Background: Parenterally administered steroids have been shown to affect the metabolism of glucose and to cause abnormal blood glucose levels in diabetic patients. These abnormal blood glucose levels in diabetic patients raise concerns that intra-articular steroid injections also may affect blood glucose levels. We performed a systematic review of studies examining the effect of intra-articular steroid injections on blood glucose levels in patients with diabetes mellitus.
Methods: A literature search of the PubMed, EMBASE, AMED, and CINAHL databases using all relevant keywords and phrases revealed 532 manuscripts. After the application of inclusion criteria, seven studies with a total of seventy-two patients were analyzed.
Results: All studies showed a rise in blood glucose levels following intra-articular steroid injection. Four of the seven studies showed a substantial increase in blood glucose. Peak values reached as high as 500 mg/dL. The peak increase in blood glucose did not occur immediately following intra-articular steroid injection, and in some cases it took several days to occur. In many patients, post-injection hyperglycemia occurred within twenty-four to seventy-two hours.
Conclusion: Intra-articular steroid injections may cause hyperglycemia in patients with diabetes mellitus, and patients should be warned of this complication. Diabetic patients should be advised to regularly monitor their blood glucose levels for up to a week after injection and should seek medical advice if safe thresholds are breached.
Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Intra-articular steroid injections are widely used for the symptomatic control of degenerative and inflammatory joint arthritis. The benefits of steroids are due to their anti-inflammatory effects. Locally injected steroids have been shown to be absorbed into the systemic circulation1. The plasma steroid levels can vary up to five times from one patient to another following injection into the knee joint2. Derendorf et al.3 showed complete absorption of triamcinolone acetonide and triamcinolone hexacetonide from the knee joint over a period of two to three weeks after intra-articular injection.
Diabetes mellitus affects about 9.3% of the general population in the United States, and nearly 50% of adults with diabetes have diagnosed arthritis4,5. The exact proportion of patients with symptomatic degenerative or inflammatory joint arthropathy who have diabetes is unknown. However, it has been estimated that a substantial proportion of such patients has diabetes. In a recent study, patients with Type-2 diabetes had higher rates of total joint (knee or hip) arthroplasty and revision arthroplasty compared with an age-matched nondiabetic cohort6.
Parentally administered steroids affect glucose metabolism and can cause abnormal blood glucose levels in patients with diabetes1. These abnormal blood glucose levels in diabetic patients are often a major concern among both patients and clinicians administering intra-articular steroid injections. Wide variations in techniques and outcomes of steroid injections have been shown previously7,8.
Understanding the effects of intra-articular steroid injections on blood glucose levels would be very important when counseling patients with regard to post-injection care. Therefore, we performed a systematic review of studies examining the effect of intra-articular steroid injections on blood glucose levels in patients with diabetes.
Materials and Methods
A search of the PubMed, EMBASE, AMED, and CINAHL databases was conducted with use of a combination of the following keywords: “steroid,” “diabetes,” “injection,” “joint,” and “articular.” There was no limit of language. “All Fields” (i.e., title, abstract, text) were utilized when searching for these keywords. The search was conducted in October 2014. The titles and abstracts of all resultant search articles were screened. All prospective and retrospective studies investigating the effect of intra-articular steroid injections on blood sugar levels in patients with diabetes were eligible for inclusion. Literature reviews (other than systematic reviews or meta-analyses), technical notes, and single case reports were excluded. The full text was reviewed for possibly relevant articles or when a decision regarding inclusion or exclusion could not be made on the basis of the title and/or abstract alone. The reference lists of all selected articles were also examined for any additional articles that were not identified through the database search.
Each article was critically appraised, and data were extracted with use of a standardized pro forma document to produce a qualitative summary of the literature. This summary included information on the design and demographic characteristics of the patients in each selected study, including authors, types of diabetes and diabetic treatments, pre-injection HbA1c levels, age, site of injection, method of monitoring blood glucose, and duration of monitoring. The outcomes data included the type and dose of steroid injections, the timing of injection, the time and level of significant increase in blood glucose after injection, the time to return to baseline glucose levels, and the definition of significant increase in each relevant study. The mean blood glucose level was calculated when raw values were provided in the studies. This screening process was performed by one of the authors.
The literature search identified 532 citations. On the basis of a review of the abstracts, 512 studies were excluded for nonrelevance. A total of twenty abstracts were identified. Removal of duplicates left eleven articles. Review of the full text of these articles led to the exclusion of three articles that did not meet the inclusion criteria. Another study was excluded9 because it investigated the effect of both epidural and shoulder steroid injections and did not differentiate the effect of shoulder injections from the effect of epidural injections on blood glucose levels. The authors of that study were contacted by e-mail three times with a request to provide additional information about their results, but no response was obtained. Seven prospective studies with a total of seventy-two patients were thus used for analysis (Fig. 1). The demographic characteristics of the patients and the methodology of the included studies are shown in Table I.
All included studies recruited patients with well-controlled diabetes and requested them to continue the same regimen of physical activity, diet, or anti-diabetic treatment for the duration of the study (see Table I for HbA1c values). None of the studies indicated any post-injection glycemic complications. Four studies2,10-12 included statistical analysis of pre-injection and post-injection glucose levels. The remaining three studies13-15 defined a substantial post-injection increase in blood glucose as an increase of more than two standard deviations from the baseline mean values. Blood glucose levels were reported in mg/dL in all studies except for one2, in which it was reported in mmol/L. For the purposes of the present systematic review, values in mmol/L were converted into mg/dL by multiplying by 18 as previously recommended16.
All studies showed an increase in blood glucose level following intra-articular steroid injection. Uboldi et al.11 reported a peak increase of blood glucose level of 70% as compared with the pre-injection level, but this difference was not significant. Habib and Abu-Ahmad10 reported no significant increase in blood glucose except on Day 7 after lunch and on Day 1 after supper, when post-injection glucose levels were significantly higher than baseline values. Zufferey et al.2 reported a mean peak of 247.5 mg/dL at forty-eight hours as compared with a mean pre-injection peak of 200.7 mg/dL.
Four studies12-15 showed substantially higher blood glucose levels after injection as compared with before injection (baseline). These four studies demonstrated that the timing of the peak increase following intra-articular injection was highly variable (Table II). However, the increase did not occur immediately following the injection. Indeed, in one study14, the earliest mean time to peak increase following injection was 13.7 hours. In another study15, the median time to peak increase was 32.5 hours. Moon et al.12 monitored fasting blood glucose rather than random blood glucose and reported a significantly higher mean fasting blood glucose (135.8 mg/dL) compared with the baseline mean value (122.3 mg/dL) one day after injection (p < 0.05). Habib et al.13 demonstrated that, after intra-articular steroid injection, the peak values can reach as high as 500 mg/dL. The time to return of blood glucose levels to the baseline values varied between studies, ranging from twenty-four hours in one study11 to twenty-one days in another12.
The present study showed that hyperglycemia can occur following an intra-articular steroid injection, with peak values reaching as high as 500 mg/dL13. The present study also showed that the peak increase in blood glucose does not occur immediately following intra-articular steroid injection but may take several hours or days to occur. In many patients a substantial post-injection hyperglycemia occurred within twenty-four to seventy-two hours, but in other patients it occurred later. In one study13, peak values occurred between five and eighty-four hours post-injection, whereas in another study10, the peak increase was observed at seven days. It is of note that the patients in the included clinical studies were asked to continue with their normal diabetic regimen for the duration of the study; hence, the observed changes reflect the metabolic effect of the steroid injection per se.
The present systematic review had certain limitations. The analyzed studies were heterogeneous with regard to patient characteristics, diabetes treatment regimens, the types of joints injected, the doses and formulations of steroid, the timing of blood glucose measurements, and the definition of significant post-injection hyperglycemia. In addition, the included studies did not specifically assess complications related to hyperglycemia following intra-articular injection, information that is clinically important. The exact type of diabetes that patients had was not stated in some studies. Furthermore, the included patients were described as having good overall glycemic control, which may limit the extent to which the observed results can be applied to patients with poor glycemic control. However, it is possible that the adverse effect of intra-articular steroid injection in patients with poorly controlled diabetes may be greater; hence, the results of the present study may be an underestimation rather than overestimation of the glycemic effects of intra-articular steroid injections.
The heterogeneity among these studies is possibly the main reason behind the large differences that were observed in terms of the absolute increase and rate of increase in blood glucose levels. Similarly, we are unable to associate the variation among these studies in terms of blood glucose levels with the type of steroid injection or its dose.
Nevertheless, despite its limitations, the present systematic review demonstrated that hyperglycemia can occur following an intra-articular steroid injection, even though additional research is needed to characterize the increase in different subgroups of diabetic patients. The current evidence suggests that patients should be advised to regularly monitor their blood glucose levels following an intra-articular steroid injection. We recommend that patients with Type-1 diabetes should check their blood glucose levels three to four times daily for seven days and should seek advice from a physician at levels of ≥360 mg/dL (≥20 mmol/L) as there is a risk of diabetic ketoacidosis, which has an associated mortality. We recommend that patients with Type-2 diabetes should check blood glucose levels at least twice daily for seven days and should seek advice from a physician at levels of ≥540 mg/dL (≥30 mmol/L). Higher blood glucose is acceptable in patients with Type-2 diabetes as higher levels are needed before potentially life-threatening complications (e.g., hyperglycemic hyperosmolar nonketotic coma) occur. Although patients with Type-2 diabetes may not routinely undertake self-monitoring of blood glucose levels, self-monitoring of blood glucose should be recommended for these patients during intercurrent illness and perioperatively (and hence following intra-articular steroid injection)17.
In conclusion, the present study emphasizes the potential risk of hyperglycemia following intra-articular steroid injections in patients with diabetes and the need for regular monitoring of blood glucose levels after injection. Additional studies to evaluate the effects of intra-articular steroid injections in patients with poorly controlled diabetes and the potentially harmful effects of hyperglycemia following intra-articular injection would be of great value. A more accurate assessment of the acute increase in and variability of blood glucose may be achieved with use of currently available continuous glucose monitoring systems.
Source of Funding: No external funds were received in support of this study.
Investigation performed at the Department of Orthopaedics, Blackpool Victoria Hospital, Blackpool, Lancashire, United Kingdom
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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