵

The remaining 6 studies found PPI use to be significantly associated with development of SBP.^16-21 A 2015 case-control cohort study of 86,418 patients with liver cirrhosis in Taiwan found that patients currently using PPI therapy had a confounder-adjusted rate ratio (aRR) of 2.77 (95% CI 1.9 to 4.04) for developing SBP, supporting the theory that PPI use is independently associated with SBP.¹⁶ In this study, H2RAs were also associated with SBP (aRR 2.62, 95% CI 2.00 to 3.42). A retrospective cohort study of 1554 patients with cirrhosis found that patients who were on PPI therapy (n=512) had a higher rate of SBP compared to the control group (10.6% vs. 5.8%; p=0.002).¹⁷ Additionally, multivariate analysis found that PPI use was significantly associated with SBP (HR 1.396, 95% CI 1.057 to 1.843, p=0.019). A case-control study conducted by Ratelle et al found PPI use to be the only factor associated with SBP (OR 2.09, 95% CI 1.04 to 4.23, p=0.04); associations with gender, diabetes, serum sodium level, and MELD score were nonsignificant.¹⁸ Similarly, a retrospective, single-center study of 65 patients found a significant association between PPI use and SBP (OR 6.41, 95% CI 1.16 to 35.7, p=0.033).¹⁹ Despite this high OR, the wide CI reflects the small sample size and decreases the external validity of the results. Two additional studies also support a link between PPI use and SBP.^20,21 Bajaj et al analyzed data from the Veterans Administration and found that patients treated with PPIs after liver decompensation had a faster onset of serious infection, with patients treated with PPIs developing infection at a rate 1.75 times faster than that of patients not on PPI therapy. Interestingly, the investigators found that H2RA use was not associated with a faster onset nor increased rate of serious infections. Another early retrospective study of 65 patients with cirrhosis found a higher incidence of recent (within 7 days) PPI use in patients with SBP compared to controls (71% vs. 42%; p<0.001).²¹      

Proton pump inhibitors and mortality

Based on the above data, PPI use appears to be associated with increased risk for SBP. However, there are also data to suggest that PPI use in patients with cirrhosis may be associated with increased mortality.^22,23 A 2015 prospective study by Dultz et al followed 272 patients with cirrhosis, 78% of whom were on PPI therapy.²² Upon multivariate regression, the investigators found that PPI use was an independent predictor of mortality in patients with cirrhosis (HR 2.33, 95% CI 1.264 to 4.296, p=0.007). This study also found a higher incidence of infection in patients on PPIs, as well as a higher number of patients colonized with multi-drug resistant organisms.

A retrospective cohort study of 1140 patients conducted by Kwon et al looked not only at PPI use and development of SBP, but also investigated independent predictors of mortality in patients with cirrhosis and SBP.²³ The authors concluded that recent PPI use (<30 days) was an independent risk factor for mortality during hospitalization or within 30 days after development of SBP (OR 1.96, 95% CI 1.19 to 3.23, p=0.008).

Conclusion

Recent literature continues to support the association of PPIs with SBP. Two meta-analyses have concluded, despite a high degree of heterogeneity, that there is a significant risk of SBP with PPI use in patients with cirrhosis. Not only have these analyses concluded that there is increased risk, but the risk is up to 3 times higher compared to patients not on PPI therapy. Since 2012, only 2 retrospective studies have failed to support this association. Recent data also support an association between PPI use and mortality in patients with cirrhosis. Unfortunately, based on the nature of observational studies no cause and effect relationship can be established.

One important concern that many studies evaluated was the necessity of PPI treatment. In the retrospective study conducted by Goel et al, 68% of patients on PPI therapy had no indication for acid suppression therapy.²¹ To decrease the risk of SBP in patients with cirrhosis, PPIs should only be used when clinically indicated.⁶ Use should be limited in patients with cirrhosis to Food and Drug Administration-labeled indications, utilizing the smallest effective dose for the shortest duration required.

References

1. Liver Lowdown. American Liver Foundation website. http://www.liverfoundation.org/education/liverlowdown/ll1013/bigpicture/. Updated October 18, 2013. Accessed January 4, 2016.
2. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 2013;61(4):1-117.
3. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis. 1998;27(4):669-674.
4. Lodato F, Azzaroli F, Di Girolamo M, et al. Proton pump inhibitors in cirrhosis: tradition or evidence based practice? World J Gastroenterol. 2008;14(19):2980-2985.
5. Dukowicz AC, Lacy BE, Levine GM. Small intestinal bacterial overgrowth; a comprehensive review. Gastroenterol Hepatol. 2007;3(2):112-122.
6. Runyon BA. Management of adult patients with ascites due to cirrhosis: update 2012. American Association for the Study of Liver Diseases website. http://www.aasld.org/sites/default/files/guideline_documents/141020_Guideline_Ascites_4UFb_2015.pdf. Accessed January 22, 2015.

7. Protonix [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc.; 2014.

8. Prilosec [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2014.
9. Xu HB, Wang HD, Li CH, et al. Proton pump inhibitor use and risk of spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and meta-analysis. Genet Mol Res. 2015;14(3):7490-7501.
10. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242.
11. O’Leary JG, Reddy KJ, Wong F, et al. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13(4):753-759.
12. Merli M, Lucidi C, De Gregorio V, et al. The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis. Liver Int. 2015;35(2):362-369.
13. van Vlerken LG, Huisman EJ, van Hoek B, et al. Bacterial infections in cirrhosis: role of proton pump inhibitors and intestinal permeability. Eur J Clin Invest. 2012;42(7):760-767.
14. Mandorfer M, Bota S, Schwabl P, et al. Proton pump inhibitor intake neither predisposes to spontaneous bacterial peritonitis or other infections nor increases mortality in patients with cirrhosis and ascites. PLoS One. 2014;9(11):e110503.
15. de Vos M, de Vroey B, Garcia BG, et al. Role of proton pump inhibitors in the occurrence and the progression of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Liver Int. 2013;33(9):1316-1323.
16. Chang SS, Lai CC, Lee MT, et al. Risk of spontaneous bacterial peritonitis associated with gastric acid suppression. Medicine (Baltimore). 2015;94(22):e944.
17. Min YW, Lim KS, Min BH, et al. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Aliment Pharmacol Ther. 2014;40(6):695-704.
18. Ratelle M, Perreault S, Villeneuve JP, Tremblay L. Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Can J Gastroenterol Hepatol. 2014;28(6):330-334.
19. Miura K, Tanaka A, Yamamoto T, Adachi M, Takikawa H. Proton pump inhibitor use is associated with spontaneous bacterial peritonitis in patients with liver cirrhosis. Intern Med. 2014;53(10):1037-1042.
20. Bajaj JS, Ratliff SM, Heuman DM, Lapane KL. Proton pump inhibitors are associated with a high rate of serious infections in veterans with decompensated cirrhosis. Aliment Pharmacol Ther. 2012;36(9):866-874.
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Prepared by:
John Lyons, PharmD
PGY1 Pharmacy Resident
College of Pharmacy
University of Illinois at Chicago

February 2016

The information presented is current as of January 13, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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