Journal of Pharmacovigilance

A Disproportionality Analysis of the Risk of Rhabdomyolysis Associated with DPP-4 Inhibitors in the Food and Drug Administration Adverse Event Reporting System

Wenhui Shi^*, Lei Ba and Zhiming Sun Department of Epidemiology, Jiangsu Institute of Planned Parenthood Research, Nanjing, China
^*Correspondence: Wenhui Shi, Department of Epidemiology, Jiangsu Institute of Planned Parenthood Research, China, Tel: +86 2586576027, Email:

Received: 15-Oct-2020 Published: 29-Nov-2020, DOI: 10.35248/2329-6887.20.8.295

Introduction

Dipeptidyl peptidase 4 inhibitors (DPP4is), also referred to as gliptins, are widely used in many countries as glucose-lowering drugs for patients with type 2 diabetes mellitus (T2DM) [1]. These agents improve glycemic control through suppressing the inactivation of glucagon-like-peptide 1 (GLP-1), leading to reduced glucagon release and increased β-cell survival [2]. Since sitagliptin, the first DPP4is approved by US Food and Drug Administration (FDA) in October 2006 [3], the excellent tolerability/safety profile of DPP4is is supported by published clinical trials [4,5]. However, post marketing experience has raised some concerns, such as potential increase in the risk of pancreatitis, heart failure and hypersensitivity reactions [6].

Recently, FDA quarterly safety report which issued in early October 2017 stated that DPP4is may be associated with rhabdomyolysis [7], a severe syndrome of muscle injury associated with myoglobinuria, electrolyte abnormalities, and often leads to acute kidney injury. In addition, several cases reported rhabdomyolysis associated with combination use of sitagliptin and statins [8-10], as rhabdomyolysis is a known adverse effect of statins and lipid-modifying drugs are commonly used in patients with diabetes, it is necessary to investigate the association between DPP4is and rhabdomyolysis by excluding effects of statins and other co-used drugs.

Many drugs can cause myopathies and may result in rhabdomyolysis such as rheumatologic and immunosuppressive drugs, antiinfectious drugs, lipid-lowering agents, gastrointestinal drugs and etc. [11]. Given that many of abovementioned drugs may be coused with DPP4is in diabetic patients because cardiovascular disease are common complications in the natural history of diabetes, considering moderation effect by drug-drug interaction is necessary.

To this end, in the present study, we analyzed the disproportional association between DPP4is and rhabdomyolysis in FDA Adverse Events Reporting system (FAERS), a global spontaneous reporting database, specifically focusing on potential drug-drug interactions, aimed to complement information from observational case reports and provide further guidance for clinicians.

Methods

FAERS database stores millions of adverse events (AE) reports which contain the demographic characteristics of the patients, drug exposures, indications for use, as well as types and outcomes of reactions [12]. FAERS is a useful tool for looking for new safety signals that might be related to a marketed product, in pharmacovigilance, when certain AE for a given drug are being reported with a greater frequency than would be expected by chance based on a statistical model, we say a safety signal may have been detected.

We used AERSmine [13], a web-based software to mine the FAERS database from 2004q1 to 2017q3, for a total of 9,906,642 reports. This tool normalized and unified drug entries to known generic names, categorized into therapeutic classes based on the Anatomical Therapeutic Chemical (ATC) nomenclature. Moreover, it aggregated clinical indications and adverse events according to Medical Dictionary for Regulatory Activities (MedDRA) Ontology (version 16.1). All the work made user-driven selection and partition across the FAERS data elements possible.

We searched all rhabdomyolysis reports in which DPP4is was used as suspect or concomitant drugs (See electronic supplementary material [ESM] Methods) to access the number of cases, indications and concomitant drugs, to calculate the rates and proportional reporting ratios (PRRs). Then we listed all drugs which were confirmed to be relevant with rhabdomyolysis in the above retrieved DPP4is-rhabdomyolysis reports, performed disproportionality analyses based upon the case/noncase approach [14], computed the PRRs for each drug combination (no DPP4is+no moderator drugs,

DPP4is+no moderator drugs, moderator drugs+no DPP4is, DPP4is+moderator drugs). According to the interaction additive model [15], when the PRR value for co-exposure exceeds the sum of the PRRs for each individual drug, a potential drug-drug interaction may exist.

In subanalysis, we performed same analysis on subgroups that classified by patients’ age, sex [working age (15-65 years) male, working age female, elderly (>65years) male and elderly female] and types of DPP4is (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin). Figure 1 illustrates the study query flow chart.

Figure 1. Study flow chart

Statistical Analysis

For each search query, we fetched the total number of rhabdomyolysis AE reports, the respective frequencies/1000 reports and calculated PRRs with 95% CI. Statistical significance was accepted at P<0.05.

Results

Rhabdomyolysis rates in reports field for DPP4is and non- DPP4is drugs

From 2004q1 to 2017q3, there were 89,719 AE reports listing DPP4is as suspect or concomitant drugs (0.91% of FAERS reports). Among these, 536 included rhabdomyolysis as an AE, the rate was 5.97/1000 reports. Among 9,816,923 reports listing any non-DPP4is as suspect or concomitant drugs, 28462 included at least one rhabdomyolysis AE, equal to a rate of 2.90/1000. As a result, the PRR for rhabdomyolysis associated with DPP4is was 2.06 (95%CI: 1.89-2.24).

Among 536 rhabdomyolysis reports with DPP4is also listing 60 other drugs categorized by 8 system organ class (ESM Table 1), which have rhabdomyolysis as a known drug reaction. As expected, the most common moderator drugs were statins and angiotensin receptor blockers, field for cardiovascular system (Figure 2).

ESM Table 1: Other drugs listed in 536 DPP4is associated rhabdomyolysis reports, which have rhabdomyolysis as a known drug reaction.

Figure 2. Numbers of concomitant drugs and reports (grouped by system organ class), which have rhabdomyolysis as a known drug reaction, in all rhabdomyolysis AE reports with DPP4is

Moderation of rhabdomyolysis rates by drug-drug interactions

In FAERS, the use of DPP4is without moderator drugs was significantly associated with reports of rhabdomyolysis (PRR: 2.49, 95%CI: 2.08-2.98). The results showed an increase rhabdomyolysis rate in reports of the concomitant use of DPP4is and moderator drugs, but it was lower than the sum of PRRs for DPP4is and moderator drugs alone, thus did not support a potential drug-drug interaction (Table 1).

Table 1: The proportional reporting ratios of rhabdomyolysis associated with DPP4is and moderator drugs, separately and in combination, in FAERS

Rhabdomyolysis rates among different population and types of DPP4is

There were a total of 5,878,881 reports that have both age and sex information, therefore we performed similar analysis for different population (ESM Table 2). The rhabdomyolysis rate was 5.18/1000 (95%CI: 3.33-7.04) for DPP4is versus 2.62/1000 (95%CI: 2.52-2.72) for non-DPP4 is, with a corresponding PRR of 1.98 (95%CI: 1.38-2.84) among working age male, while no significant difference was observed in working age female with a PRR of 1.27 (95%CI: 0.61-2.67). However, increase of PRRs was showed in elderly people than working age population, both male and female (Figure 3a). For different types of DPP4is, the PRRs for rhabdomyolysis also varied. Alogliptin, with a PRR of 11.89 (95%CI: 6.77-20.87), was significantly higher than sitagliptin and linagliptin, while saxagliptin and vildagliptin approved to be not associated with rhabdomyolysis after excluding the effects of moderator drugs (Figure 3b).

ESM Table 2: The proportional reporting ratios of rhabdomyolysis associated with DPP4is and moderator drugs, separately and in combination, among different population.

Figure 3. Disproportional analysis for rhabdomyolysis adverse event in FAERS from 2004q1 to 2017q3 according to patients’ age, sex (a) and types of DPP4is (b), excluding moderator drugs. The proportional reporting ratios were reported along with their 95%CI.

Electronic Supplementary Material

Methods

AERSmine QUERY

So far there are five gliptins approved for marketing, alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin. According to the AERSmine ontology vocabulary, the query terms listed as follows for each type of DPP4is:

Alogliptin: "alogliptin" OR "metformin and alogliptin" OR "pioglitazone and alogliptin"

Linagliptin: "linagliptin" OR "metformin and linagliptin" OR "linagliptin and empagliflozin"

Saxagliptin: "saxagliptin" OR "metformin and saxagliptin" OR "saxagliptin and dapagliflozin"

Sitagliptin: "sitagliptin" OR "metformin and sitagliptin" OR "pioglitazone and sitagliptin" OR "sitagliptin and simvastatin"

Vildagliptin: "vildagliptin" OR "metformin and vildagliptin"

First, we searched all rhabdomyolysis reports listed DPP4is as suspect or concomitant drug, the search string listed as follows:

Drug: "saxagliptin" OR "metformin and saxagliptin" OR "saxagliptin and dapagliflozin" OR "alogliptin" OR "metformin and alogliptin" OR "pioglitazone and alogliptin" OR "sitagliptin" OR "metformin and sitagliptin" OR "pioglitazone and sitagliptin" OR "sitagliptin and simvastatin" OR "linagliptin" OR "metformin and linagliptin" OR "linagliptin and empagliflozin" OR "vildagliptin" OR "metformin and vildagliptin"

Adverse Events: "rhabdomyolysis"

No restrictions on other variables were used.

Among 536 reports that retrieved using the above query, we listed all drugs that were concomitantly used, and found a total of 60 drugs which were confirmed to be associated with rhabdomyolysis. We defined these 60 drugs as “moderator drugs”.

"valsartan" OR "olmesartan medoxomil" OR "hydrochlorothiazide" OR "pitavastatin" OR "rosuvastatin" OR "irbesartan" OR "losartan" OR "atorvastatin" OR "rabeprazole" OR "pantoprazole" OR "irbesartan and diuretics" OR "ezetimibe" OR "amiodarone" OR "candesartan" OR "tizanidine" OR "simvastatin" OR "pregabalin" OR "aliskiren" OR "olmesartan medoxomil and diuretics" OR "bezafibrate" OR "lovastatin" OR "telmisartan" OR "ciprofloxacin" OR "colchicine" OR "febuxostat" OR "fenofibrate" OR "tolvaptan" OR "theophylline" OR "benzylpenicillin" OR "oxycodone" OR "risperidone" OR "sulfamethoxazole" OR "pravastatin" OR "cefdinir" OR "gemfibrozil" OR "daptomycin" OR "indapamide" OR "temazepam" OR "fluvastatin" OR "ciclosporin" OR "sunitinib" OR "efavirenz" OR "citalopram" OR "sulfasalazine" OR "escitalopram" OR "bupropion" OR "nicotinic acid" OR "pramipexole" OR "lamivudine" OR "aripiprazole" OR "levofloxacin" OR "clarithromycin" OR "terbinafine" OR "cytarabine" OR "venlafaxine" OR "fusidic acid" OR "olanzapine" OR "quetiapine" OR "tenofovir disoproxil" OR "propofol".

Then we performed 4 queries to get the case numbers of rhabdomyolysis associated with DPP4is and moderator drugs, separately and in combination, as follows:

1) No DPP4is, no moderator drugs

Drug:

Include: None.

Exclude: "saxagliptin" OR "metformin and saxagliptin" OR "saxagliptin and dapagliflozin" OR "alogliptin" OR "metformin and alogliptin" OR "pioglitazone and alogliptin" OR "sitagliptin" OR "metformin and sitagliptin" OR "pioglitazone and sitagliptin" OR "sitagliptin and simvastatin" OR "linagliptin" OR "metformin and linagliptin" OR "linagliptin and empagliflozin" OR "vildagliptin" OR "metformin and vildagliptin" OR "valsartan" OR "olmesartan medoxomil" OR "hydrochlorothiazide" OR "pitavastatin" OR "rosuvastatin" OR "irbesartan" OR "losartan" OR "atorvastatin" OR "rabeprazole" OR "pantoprazole" OR "irbesartan and diuretics" OR "ezetimibe" OR "amiodarone" OR "candesartan" OR "tizanidine" OR "simvastatin" OR "pregabalin" OR "aliskiren" OR "olmesartan medoxomil and diuretics" OR "bezafibrate" OR "lovastatin" OR "telmisartan" OR "ciprofloxacin" OR "colchicine" OR "febuxostat" OR "fenofibrate" OR "tolvaptan" OR "theophylline" OR "benzylpenicillin" OR "oxycodone" OR "risperidone" OR "sulfamethoxazole" OR "pravastatin" OR "cefdinir" OR "gemfibrozil" OR "daptomycin" OR "indapamide" OR "temazepam" OR "fluvastatin" OR "ciclosporin" OR "sunitinib" OR "efavirenz" OR "citalopram" OR "sulfasalazine" OR "escitalopram" OR "bupropion" OR "nicotinic acid" OR "pramipexole" OR "lamivudine" OR "aripiprazole" OR "levofloxacin" OR "clarithromycin" OR "terbinafine" OR "cytarabine" OR "venlafaxine" OR "fusidic acid" OR "olanzapine" OR "quetiapine" OR "tenofovir disoproxil" OR "propofol"

2) DPP4is, no moderator drugs

Drug:

Include: "saxagliptin" OR "metformin and saxagliptin" OR "saxagliptin and dapagliflozin" OR "alogliptin" OR "metformin and alogliptin" OR "pioglitazone and alogliptin" OR "sitagliptin" OR "metformin and sitagliptin" OR "pioglitazone and sitagliptin" OR "sitagliptin and simvastatin" OR "linagliptin" OR "metformin and linagliptin" OR "linagliptin and empagliflozin" OR "vildagliptin" OR "metformin and vildagliptin"

Exclude: "valsartan" OR "olmesartan medoxomil" OR "hydrochlorothiazide" OR "pitavastatin" OR "rosuvastatin" OR "irbesartan" OR "losartan" OR "atorvastatin" OR "rabeprazole" OR "pantoprazole" OR "irbesartan and diuretics" OR "ezetimibe" OR "amiodarone" OR "candesartan" OR "tizanidine" OR "simvastatin" OR "pregabalin" OR "aliskiren" OR "olmesartan medoxomil and diuretics" OR "bezafibrate" OR "lovastatin" OR "telmisartan" OR "ciprofloxacin" OR "colchicine" OR "febuxostat" OR "fenofibrate" OR "tolvaptan" OR "theophylline" OR "benzylpenicillin" OR "oxycodone" OR "risperidone" OR "sulfamethoxazole" OR "pravastatin" OR "cefdinir" OR "gemfibrozil" OR "daptomycin" OR "indapamide" OR "temazepam" OR "fluvastatin" OR "ciclosporin" OR "sunitinib" OR "efavirenz" OR "citalopram" OR "sulfasalazine" OR "escitalopram" OR "bupropion" OR "nicotinic acid" OR "pramipexole" OR "lamivudine" OR "aripiprazole" OR "levofloxacin" OR "clarithromycin" OR "terbinafine" OR "cytarabine" OR "venlafaxine" OR "fusidic acid" OR "olanzapine" OR "quetiapine" OR "tenofovir disoproxil" OR "propofol"

3) moderator drugs, no DPP4is

Drug:

Include: "valsartan" OR "olmesartan medoxomil" OR "hydrochlorothiazide" OR "pitavastatin" OR "rosuvastatin" OR "irbesartan" OR "losartan" OR "atorvastatin" OR "rabeprazole" OR "pantoprazole" OR "irbesartan and diuretics" OR "ezetimibe" OR "amiodarone" OR "candesartan" OR "tizanidine" OR "simvastatin" OR "pregabalin" OR "aliskiren" OR "olmesartan medoxomil and diuretics" OR "bezafibrate" OR "lovastatin" OR "telmisartan" OR "ciprofloxacin" OR "colchicine" OR "febuxostat" OR "fenofibrate" OR "tolvaptan" OR "theophylline" OR "benzylpenicillin" OR "oxycodone" OR "risperidone" OR "sulfamethoxazole" OR "pravastatin" OR "cefdinir" OR "gemfibrozil" OR "daptomycin" OR "indapamide" OR "temazepam" OR "fluvastatin" OR "ciclosporin" OR "sunitinib" OR "efavirenz" OR "citalopram" OR "sulfasalazine" OR "escitalopram" OR "bupropion" OR "nicotinic acid" OR "pramipexole" OR "lamivudine" OR "aripiprazole" OR "levofloxacin" OR "clarithromycin" OR "terbinafine" OR "cytarabine" OR "venlafaxine" OR "fusidic acid" OR "olanzapine" OR "quetiapine" OR "tenofovir disoproxil" OR "propofol"

Exclude："saxagliptin" OR "metformin and saxagliptin" OR "saxagliptin and dapagliflozin" OR "alogliptin" OR "metformin and alogliptin" OR "pioglitazone and alogliptin" OR "sitagliptin" OR "metformin and sitagliptin" OR "pioglitazone and sitagliptin" OR "sitagliptin and simvastatin" OR "linagliptin" OR "metformin and linagliptin" OR "linagliptin and empagliflozin" OR "vildagliptin" OR "metformin and vildagliptin"

4) DPP4is and moderator drugs

Drug:

Include: ("saxagliptin" OR "metformin and saxagliptin" OR "saxagliptin and dapagliflozin" OR "alogliptin" OR "metformin and alogliptin" OR "pioglitazone and alogliptin" OR "sitagliptin" OR "metformin and sitagliptin" OR "pioglitazone and sitagliptin" OR "sitagliptin and simvastatin" OR "linagliptin" OR "metformin and linagliptin" OR "linagliptin and empagliflozin" OR "vildagliptin" OR "metformin and vildagliptin") AND ("valsartan" OR "olmesartan medoxomil" OR "hydrochlorothiazide" OR "pitavastatin" OR "rosuvastatin" OR "irbesartan" OR "losartan" OR "atorvastatin" OR "rabeprazole" OR "pantoprazole" OR "irbesartan and diuretics" OR "ezetimibe" OR "amiodarone" OR "candesartan" OR "tizanidine" OR "simvastatin" OR "pregabalin" OR "aliskiren" OR "olmesartan medoxomil and diuretics" OR "bezafibrate" OR "lovastatin" OR "telmisartan" OR "ciprofloxacin" OR "colchicine" OR "febuxostat" OR "fenofibrate" OR "tolvaptan" OR "theophylline" OR "benzylpenicillin" OR "oxycodone" OR "risperidone" OR "sulfamethoxazole" OR "pravastatin" OR "cefdinir" OR "gemfibrozil" OR "daptomycin" OR "indapamide" OR "temazepam" OR "fluvastatin" OR "ciclosporin" OR "sunitinib" OR "efavirenz" OR "citalopram" OR "sulfasalazine" OR "escitalopram" OR "bupropion" OR "nicotinic acid" OR "pramipexole" OR "lamivudine" OR "aripiprazole" OR "levofloxacin" OR "clarithromycin" OR "terbinafine" OR "cytarabine" OR "venlafaxine" OR "fusidic acid" OR "olanzapine" OR "quetiapine" OR "tenofovir disoproxil" OR "propofol").

Exclude: none.

Discussion

In this study, among the rhabdomyolysis reports for DPP4is, the most commonly represented co-exposed drugs are 3-hydroxy-3- methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and Angiotensin II receptor blockers (ARBs), related to abnormal cholesterol and hypertension. With a comparison of rhabdomyolysis rates for DPP4is use with and without moderator drugs, there was no evidence of drug-drug interaction between DPP4is and moderators. This finding is in line with a previous analysis of French Base Nationale de Pharmacovigilance (BNPV) and VigiBase, which suggested that no interaction between DPP4is and statins was found [16]. According to pharmacokinetics characteristics, DPP4is, except saxagliptin, generally do not interfere with cytochrome P450 (CYP) and do not act as inducers or inhibitors of CYP system, suggest that they are not exposed to a high risk of drug–drug interactions [17].

Within the FAERS, DPP4is were disproportionally reported in association with rhabdomyolysis, with a PRR of 2.49 (95%CI 2.08- 2.98), but it was small to be considered robust. According to Huerta- Alardín [18], any drug that impairs the production or use of ATP by skeletal muscle, or increases energy requirements that exceed the rate of ATP production can cause rhabdomyolysis. However, no studies suggested such association at present. In subanalysis, it should be noted that alogliptin has a much higher PRR than other gliptins. As alogliptin was later approved by FDA than sitagliptin (Jan 2013 vs Oct 2006), we recomputed the PRR using data from 2010q2 to 2017q3 (alogliptin was first approved in Japan in April 2010) [19] to exclude potential inflation of PRR (ESM Table 3). The result (PRR: 15.37, 95%CI 8.75-26.99) indicated a solid internal validation for association between alogliptin and rhabdomyolysis. Several literature review [20,21] said alogliptin has no demonstrable advantages over other agents and the side effect profile also does not differ from that of other DPP4is, but according to a comparative study of the binding properties of DPP4is [22], the DPP-4 binding pocket is a large cavity characterized by a certain degree of flexibility, although each of the inhibitors occupy the S1 and S2 sites of the enzymatic cleft, with other areas of the binding site, they showed somewhat different interactions. More dedicated studies are needed to figure out the reason for the difference between alogliptin and other gliptins on rhabdomyolysis.

ESM Table 3: The proportional reporting ratios of rhabdomyolysis associated with alogliptin, based on FAERS data from 2010q2 to 2017q3.

Together with the differences of rhabdomyolysis rates among each DDP4i, these data also showed age imbalance, for PRRs in elderly people were higher than that in working age population in male, female and both. This may partly contribute to the characteristics of DPP4is users because the prevalence of T2DM increases markedly with age. On the other hand, analysis based on all rhabdomyolysis AE reports regardless of drugs in FAERS indicated the same trend that the proportion of rhabdomyolysis in elderly people was higher than that in working age people (9,482/1,994,426 vs 13,215/3,884,455). It demonstrated DPP4is associated rhabdomyolysis shared the same characteristics with drug associated rhabdomyolysis (especially statins-induced rhabdomyolysis) on patients’ age [23].

This study has several limitations due to the nature of FAERS data. FDA does not require that a causal relationship between a drug and adverse event be proven, the information in these reports reflects only the reporter's observations and opinions and Submission of a report does not mean that the information included in it has been medically confirmed. Furthermore, FAERS lacks the denominators- the number of patients using the drug. Third, FDA does not receive reports for every adverse event that occurs with a drug because many factors can influence whether an event will be reported, such as the time a product has been marketed and publicity about an event by FDA alerts. Therefore, FAERS data cannot be used to calculate the incidence of an adverse event and make casual inference.

Conclusion

In summary, the analysis indicated that use of DPP4is may be associated with an increased risk of rhabdomyolysis, especially alogliptin. Although causal inference can’t be done and further investigation is warranted, our study is important from a safety prospective and helpful for clinicians to pay attention on the risk of DPP4is-associated rhabdomyolysis.

Acknowledgments

The authors would like to thank Mayur Sarangdhar (Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA) for developing AERSmine.

Sources of Funding

This study was supported by Women's and Children's Health Research Project from Jiangsu Commission of Health (F201867); Project from Department of Science and Technology of Jiangsu Province (BM2018033-2); Young Medical Talent Project from Jiangsu Commission of Health (QNRC2016555); Key Discipline Project on Women's and Children's Health from Jiangsu Commission of Health (FXK201755)

Conflict of Interest

None to report.

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