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Journal of General Internal Medicine

, Volume 32, Issue 10, pp 1156–1159 | Cite as

Rhabdomyolysis and AKI with Atorvastatin and Sitagliptin Use in the Setting of Low 25-Hydroxyvitamin D Levels

  • Rupinder Singh Buttar
  • Jasveen Batra
  • Jacqueline Kreimerman
  • Melissa Aleta
  • Michal L. Melamed
Clinical Practice: Clinical Vignettes

Abstract

We report a case of an 86-year-old woman admitted to the hospital with rhabdomyolysis and acute kidney injury 3 weeks after starting sitagliptin while on long-term atorvastatin therapy. She also had low levels of 25-hydroxyvitamin D and mild chronic kidney disease, which may have contributed to the development of rhabdomyolysis. A review of the literature reveals four previous reports of this drug interaction in elderly patients, some with underlying kidney disease.

KEY WORDS

sitagliptin statins vitamin D rhabdomyolysis drug interaction acute kidney injury 

CASE

An 86-year-old Hispanic woman presented to the emergency department with a chief complaint of generalized weakness and muscle pains for 2 weeks. She also complained of nausea, vomiting, diarrhea, yellow skin, dark-colored urine, and light stools. The patient reported that her generalized weakness and other symptoms developed 1 week after starting sitagliptin and progressively worsened. Her past medical history included type 2 diabetes mellitus (DM), hypertension, hyperlipidemia, and stage 3 chronic kidney disease (CKD). Her medications on admission included aspirin 81 mg daily, atorvastatin 20 mg daily, sitagliptin 100 mg daily, glipizide 10 mg daily, and metformin 500 mg twice daily (BID). The sitagliptin was started 3 weeks prior to presentation.

Her vital signs were remarkable for a temperature of 99.2 °F (37 °C) and blood pressure of 154/65 mmHg. Otherwise, vitals were in the normal ranges. Her examination was notable for tenderness in the arms and legs, jaundice, and scleral icterus. She did not have any abdominal tenderness or hepatosplenomegaly. Her lab values at the time of admission are shown in Table 1 and are notable for elevated creatinine (4.44 mg/dL), creatine phosphokinase (CPK) 13,636 U/L, alkaline phosphatase (859 U/L) and bilirubin (8.3 mg/dL). Her 25-hydroxyvitamin D (25(OH)D) was low at 13.7 ng/mL (normal range: 30–100 ng/mL). She was admitted to the hospital, and her oral antidiabetic agents and atorvastatin were stopped. She was started on intravenous isotonic sodium bicarbonate along with insulin for glycemic control.
Table 1

Lab Values at Admission and Discharge

Lab test

Admission

Discharge

Sodium (meq/L)

139

138

Potassium (meq/L)

3.6

3.2

Chloride (meq/L)

101

97

Bicarbonate (meq/L)

17

18

Creatinine (mg/dL)

4.44

2.03

BUN (mg/dL)

65

22

CPK (U/L)

13,636

609

Alkaline phosphatase (U/L)

859

574

Bilirubin (mg/dL)

8.3

3.7

SGOT (U/L)

721

182

SGPT (U/L)

261

262

Magnesium (mg/dL)

1.9

1.9

Calcium (mg/dL)

8.9

8.7

Phosphorus (mg/dL)

3.6

3.7

Amylase (U/L)

180

188

Lipase (U/L)

289

132

INR

1.8

1.1

PT (s)

18.2

 

PTT (s)

38.7

 

25(OH)D (ng/mL)

13.7

27.1 (2 months after discharge)

BUN blood urea nitrogen, CPK Creatine Phosphokinase, SGOT serum glutamicoxaloacetic transaminase, SGPT serum glutamic-pyruvic transaminase, INR international normalized ratio, PT prothrombin time, s seconds, PTT partial thromboplastin time, 25(OH)D 25-hydroxyvitamin D

The patient underwent several diagnostic procedures for evaluation of her muscle weakness and abnormal laboratory findings. Hepatic imaging showed no relevant findings on right-upper-quadrant ultrasound and magnetic resonance cholangiopancreatography (MRCP). Hepatitis A, B, and C serology test results were negative. Her acetaminophen levels were within normal range. She underwent a workup for possible causes of rhabdomyolysis including an autoimmune panel that was negative for antinuclear and anti-smooth muscle antibodies. Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) tests were negative. Thyroid-stimulating hormone (TSH) and free T4 test results were normal.

She was continued on intravenous hydration and monitored. The CPK continued to rise, peaking at 49,875 U/L before trending down to 609 U/L at the time of discharge on hospital day 16. The patient reported a significant improvement in her symptoms of muscle weakness and pain. Although her kidney function continued to improve over time, it never returned to baseline. She was discharged to a rehabilitation center, with Levemir for glycemic control along with sodium bicarbonate 650 mg BID and aspirin 81 mg once daily. She was not discharged on oral antidiabetic agents, vitamin D, or statins. One week later her creatinine was 1.73 mg/dL, which trended down to 1.30 mg/dL 5 months later and finally to 1.10 mg/dL. The level of 25 (OH)D measured 2 months after discharge was 27.1 ng/mL. She was restarted on atorvastatin 20 mg with no recurrence. Sitagliptin is now listed as an allergy in the medical record.

DISCUSSION

Here we report the case of an 86-year-old woman with stage 3 CKD who developed severe rhabdomyolysis and acute kidney injury (AKI) in the setting of a recent addition of sitagliptin to her chronic atorvastatin use. We believe that the interaction between these two medications caused the rhabdomyolysis. Possible contributors to the rhabdomyolysis were her CKD and low 25(OH)D levels. A literature review showed four previously reported cases of rhabdomyolysis in the setting of the use of sitagliptin and a statin (Table 2). All of the cases were in patients 75 years of age or older, some with underlying CKD. All had recently been started (6 months or less) on sitagliptin.
Table 2

Case Reports of Rhabdomyolysis from Combining Sitagliptin and Statin Therapies

Case report

Medications

Duration of statin use

Duration of sitagliptin use

Patient baseline characteristics

Medical history

Peak CPK levels

Baseline kidney function

Bhome and Penn 20121

Atorvastatin + sitagliptin

5 years

6 months

75, male, white

Type 2 DM, HTN, dyslipidemia,

10,9710

Normal

Kao et al. 20082

Simvastatin 80 mg + sitagliptin 100 mg

4 months

3 weeks

76, male

Type 2 DM, dyslipidemia, CAD, AFib

22,000

Baseline CKD with baseline creatinine 2.3 mg/dL

DiGregorio and Pasikhova 20093

Lovastatin 40 mg + sitagliptin 100 mg

12 years

19 days

75, female, white

Type 2 DM, HTN, dyslipidemia

N/A

N/A

Campos-Davila et al. 20144

Atorvastatin 80 mg + sitagliptin

N/A

N/A

80, male

Type 2 DM, HTN, dyslipidemia, MI, recent stroke

1253

N/A

Current case report

Atorvastatin 20 mg, sitagliptin 100 mg

1 year

3 weeks

86, female, Hispanic

Type 2 DM, HTN, osteoporosis, hypomagnesaemia, dyslipidemia

49,875

Baseline CKD stage 3 (eGFR 50–60)

HTN hypertension, CAD coronary artery disease, AFib atrial fibrillation, DM diabetes mellitus, MI myocardial infarction, CKD chronic kidney disease, CPK creatine phosphokinase, N/A not available

Sitagliptin, an oral antihyperglycemic agent approved by the U.S. Food and Drug Administration (FDA) in 2006, is used for controlling blood sugars in patients with type 2 DM. It belongs to a class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors, which act by inhibiting the inactivation of GLP-1 and GIP by the DPP-4 enzyme. Increased levels of GLP-1 and GIP stimulate the glucose-dependent release of insulin and suppress glucagon secretion. This leads to lower glucose levels without the risk of inducing hypoglycemia and weight change, making it a safer alternative to sulfonylureas.5 Side effects commonly seen with sitagliptin include runny nose, sore throat, headache, back pain, joint or muscle pain, nausea, abdominal pain, diarrhea, constipation, and pancreatitis. Sitagliptin, like most DPP-4 inhibitors, is excreted by the kidney, requiring appropriate dose adjustments in patients with reduced kidney function.6 Low 25-hydroxyvitamin D [25(OH)D] levels have been independently associated with varying degrees of muscle-related adverse events such as myopathy and myalgias. There have also been case reports and cross-sectional studies linking an increased risk of statin-induced myopathy with low 25(OH)D.7 , 8

Sitagliptin is mostly (80%) excreted via the kidneys, and dose adjustments are recommended for patients with CKD.9 Statins, on the other hand, are mainly metabolized by hepatic cytochrome CYP450 enzymes, although they are also excreted by the kidney. Various mechanisms have been proposed for the interaction between the two medications, ranging from the effects of sitagliptin on renal excretion of statins to interaction at the level of hepatic metabolism.1 4

One case report of simvastatin-induced rhabdomyolysis in the presence of sitagliptin proposed that the nephrotoxicity of sitagliptin led to reduced renal excretion of simvastatin.2 This was based on a study showing that sitagliptin caused renal tubular necrosis and loss of renal parenchyma in rats.10 The case report noted that the serum concentration and terminal half-life of sitagliptin can be increased in kidney disease, possibly leading to increased serum concentration of the statin, and subsequently to dose-related muscle breakdown in the patient.

However, a clinical trial studying the effects of sitagliptin on the pharmacokinetics of simvastatin in 12 healthy human subjects 18–45 years of age, both men and women, showed no effect on the metabolism of simvastatin.11 The authors recommended no dose adjustment when simvastatin was co-administered with sitagliptin. Similarly, another study in 10 patients found no effects of simvastatin use on the pharmacokinetics of sitagliptin, and no dose adjustment was recommended for either drug.12

In one case report of rhabdomyolysis induced by lovastatin and sitagliptin, the authors suggested an interaction between the statin and sitagliptin at the level of CYP3A4 as the cause. They posited that because both are metabolized by CYP3A4, when co-administered, they may compete for the same enzyme, resulting in increased serum concentration of the statin, leading to statin-induced rhabdomyolysis.3 Two other case reports of rhabdomyolysis with atorvastatin and sitagliptin had similar suggestions, indicating that sitagliptin leads to increased serum concentration of atorvastatin through its effects on hepatic metabolism by CYP3A4 rather than on renal excretion.1 , 2 , 4 A comprehensive review of the literature suggests that atorvastatin and sitagliptin are not prone to pharmacokinetic drug–drug interactions, either separately or in a fixed-drug combination.13

Statins reported thus far to induce rhabdomyolysis in interaction with sitagliptin are lovastatin, atorvastatin, and simvastatin. These are all metabolized by hepatic CYP3A4. The link to cytochrome metabolism is further supported by the lack of any reported rhabdomyolysis14 caused by interaction of sitagliptin with statins that are not significantly metabolized by CYP3A4, such as pravastatin, rosuvastatin, pitavastatin, and fluvastatin.14

The other factor considered to contribute to the patient’s rhabdomyolysis was her low level of 25(OH)D. This was not fully investigated in previous case reports of sitagliptin and statins (Table 2). The 25(OH)D levels, which were likely chronically low, were probably a contributing factor to the rhabdomyolysis, but the sitagliptin was the direct precipitating factor.

Low levels of 25(OH)D have been associated with varying degrees of myopathy independently as well as with an increased risk of statin-induced myopathy.15 Various possible mechanisms have been proposed for this interaction between 25(OH)D and statins, as 25(OH)D affects the muscle at both genomic and non-genomic levels. It plays an important role in muscle cell differentiation and proliferation through modulation of transcription factors, and is essential for maintaining contractility and myogenesis via the transport of calcium into the sarcoplasmic reticulum.16 18 This suggests a possible mechanism via increased predisposition to statin-induced myopathy because of decreased transcription of proteins required to maintain the structure and functioning of myocytes and sarcolemma.

The binding of the 1,25-dihydroxyvitamin D to the vitamin D receptors (VDRs) found in the small intestinal mucosa, kidney, and certain specialized cells in the liver (including Kupffer, stellate, and endothelial cells) has been suggested as a pathway for enhancing the transcription of CYP3A4.19 This introduces the idea that the catabolism of 25(OH)D can lead to increased levels of the CYP3A4 enzyme. Vitamin D and its hydroxylated compounds are also known to induce CYP450, CYP2C9, and CYP2B6.20 This could explain statin-induced myopathy in patients with reduced vitamin D levels, where insufficient CYP activity may lead to decreased metabolism of the statin and increased toxicity.21 These findings may be further corroborated by studies evaluating statin reintroduction after 25(OH)D supplementation in patients with low 25(OH)D levels who were statin-intolerant because of muscle-related adverse events. A study showed that of 146 patients with statin intolerance due to myopathy or myonecrosis, 131 (88%) patients showed reversal of the intolerance with supplementation of vitamin D.8 A proposed marker of vitamin D levels <20 ng/mL has been introduced as a predictor of muscular adverse events during statin treatment.7 As discussed previously, most of the reported cases of statin-induced rhabdomyolysis have been associated with statins metabolized by CYP enzymes, substantiating the role of cytochrome metabolism.

CONCLUSION

The co-prescription of statins and sitagliptin is becoming common in patients with type 2 DM and hyperlipidemia. Our patient had been taking atorvastatin for a year, and her symptoms began 1 week after starting sitagliptin. This is the fifth report of rhabdomyolysis caused by the interaction of a statin with sitagliptin. Previous case reports, however, did not look at the role of vitamin D within the statin–sitagliptin interaction. We suggest that clinicians remain vigilant when using these medications in combination, especially in older patients with underlying CKD. Further studies are needed to confirm the associations between sitagliptin, statins, low 25(OH)D levels, and rhabdomyolysis.

Notes

Acknowledgements

Dr. Melamed is supported by grants R01 DK102952 and R34 DK102174 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. A previous version was presented as a poster at the National Kidney Conference in Boston in 2016.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they do not have a conflict of interest.

References

  1. 1.
    Bhome R, Penn H. Rhabdomyolysis precipitated by a sitagliptin-atorvastatin drug interaction. Diabet Med. 2012;29(5):693–694.CrossRefPubMedGoogle Scholar
  2. 2.
    Kao DP, Kohrt HE, Kugler J. Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use. Diabet Med. 2008;25(10):1229–30.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    DiGregorio RV, Pasikhova Y. Rhabdomyolysis caused by a potential sitagliptin-lovastatin interaction. Pharmacotherapy. 2009;29(3):352–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Campos-Davila E, Puerto-Alonso J, Perez-Vazquez G, Ramos-Baez J, Marquez-Fernandez E, Guerra-Estevez D. PS-006 Rhabdomyolysis possiblz provoked by a sitagliptin-atorvastatin interaction. Eur J Hosp Pharm: Sci Pract. 2014;21(Suppl 1):A145–6.Google Scholar
  5. 5.
    Arechavaleta R, Seck T, Chen Y, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011;13(2):160–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Plosker GL. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74(2):223–42.CrossRefPubMedGoogle Scholar
  7. 7.
    Ovesjo ML, Skilving I, Bergman P, Rane A, Ekstrom L, Bjorkhem-Bergman L. Low vitamin D levels and genetic polymorphism in the vitamin D receptor are associated with increased risk of statin-induced myopathy. Basic Clin Pharmacol Toxicol. 2016;118(3):214–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Khayznikov M, Hemachrandra K, Pandit R, Kumar A, Wang P, Glueck CJ. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci. 2015;7(3):86–93.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007;30(7):1862–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Pharmacology/ToxicologyReviewandEvaluation-NDA21–995.2006; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_PharmR.pdf. Accessed 30 May 2017.
  11. 11.
    Bergman AJ, Cote J, Maes A, et al. Effect of sitagliptin on the pharmacokinetics of simvastatin. J Clin Pharmacol. 2009;49(4):483–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Cerra M, Luo WL, Li SX, et al. The effects of simvastatin on the pharmacokinectics of sitagliptin. J Popul Ther Clin Pharmacol. 2012;19(3):e356–60.PubMedGoogle Scholar
  13. 13.
    Scheen AJ. Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2012;8(6):745–58.CrossRefPubMedGoogle Scholar
  14. 14.
    Alagona P, Jr. Pitavastatin: evidence for its place in treatment of hypercholesterolemia. Core Evid. 2010;5:91–105.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lee P, Greenfield JR, Campbell LV. Vitamin D insufficiency—a novel mechanism of statin-induced myalgia? Clin Endocrinol. 2009;71(1):154–5.CrossRefGoogle Scholar
  16. 16.
    De Boland AR, Boland RL. Non-genomic signal transduction pathway of vitamin D in muscle. Cell Signal. 1994;6(7):717–24.CrossRefPubMedGoogle Scholar
  17. 17.
    Ceglia L, Harris SS. Vitamin D and its role in skeletal muscle. Calcif Tissue Int. 2013;92(2):151–162.CrossRefPubMedGoogle Scholar
  18. 18.
    Pleasure D, Wyszynski B, Sumner A, et al. Skeletal muscle calcium metabolism and contractile force in vitamin D-deficient chicks. J Clin Investig. 1979;64(5):1157–67.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang Z, Schuetz EG, Xu Y, Thummel KE. Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol. 2013;136:54–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Drocourt L, Ourlin JC, Pascussi JM, Maurel P, Vilarem MJ. Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. J Biol Chem. 2002;277(28):25125–32.CrossRefPubMedGoogle Scholar
  21. 21.
    Bhattacharyya S, Bhattacharyya K, Maitra A. Possible mechanisms of interaction between statins and vitamin D. QJM: Mon J Assoc Phys. 2012;105(5):487–491.CrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2017

Authors and Affiliations

  • Rupinder Singh Buttar
    • 1
  • Jasveen Batra
    • 1
  • Jacqueline Kreimerman
    • 1
  • Melissa Aleta
    • 1
  • Michal L. Melamed
    • 1
  1. 1.Department of Medicine/NephrologyAlbert Einstein College of Medicine/Montefiore Medical CenterBronxUSA

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