Treatment Challenges of Comorbid Rheumatic Disease and Diabetes

Immune modulators are the foundation of treatment in various rheumatologic diseases.¹ These medications have proven to be effective for these conditions by altering the immune system, however, they have also been found to produce a variety of endocrine effects in patients as well. These effects include improving pancreatic function and altering erythrocyte survival in both diabetic and non-diabetic patients. Because of this, it is important for providers to consider the properties of a particular immune modulator when prescribing treatment as they can greatly affect a patient’s disease management.

Research has shown that rheumatologic disease and diabetes frequently go hand-in-hand.¹ It has been found that in patients with type 1 diabetes, there is an increased risk in the development of rheumatoid arthritis. Additionally, patients with rheumatologic disease have increased rates of type 2 diabetes, cardiovascular risk factors, and cardiovascular mortality. Due to their ability to affect both rheumatologic disease as well as diabetes, it is particularly important for providers to know and understand the implications of use of immune-modulating agents in their patients.

A recent analysis by Pilla et al summarized the various effects immune modulators have on diabetic patients.¹ The authors reviewed several studies analyzing the effects these agents have on type 1 and 2 diabetic patients as well as the effects of these agents on the prevention of diabetes. Several important conclusions were obtained regarding the effects of these agents on patients with type 2 diabetes (Table 1).

Researchers also found that, despite obtaining many important results, many of the immune-modulating agents analyzed did not have any studies completed in patients with type 2 diabetes. Several medications did not have any associated studies in this patient population (Table 2).

In their review, Pilla et al described several studies that demonstrated the antihyperglycemic effect of hydroxychloroquine in patients with type 2 diabetes.¹ This antimalarial agent is used first-line for rheumatoid arthritis and systemic lupus erythematosus and is thought to produce its glycemic effect by causing intracellular insulin metabolism changes in peripheral tissues. One randomized controlled trial found that, after 18 months, there was a 1.02% reduction in a patient’s HbA1c measurement when hydroxychloroquine was added to their sulfonylurea therapy (95% confidence interval [CI] 0.24%, 1.81%). 

Another study found that addition of hydroxychloroquine to insulin therapy significantly reduced a patient’s HbA1c value versus placebo after 6 months. A small retrospective cohort study also discussed in this review found that, compared to methotrexate, hydroxychloroquine had a greater HbA1c reduction from baseline to the lowest value obtained within 12 months of therapy. Hydroxychloroquine also demonstrated its glycemic effect in a non-inferiority trial, which found it to have comparable antihyperglycemic efficacy to pioglitazone.  

Pilla et al also discussed several important factors that should be considered for patients with rheumatologic disease.¹ First, immune-modulating agents that possess antihyperglycemic properties should be utilized in rheumatologic patients with type 2 diabetes or type 2 diabetes risk factors. As seen by the results of various studies discussed in this review, hydroxychloroquine is the preferred agent in patients with difficult to control hyperglycemia who require immune-modulating therapy. In addition, based on the evidence of several cohort studies, hydroxychloroquine or a tumor necrosis factor (TNF)-inhibitor may be considered in patients at risk of developing type 2 diabetes.

Another important aspect in the management of a patient with a rheumatologic condition is the appropriate monitoring of that patient after initiation of an immune-modulating agent. Although the glycemic effect of immune modulators is not always immediate, it is important for a patient to be informed of the risk of hypoglycemia as well as the symptoms that may occur prior to the initiation of therapy. The authors also stated that collaboration with the patient, as well as their full care team, is crucial for successful disease management.

Immune modulators are effective medications used in the treatment of several rheumatologic conditions. Many of these agents also produce endocrine effects in patients, which are important for providers to know about and thoroughly understand. Although several studies have been completed, additional analyses regarding the effects of these medications on diabetes and cardiovascular outcomes are needed in the future.

      Table 1. Effects of Immune-Modulating Agents on Patients with Type 2 Diabetes

Medication	Use	Evidence
Colchicine	Gout prophylaxis and treatment	Placebo-controlled crossover study (12 patients): significantly lower glucose level measured by oral glucose tolerance test in patients taking colchicine Large retrospective cohort study: colchicine did not cause a significantly lower diabetes incidence
Dapsone	Off-label for complications of lupus and vasculitides	Can falsely lower HbA1c measurements Diabetic patients should be monitored with fructosamine or glycated albumin after initiation of medication Screen for type 2 diabetes using fasting serum glucose (2 occasions) or a 2-hour oral glucose tolerance test
Glucocorticoids	Widely used for their anti-inflammatory and immunosuppressive properties	Produces hyperglycemia Can cause new-onset diabetes in non-diabetic patients
Hydroxychloroquine	RA, SLE, and off-label for a variety of other conditions	Case reports: caused hypoglycemia in non-diabetic patients Demonstrated antihyperglycemic effects in patients with type 2 diabetes in various studies RCT: reduction of HbA1c by 1.02% (95% CI 1.24%, 1.81%) when added to sulfonylurea therapy (duration: 18 months) Significantly reduced HbA1c compared to placebo when added to insulin therapy (duration: 6 months) Non-inferiority trial: similar antihyperglycemic efficacy compared to pioglitazone Small retrospective cohort study: greater reduction in HbA1c from baseline to lowest value within 12 months of therapy compared to methotrexate Four large cohort studies: prevented incident diabetes in adults with rheumatologic disease (most likely type 2 diabetic patients based on participant age)
Methotrexate	RA, JIA, and off-label for a variety of other conditions	Very little evidence regarding effect on diabetes; evidence found suggests there are no significant effects
Sulfasalazine	Mild-moderate RA and JIA, and off-label for a variety of other conditions	Can falsely lower HbA1c measurements Diabetic patients should be monitored with fructosamine or glycated albumin after initiation of medication Screen for type 2 diabetes using fasting serum glucose (2 occasions) or a 2-hour oral glucose treatment test
Tumor Necrosis Factor Inhibitors	RA, psoriatic arthritis, ankylosing spondylitis, JIA, and off-label for a variety of other conditions	Evidence suggests improvement in glycemic control Retrospective study with 8 patients treated with etanercept or infliximab: lower fasting glucose after treatment with TNF inhibitors compared to other treatment Case reports of patients treated with etanercept and adalimumab: improved glycemic control and/or hypoglycemic episodes Case report of 1 patient treated with infliximab: able to discontinue insulin therapy during infliximab treatment; required insulin therapy once infliximab was discontinued Large retrospective cohort study: decrease in the risk of incident diabetes in rheumatologic patients (most likely type 2 diabetes patients based on participant age)
Anakinra	RA	Antihyperglycemic effects in type 2 diabetic patients RCT of overweight adults with type 2 diabetes: 0.46% reduction in HbA1c in patients taking anakinra versus placebo after 13 weeks (95% CI 0.01%, 0.90%) Case series (2 patients): improved glycemic control when taking anakinra

IL= interleukin; JIA = juvenile idiopathic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; RCT = randomized controlled trial; TNF = tumor necrosis factor.

      Table 2. Immune Modulators With No Completed Studies in Type 2 Diabetes

This article originally appeared on MPR