Isotretinoin and diabetes: Of familiarity and surprise
By Warren R. Heymann, MD, FAAD
July 6, 2022
Vol. 4, No. 27
On a gloriously sparkling, warm spring afternoon in 2009 I sat with my family in the right field bleachers of the new Yankee Stadium as the Bronx Bombers took on the Phillies. I relished the expansive majesty designed to recreate the glory of the original house that Ruth built. My late father-in-law owned the former G&R Bakery, just footsteps away. Baseball luminaries such as Yogi Berra, Mickey Mantle, and Whitey Ford would frequent the shop for bread and pastries. Naturally, my wife’s family were rabid Yankee fans.
My wife leaned over and whispered, “How does this compare to the original Yankee Stadium?”
“What are you talking about? Haven’t you been to a Yankees game before?” I asked incredulously.
“No,” she responded sheepishly.
“How on earth is that possible? The bakery was across the street, your family lived here when you were little, and you love the Yankees!”
“It never happened, okay?”
(Answering the original question, I thought the architects did a splendid job recreating the ambiance of the erstwhile Stadium while providing the expected modern amenities.)
Since 1982 I have been married to my wife and isotretinoin. Before its availability, only limited options were available for treating severely inflammatory acne, such as dapsone. I am astounded that after approximately 15,000 days there is something new to learn about each.
This commentary was prompted by a case report by Connolly and Walsh detailing the case of a 23-year-old woman, with a history of well-controlled insulin-dependent diabetes mellitus (DM) and nodulocystic acne, whose glucose levels became erratic within 2 weeks of isotretinoin initiation. Her hepatic and lipid studies were normal. Isotretinoin was able to be continued with additional short-acting insulin support. The authors hypothesized that the patient developed an increase in insulin resistance from isotretinoin and advised that patients with insulin-dependent diabetes be counseled about the possibility of poor glycemic control upon isotretinoin administration. (1)
This straightforward case report surprised me — I have been prescribing isotretinoin since its release to a countless number of patients over 4 decades. I cannot recall if any were diabetic (I surmise that there must have been a few). I am confident that I have never advised patients — diabetic or not — to be concerned about their glycemic control. Perhaps this is a function of primarily checking only liver function studies, lipids, pregnancy, creatine kinase (on occasion), and CBC (formerly). As readers are aware, the need for routine monthly laboratory testing (other than pregnancy testing per iPledge) is no longer necessary based on the pioneering work by Lee et al. (2)
What does the isotretinoin package insert state about glucose? Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established.
Such examples include the case of a 28-year-old man whose ultimately insulin-dependent DM first became manifest following the administration of isotretinoin (3) and the development of insulin-dependent DM in a 17-year-old man who had a blood glucose level of 131 mg/dL at the onset of therapy. (4)
Precisely how isotretinoin affects insulin sensitivity is a matter of speculation and controversy because of conflicting data. Adiponectin is an adipocyte-specific protein suggested to play a role in the development of insulin resistance and atherosclerosis. Adiponectin levels are reduced in association with insulin resistance and type 2 diabetes. (5) Insulin resistance may be measured in the homeostasis model assessment for insulin resistance (HOMA-IR). In a study of 29 acne vulgaris (AV) patients with 29 healthy volunteers, isotretinoin had a statistically significant increase in HOMA-IR but not mean adiponectin levels. Including other additional data, the authors suggest that 5 months of isotretinoin therapy in AV patients causes insulin resistance and the increase in insulin resistance is not dependent on age, body mass index, body fat mass, and lipid levels in these patients. (6)
In their study of 48 patients with AV, Ertugrul et al measured insulin resistance before and after 3 months of isotretinoin treatment. There was no significant change in fasting blood glucose levels, insulin, C-peptide, or HOMA-IR. (7) Tsai et al performed a systematic review and meta-analysis regarding insulin resistance and isotretinoin. Pooled analysis showed that HOMA-IR values did not change significantly after isotretinoin treatment whereas the level of adiponectin significantly increased. The authors concluded that isotretinoin treatment for patients with acne resulted in an increased serum level of adiponectin but did not have a substantial impact on the status of insulin resistance. (8)
Will this information alter my approach to managing AV patients for whom I prescribe isotretinoin? Not by much. I will certainly advise diabetic patients to carefully monitor their glucose. I do not intend on getting more laboratory studies than I already do. I also have no intent on warning patients that they could develop diabetes based on just a few case reports over decades of use. It is hard enough already to convince some patients about the benefits of this marvelous drug. On a personal note, this subject reminds me that there is always more to learn no matter how familiar you are with the subject — be it a drug, or your spouse.
Point to Remember: Rarely, isotretinoin may be associated with new onset insulin-dependent diabetes mellitus or worsening of glycemic control in existing diabetic patients.
Our expert’s viewpoint
Joslyn S. Kirby, MD, MeD, MS, FAAD
Associate Professor and Vice Chair of Clinical Education, Dermatology
Penn State University
“One of my patients took isotretinoin and instead of just needing metformin for their diabetes, it got so bad they needed insulin.” This anecdote, published as a case report or exchanged between colleagues at a meeting, is the lowest rung of the evidence-based, but can have a disproportionate impact on us and our patient care.
Anecdotes derive their power from their emotion and repeatability. Case reports are compelling because they convey emotion. They can elicit empathy from those who hear them, like the case report about newly insulin-dependent diabetes during isotretinoin therapy because dermatologists are often prescribing isotretinoin and knowledgeable about the risks of diabetes. Case reports and anecdotes can have out-sized influence because they can easily be repeated to others. This enables the anecdote to influence people who didn’t hear the story or read the case report.
As we read case reports, we’re subject to a variety of cognitive biases that can influence how we interpret it and its impact on our patient care. Here are two examples to consider:
Availability Heuristic: We tend to estimate the probability of events based on how easy it is to imagine those events occurring, rather than on actual numbers or serious estimates of likelihoods. For example, a reader might think insulin-dependent diabetes is an unrecognized and common risk of isotretinoin because we prescribe isotretinoin frequently and know insulin-dependent diabetes isn’t rare (these are both ‘available’ in our thoughts).
Focusing Illusion: We overinterpret one aspect of a case report. For example, we focus on the occurrence of the insulin-dependent diabetes occurred at the time of the isotretinoin. The case report says nothing about the risk to anyone of developing insulin-dependent diabetes at a similar age.
In closing, let me admit that I love reading case reports, because they are typically extreme. I read them with insight, recognizing my biases and the opportunity they present to do further research.
Connolly A, Walsh S. Effect of isotretinoin on glucose metabolism in patients with diabetes. Clin Exp Dermatol. 2021 Apr;46(3):549-550.
Lee YH, Scharnitz TP, Muscat J, Chen A, Gupta-Elera G, Kirby JS. Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis. JAMA Dermatol. 2016 Jan;152(1):35-44.
Dicembrini I, Bardini G, Rotella CM. Association between oral isotretinoin therapy and unmasked latent immuno-mediated diabetes. Diabetes Care. 2009 Aug;32(8):e99.
Santos-Pérez MI, García-Rodicio S, del Olmo-Revuelto MA, Cuellar-Olmedo LÁ. Sospecha de diabetes mellitus por isotretinoína [Suspicion of diabetes mellitus isotretinoin-induced]. Farm Hosp. 2013 Jul-Aug;37(4):340-2.
Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev. 2005 Feb;6(1):13-21.
Soyuduru G, Ösoy Adışen E, Kadıoğlu Özer İ, Aksakal AB. The effect of isotretinoin on insulin resistance and adipocytokine levels in acne vulgaris patients. Turk J Med Sci. 2019 Feb 11;49(1):238-244.
Ertugrul DT, Karadag AS, Tutal E, Akin KO. Isotretinoin does not induce insulin resistance in patients with acne. Clin Exp Dermatol. 2011 Mar;36(2):124-8
Tsai TY, Liu HW, Chao YC, Huang YC. Effects of isotretinoin on glucose metabolism in patients with acne: A systematic review and meta-analysis. J Dtsch Dermatol Ges. 2020 Jun;18(6):539-545.
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