Ассоциация " Доза-реакция " между системным и дерматологическим использованием и типом глюкокортикоидных средств 2 Диабет Mellitus: Общегосударственное исследование по вопросам контроля за рассмотрением дел.

Introduction

Glucocorticoids have potent anti‐inflammatory and immunosuppressive effects and are among the most widely prescribed medications worldwide [ 1 , 2 ]. They are used across a broad range of inflammatory and autoimmune conditions, particularly within rheumatologic, inflammatory bowel, respiratory, and dermatologic diseases [ 3 , 4 ]. In Denmark, approximately 3% of the population redeems a prescription for systemic glucocorticoids each year, increasing to 10% among people older than 70 years, with about 1% being regular users [ 5 ]. Glucocorticoids are available in multiple formulations and can be administered systemically or topically, including by inhalation, dermatologic application, or ophthalmic instillation. Although topical routes are commonly assumed to result in minimal systemic exposure, absorption varies considerably depending on route and corticosteroid potency [ 6 , 7 , 8 ].

Glucocorticoid exposure has been consistently associated with adverse metabolic effects, including the development of Type 2 diabetes mellitus [ 9 , 10 ]. Mechanistically, glucocorticoids induce hepatic insulin resistance, impair pancreatic beta cell function, reduce glucose uptake in peripheral tissues, increase appetite and attenuate incretin responses [ 11 , 12 ]. These combined effects can lead to persistent hyperglycaemia and the progression from transient dysglycaemia to overt Type 2 diabetes mellitus [ 11 , 12 , 13 ].

It is estimated 6.3% of the global population are living with Type 2 diabetes mellitus at elevated risk of premature mortality [ 14 ]. Prior studies suggest that glucocorticoid‐related diabetes risk varies by administration route, daily dose and treatment duration, with oral systemic glucocorticoids being the most strongly implicated in elevated diabetes risk [ 4 , 15 , 16 ]. However, the extent to which risk differs across systemic and topical preparations has not been examined, and it also remains unclear whether cumulative exposure exhibits a clear dose–response pattern. Dose–response evidence is particularly important because it strengthens causal inference and can directly inform clinical prescribing practice.

We therefore conducted a nationwide case–control study to examine the association between systemic and topical glucocorticoid exposure and the odds of Type 2 diabetes mellitus, with specific emphasis on cumulative prednisolone‐equivalent dose to assess dose–response relationships.

Materials and Methods

Study Data Source

This study was reported according to the STROBE (The Strengthening the Reporting of Observational Studies in Epidemiology) Statement [ 17 ]. Data were obtained from the Danish National Patient Registry, Register of Medicinal Products Statistics, and Danish Civil Registration System [ 18 , 19 ]. The Danish National Patient Registry contains information on hospital‐based diagnoses, while the Register of Medicinal Products Statistics of the Danish Medicines includes all redeemed prescriptions from community pharmacies. Cross‐linkage was performed using unique civil registration numbers assigned to all Danish residents.

The study was approved by Statistics Denmark (ID 703382) and conducted in accordance with Danish regulations and the Helsinki Declaration [ 20 , 21 ].

Study Design and Population

We conducted a nationwide case–control study including people aged 40 years or older who received a new diagnosis of Type 2 diabetes mellitus in Denmark between 1 January 2013 and 31 December 2020 (catchment population ~5.86 million) (Figure  1 ).

Flowchart of design.

Type 2 diabetes mellitus was defined by an ICD‐10 code E11, E13 or E14 or an ICD‐8 code 250 or a redeemed prescription for an Anatomical Therapeutic Chemical (ATC) code A10B (non‐insulin glucose‐lowering drugs). People with a prior diagnosis of Type 2 diabetes mellitus, polycystic ovary syndrome (ICD‐10 code E28.2, ICD‐8 code 25690, ATC code G03C, G03H or G03GB in combination with A10BA02), Type 1 diabetes mellitus (ICD‐10 code E10 or ICD‐8 code 249 or treatment with A10A [insulin and analogues] without combination of other glucose‐lowering drugs), diabetes due to malnutrition (ICD‐10 code E12) or gestational diabetes (ICD‐10 code O24) were excluded. Each case was matched 1–3 with controls without Type 2 diabetes mellitus using incidence density sampling on age, sex and a weighted Charlson Comorbidity Index (Table  S1 ) [ 22 ].

Exposure Classification

Glucocorticoid exposure was defined as at least one redeemed prescription within 1 year before the date of diabetes diagnosis (or the equivalent index date), and a minimum of two prescriptions within the preceding 3 years. This definition was chosen to capture recent and recurrent use and to identify clinically relevant exposure. Exposure was categorised according to administration route using the following ATC codes: systemic (H02AB), inhaled (R03BA, R03AK or R03AL), dermatologic (D07), rectal or colonic (A07EA or C05AA), nasal (R01AD), ophthalmic (S01B or S01C) and otic (S02B or S02C). Systemic exposure was further categorised according to formulation into oral and injectable preparations. Injectable preparations were defined as liquid formulations intended for injection. The cumulative glucocorticoid dose was converted to a prednisolone‐equivalent dose (Table  S2 ) [ 23 ]. The daily dose was calculated by dividing the total amount of glucocorticoid redeemed during the observation period by the time interval between the first glucocorticoid prescription and the date of diabetes diagnosis. The dose intervals were grouped as none, < 2.5, 2.5–7.4, and ≥ 7.5 mg/day.

Covariates

We identified clinical conditions commonly treated with glucocorticoids to account for confounding by indication [ 2 ]. These included rheumatoid arthritis, ulcerative colitis, Crohn's disease, polymyalgia rheumatica, Addison's disease, multiple sclerosis, Covid, chronic obstructive pulmonary disease (COPD), COPD exacerbation, status asthmaticus, asthma, idiopathic thrombocytopenic purpura, dermatitis, systemic lupus erythematosus and psoriasis, defined using ICD‐10 and ICD‐8 diagnostic codes (Table  S3 ).

Statistical Analysis

Baseline characteristics were summarised using means with standard deviations for continuous variables and frequencies with percentages for categorical variables. Differences between cases and controls were assessed using standardised mean difference (SMD) and χ
2 tests for categorical variables and the Mann–Whitney U test for non‐normally distributed continuous variables.

Conditional logistic regression was used to estimate ORs with 95% CIs for the association between glucocorticoid exposure and Type 2 diabetes mellitus. The crude model accounted for the matching by design and included no additional covariates. The adjusted model was fitted, including administration routes and relevant covariates.

SMDs equal to or greater than 0.10 or equal to or lower than −0.10 were interpreted as indicating meaningful group difference. A two‐sided p  < 0.05 was considered statistically significant. p values were not adjusted for multiple testing, and analyses were conducted using complete‐case analysis. Data management and analyses were performed using SAS (version 9.4) and R (build 513).

Data and Resource Availability

Data is stored on secure servers at Statistics Denmark and cannot be shared according to Danish law. Access to Statistics Denmark servers and the associated data can be granted by Statistics Denmark upon adequate permission. SAS and R code used for data management and statistical analyses are available in the associated Figshare repository [ 24 ].

Results

Baseline Characteristics

A total of 149 113 people with Type 2 diabetes mellitus and 447 339 matched controls were included (Figure  1 ). The mean age was 64 years, predominantly male (59.7%), with a Charlson Comorbidity Index of 1.48. As expected, cases had a higher prevalence of any condition commonly treated with glucocorticoids, and especially conditions associated with systemic inflammation and respiratory disease, most notably COPD (6.68% vs. 4.94%, SMD 0.07). Full baseline characteristics are presented in Table  1 .

TABLE 1 Baseline characteristics. Variable People with Type 2 diabetes mellitus ( n  = 149 113) Controls ( n  = 447 339) SMD Mean age (years), SD 63.56 ± 11.93 63.56 ± 11.93 — Men, % 59.74 59.74 — Any condition, % ( n ) 15.97 (23812) 14.21 (63581) 0.05 CCI, SD 1.48 ± 1.90 1.48 ± 1.90 — Autoimmune and inflammatory diseases Rheumatoid arthritis, % ( n ) 0.99 (1480) 1.13 (5041) −0.01 Ulcerative colitis, % ( n ) 1.03 (1534) 0.93 (4180) 0.01 Crohn's disease, % ( n ) 0.52 (773) 0.54 (2430) −0.00 Polymyalgia rheumatica, % ( n ) 1.09 (1618) 0.92 (4109) 0.02 Endocrine disorders Addison's disease, % ( n ) 0.09 (135) 0.07 (297) 0.01 Neurological disease Multiple sclerosis, % ( n ) 0.45 (676) 0.53 (2379) −0.01 Lung diseases Covid, % ( n ) 0.27 (397) 0.10 (428) 0.04 COPD, % ( n ) 6.68 (9962) 4.94 (22081) 0.07 COPD exacerbation, % ( n ) 2.35 (3498) 1.39 (6240) 0.07 Status asthmaticus, % ( n ) 0.24 (364) 0.17 (739) 0.02 Asthma, % ( n ) 5.60 (8343) 5.52 (24681) 0.00 Haematological diseases ITP, % ( n ) 0.14 (206) 0.11 (501) 0.01 Autoimmune haemolytic anaemia, % ( n ) 0.05 (71) 0.04 (157) 0.00 Skin diseases Dermatitis, % ( n ) 1.08 (1610) 1.02 (4572) 0.01 Systemic lupus erythematosus, % ( n ) 0.14 (214) 0.18 (799) −0.01 Psoriasis, % ( n ) 0.59 (877) 0.42 (1860) 0.02
Note: Patient characteristics stratified by cases (Type 2 diabetes mellitus) and controls. Data are presented as a mean with SD (standard deviation) or as a percentage (number). Groups were matched 1:3 on CCI, sex and age. SMD refers to the comparison between cases and controls. Variables with counts are suppressed in accordance with data protection regulations. Abbreviations: CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary disease; ITP, idiopathic thrombocytopenia purpura; SMD, standardised mean difference.

Baseline characteristics.

Note: Patient characteristics stratified by cases (Type 2 diabetes mellitus) and controls. Data are presented as a mean with SD (standard deviation) or as a percentage (number). Groups were matched 1:3 on CCI, sex and age. SMD refers to the comparison between cases and controls. Variables with counts are suppressed in accordance with data protection regulations.

Abbreviations: CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary disease; ITP, idiopathic thrombocytopenia purpura; SMD, standardised mean difference.

Dose–Response

In crude analyses, glucocorticoid exposure was associated with increased odds of Type 2 diabetes mellitus across every administration route (Table  2 ). After multivariable adjustment, significant dose‐dependent associations persisted for oral systemic, injected, dermatologic and inhaled glucocorticoids.

TABLE 2 Dose‐dependent risk of Type 2 diabetes mellitus associated with glucocorticoid use, expressed as daily prednisolone‐equivalent dose (mg/day). Route and dose category People with Type 2 diabetes mellitus/controls Crude OR (95% CI); p
Adjusted OR
a
(95% CI); p
Oral systemic No exposure (reference) < 2.5 mg/day 5473/12 801 1.38 (1.33–1.42); < 0.001 1.25 (1.21–1.29); < 0.001 2.5–7.49 mg/day 3486/7019 1.61 (1.55–1.68); < 0.001 1.49 (1.43–1.56); < 0.001 ≥ 7.5 mg/day 4671/4675 3.23 (3.10–3.37); < 0.001 3.02 (2.90–3.15); < 0.001 Injected No exposure (reference) < 2.5 mg/day 2866/6842 1.26 (1.21–1.32); < 0.001 1.10 (1.05–1.15); < 0.001 2.5–7.49 mg/day 63/98 1.95 (1.42–2.67); < 0.001 1.73 (1.26–2.39); < 0.001 ≥ 7.5 mg/day 33/48 2.08 (1.34–3.24); 0.001 1.51 (0.96–2.39); 0.07 Inhaled No exposure (reference) < 2.5 mg/day 6488/16 084 1.24 (1.20–1.28); < 0.001 1.08 (1.05–1.11); < 0.001 2.5–7.49 mg/day 3157/7686 1.26 (1.21–1.32); < 0.001 1.08 (1.03–1.13); < 0.001 ≥ 7.5 mg/day 895/1881 1.47 (1.36–1.59); < 0.001 1.16 (1.07–1.26); < 0.001 Dermatologic No exposure (reference) < 2.5 mg/day 14 746/35 072 1.31 (1.28–1.34); < 0.001 1.21 (1.18–1.23) < 0.001 2.5–7.49 mg/day 2870/5986 1.49 (1.43–1.56); < 0.001 1.37 (1.31–1.44) < 0.001 ≥ 7.5 mg/day 1073/1937 1.73 (1.60–1.86); < 0.001 1.51 (1.40–1.63) < 0.001 Rectal or colonic No exposure (reference) < 2.5 mg/day 1826/4650 1.18 (1.12–1.25); < 0.001 1.01 (0.96–1.07); 0.69 2.5–7.49 mg/day 143/420 1.03 (0.85–1.24); 0.80 0.80 (0.66–0.97); 0.02 ≥ 7.5 mg/day 291/691 1.27 (1.10–1.45); < 0.001 1.09 (0.95–1.25); 0.24 Nasal No exposure (reference) < 2.5 mg/day 10 602/30 568 1.04 (1.02–1.07); < 0.001 0.90 (0.88–0.92); < 0.001 2.5–7.49 mg/day 219/646 1.02 (0.88–1.19); 0.80 0.86 (0.74–1.00); 0.06 ≥ 7.5 mg/day 42/94 1.34 (0.93–1.93); 0.11 1.04 (0.71–1.50); 0.86 Ophthalmic or otic No exposure (reference) < 2.5 mg/day 9172/21 772 1.29 (1.26–1.32); < 0.001 1.12 (1.09–1.15); < 0.001 2.5–7.49 mg/day 173/392 1.35 (1.13–1.62); 0.001 1.16 (0.97–1.39); 0.11 ≥ 7.5 mg/day 35/91 1.17 (0.79–1.73); 0.43 1.02 (0.69–1.51); 0.92
Note: Conditional logistic regression was used for OR. Daily glucocorticoid dose expressed as prednisolone‐equivalent mg/day based on redeemed prescriptions in the year before diagnosis.
a
Adjusted for all administration routes.

Dose‐dependent risk of Type 2 diabetes mellitus associated with glucocorticoid use, expressed as daily prednisolone‐equivalent dose (mg/day).

Note: Conditional logistic regression was used for OR. Daily glucocorticoid dose expressed as prednisolone‐equivalent mg/day based on redeemed prescriptions in the year before diagnosis.

Adjusted for all administration routes.

Systemic glucocorticoids showed the strongest gradient. Compared with no exposure, the adjusted OR for oral glucocorticoids increased from 1.25 (95% CI, 1.21–1.29) at < 2.5 mg/day; to 1.49 (95% CI, 1.43–1.56) at 2.5–7.4 mg/day; to 3.02 (95% CI, 2.90–3.15) at ≥ 7.5 mg/day. This is visualised in Figure  2 . The adjusted OR for injected glucocorticoids was 1.10 (95% CI, 1.05–1.15) at < 2.5 mg/day; to 1.73 (95% CI, 1.26–2.39) at 2.5–7.4 mg/day. For doses of ≥ 7.5 mg/day, the adjusted OR was 1.51 (95% CI, 0.96–2.39), although the CI included 1.00.

Dose–response for oral systemic administration route.

Dermatologic glucocorticoids also showed a similar, though less pronounced, pattern. The adjusted OR increased from 1.21 (95% CI, 1.18–1.23) at < 2.5 mg/day to 1.37 (95% CI, 1.31–1.44) at 2.5–7.4 mg/day to 1.51 (95% CI, 1.40–1.63) at ≥ 7.5 mg/day.

The weakest gradient was found for inhaled glucocorticoids where adjusted. OR was 1.08 (95% CI, 1.05–1.11) at < 2.5 mg/day; 1.08 (95% CI, 1.03–1.13) at 2.5–7.4 mg/day and 1.16 (95% CI, 1.07–1.26) at ≥ 7.5 mg/day.

By contrast, rectal, nasal, ophthalmic and otic formulations did not show significant associations after adjustment. These findings indicate that the odds of Type 2 diabetes mellitus are driven primarily by cumulative exposure to oral systemic and dermatologic glucocorticoids.

Glucocorticoid Exposure

Across all administration routes, a higher proportion of people with Type 2 diabetes mellitus than controls had been exposed to glucocorticoids, with significant differences for every route (Table  3 ). The median cumulative prednisolone‐equivalent dose was higher among people with Type 2 diabetes mellitus (39 232 users) compared with controls (95 300 users) (960 vs. 756 mg; p  < 0.001). This pattern was most pronounced for oral systemic glucocorticoids, where the cumulative prednisolone‐equivalent dose was substantially higher in cases (13 732 users) than in controls (24 523 users) (1500 vs. 1000 mg; p  < 0.001).

TABLE 3 Exposure to corticosteroids by administration route. Route and dose category People with Type 2 diabetes mellitus ( n  = 149 113) Controls ( n  = 447 339)
p
Ever used, % ( n ) 26.3 (39 232) 21.3 (95 300) < 0.001 Oral systemic, % ( n ) 9.2 (13 732) 5.5 (24 523) < 0.001 Injected, % ( n ) 2.0 (2978) 1.6 (6991) < 0.001 Topical use Inhaled, % ( n ) 10.3 (15 322) 8.2 (36 797) < 0.001 Dermatologic, % ( n ) 12.6 (18 840) 9.6 (43 034) < 0.001 Rectal or colonic, % ( n ) 1.5 (2284) 1.3 (5770) < 0.001 Nasal, % ( n ) 7.3 (10 922) 7.0 (31 331) < 0.001 Ophthalmic or otic, % ( n ) 6.3 (9418) 5.0 (22 274) < 0.001 Cumulated prednisolone‐equivalent dose (mg) per user, median (range) Any corticosteroid 960 (8–110 533) 756 (8–281 250) < 0.001 Oral systemic 1500 (125–75 000) 1000 (60–102 500) < 0.001 Injected 100 (25–15 000) 97 (25–16 017) 0.97 Topical use Inhaled 1280 (22–34 080) 1420 (22–35 760) < 0.001 Dermatologic 417 (16–110 400) 375 (16–102 907) < 0.001 Rectal or colonic 38 (15–102 473) 45 (15–281 250) 0.51 Nasal 158 (2–10 962) 168 (2–10 192) < 0.001 Ophthalmic or otic 67 (8–6605) 67 (8–9048) < 0.001
Note: Exposure to corticosteroids is demonstrated as a percentage being exposed to corticosteroids and the cumulated prednisolone equivalent dose, stratified by cases (Type 2 diabetes mellitus) and controls. Data are presented as percentages and medians (range). p values are from χ
2 test and Mann–Whitney U test.

Exposure to corticosteroids by administration route.

Note: Exposure to corticosteroids is demonstrated as a percentage being exposed to corticosteroids and the cumulated prednisolone equivalent dose, stratified by cases (Type 2 diabetes mellitus) and controls. Data are presented as percentages and medians (range). p values are from χ
2 test and Mann–Whitney U test.

Discussion

In this large nationwide case–control study, systemic, dermatologic and inhaled glucocorticoid use was associated with a clear dose–response increase in the odds of Type 2 diabetes mellitus, extending to prednisolone‐equivalent doses < 2.5 mg/day. The gradient was most pronounced for oral systemic preparations, whereas rectal, nasal, ophthalmic and otic formulations did not show clinically meaningful associations after adjustment. Together, these findings suggest that glucocorticoid‐related diabetes is driven primarily by cumulative systemic exposure, irrespective of whether it is achieved through oral or high‐dose dermatologic use.

Systemic Glucocorticoids and Odds of Diabetes

Oral systemic glucocorticoids showed the steepest dose–response relationship, with adjusted odds of Type 2 diabetes mellitus almost tripling as the prednisolone‐equivalent dose increased from < 2.5 to ≥ 7.5 mg/day. This pattern is consistent with prior observational data in inflammatory disease populations, where higher daily doses and longer duration have been linked to newly diagnosed diabetes, and aligns closely with established mechanisms of glucocorticoid‐induced dysglycaemia [ 4 ]. Together, these findings reinforce a causal interpretation supported by mechanistic pathways involving reduced peripheral glucose uptake, impaired beta cell function, altered incretin responses, and increased hepatic glucose production [ 12 ].

Importantly, our data indicate that the threshold for clinically relevant risk is lower than often appreciated in routine care, with a measurable increase in odds of diabetes already at cumulative exposure equivalent to prednisolone doses < 2.5 mg/day [ 16 , 25 ]. From a clinical perspective, this supports a cautious approach even to so‐called ‘low‐dose’ long‐term regimens and reinforces recommendations to use the lowest effective dose for the shortest possible duration, particularly in people with existing metabolic risk factors.

Dermatologic Glucocorticoids

A central and clinically novel finding is the dose‐dependent association observed for dermatologic glucocorticoids. Although topical preparations are frequently perceived as metabolically benign, the odds of Type 2 diabetes mellitus increased across cumulative prednisolone‐equivalent dose categories in a pattern broadly resembling systemic therapy, albeit with smaller effect sizes [ 3 , 6 ]. This suggests that, in real‐world use, dermatologic glucocorticoids can contribute to meaningful systemic exposure, especially when high‐potency agents are used over large body surface areas, under occlusion, or for prolonged periods.

These results extend previous work reporting an association between topical corticosteroid use and diabetes but without formal dose–response evaluation. Our findings provide a rationale for incorporating cumulative dermatologic exposure into glucocorticoid risk assessment and for reconsidering long‐term, high‐dose topical regimens in people with prediabetes, obesity or other markers of elevated metabolic risk [ 6 ].

Inhaled and Other Topical Glucocorticoids

Inhaled glucocorticoids were associated with a statistically significant but clinically negligible increase in the odds of Type 2 diabetes mellitus, with only a limited dose–response pattern. In contrast, nasal, rectal, ophthalmic and otic glucocorticoids did not show a significant association after multivariable adjustment.

The excess odds observed in crude analyses and for inhaled glucocorticoids in adjusted analyses likely reflect residual confounding as well as confounding by indication, including greater underlying disease severity in chronic respiratory conditions and comorbidity in people with chronic respiratory or inflammatory conditions.

Similar patterns have been reported in prior studies of inhaled corticosteroids, where the initial crude associations with diabetes risk weakened substantially after accounting for clinical severity [ 21 , 22 ].

Taken together, our results suggest that these formulations are metabolically neutral when used at standard therapeutic doses. This is clinically reassuring and indicates that, in people who require non‐dermatologic topical glucocorticoids for adequate disease control, concerns about diabetes should not be a primary reason to withhold or underdose these treatments. Nonetheless, people with substantial underlying metabolic risk may still warrant routine glycaemic monitoring as part of general risk management rather than specifically due to these formulations.

Clinical Implications

Glucocorticoid prescribing is pervasive across general medicine, rheumatology, dermatology, gastroenterology, and respiratory medicine, and in our study one in four people with newly diagnosed Type 2 diabetes mellitus had been exposed to glucocorticoids in the year preceding diagnosis [ 1 , 2 ]. The presence of a consistent dose–response gradient, including at prednisolone‐equivalent doses < 2.5 mg/day, underscores that even low‐dose, chronic exposure can meaningfully contribute to diabetes development in susceptible people.

Clinically, our findings support three practical strategies. First, risk stratification at the time of prescribing: people with older age, reduced kidney function, prediabetes or other features of metabolic syndrome should be recognised as particularly vulnerable to glucocorticoid‐induced dysglycaemia [ 26 ]. In such people, steroid‐sparing regimens, step‐down strategies, or alternative therapies should be considered whenever feasible.

Second, targeted glycaemic monitoring should accompany systemic and higher‐dose dermatologic glucocorticoid use. Early measurement of fasting plasma glucose or HbA 1c shortly after treatment initiation and at intervals during ongoing therapy may help detect emerging dysglycaemia while changes are still reversible. This is particularly relevant when repeated courses or continuous low‐dose regimens accumulate to substantial total exposure.

Third, interdisciplinary communication between prescribing specialists and diabetes care providers is essential. Awareness that both low‐dose systemic and dermatologic glucocorticoids are associated with diabetes should encourage proactive counselling and, where appropriate, timely referral for preventive lifestyle interventions or pharmacologic management. Our data also provide reassurance that non‐dermatologic topical formulations can usually be maintained without major concern for additional metabolic harm, helping to balance risk–benefit judgements in complex multimorbid patients.

Strengths and Limitations

This nationwide study draws on a large, unselected population and high‐quality registry data with near‐complete capture of diagnoses and redeemed prescriptions, allowing quantification of cumulative prednisolone‐equivalent dose across all major glucocorticoid routes in routine care.

However, important limitations must be considered. Residual confounding and confounding by indication are likely present and cannot be fully excluded, as we lacked information on lifestyle and metabolic factors (e.g., BMI, smoking, physical activity and baseline glycaemia) and on disease activity or treatment escalation, all of which may influence both prescribing and diabetes risk. This might bias the estimates away from the null, as patients receiving glucocorticoids may have a higher underlying metabolic risk independent of glucocorticoid exposure itself. Consequently, part of the observed association may reflect characteristics of the underlying disease rather than a direct pharmacological effect of glucocorticoids, particularly for lower cumulative doses where no clear dose–response association was observed.

In‐hospital glucocorticoid administration was not captured, and redeemed prescriptions do not confirm adherence, likely leading to underestimation of true exposure. Missing inpatient exposure primarily reflects under‐ascertainment of high‐dose use and would be expected to bias dose–response estimates towards the null. In contrast, non‐adherence represents likely non‐differential misclassification of exposure between groups. Finally, our findings reflect prescribing patterns in a high‐income setting with universal healthcare and may not generalise fully to health systems with different glucocorticoid use or background risk.

Conclusion

Systemic, dermatologic and inhaled glucocorticoid use was associated with a dose‐dependent increase of Type 2 diabetes mellitus risk, extending to cumulative exposure equivalent to prednisolone doses < 2.5 mg/day. Other non‐dermatologic formulations appeared metabolically safe at standard therapeutic doses. These findings support more proactive glycaemic monitoring and careful consideration of cumulative glucocorticoid exposure when treating people at heightened metabolic risk.

Author Contributions

D.V. and A.V.K. were involved in statistical management and analysis. N.H.R. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in the conception and design of the study and interpretation of the results; edited, reviewed and approved the final version of the manuscript.

Funding

This work was supported by the National Heart Foundation of Australia Future Leader Fellowship (107323) and Danish Diabetes and Endocrine Academy (NNF22SA0079901).

Conflicts of Interest

Peter Vestergaard is head of research in the Steno Diabetes Center North Denmark, sponsored by the Novo Nordisk Foundation. Nicklas H. Rasmussen holds shares in Novo Nordisk and a grant from DDEA. Johan Røikjer has received lecture fees from Novo Nordisk and Boehringer Ingelheim. Annika V. Kvist holds shares in Novo Nordisk. David Vadsholt holds shares in Novo Nordisk. The other authors declare no conflicts of interest.

Supporting information

Table S1: ICD‐8 and ICD‐10 diagnosis codes used to make Charlson Comorbidity Index (CCI) scores, including weights.

Table S2: Equipotent doses of selected glucocorticoids.

Table S3: ICD‐8 and ICD‐10 diagnosis codes used to identify conditions commonly treated with glucocorticoids.

Data S1: STROBE Statement—checklist of items that should be included in reports of observational studies.

Acknowledgements

We thank the Danish Diabetes and Endocrine Academy for research funding (grant NNF22SA0079901) and Steno Diabetes Center North Denmark for institutional support. The salary of J.R.L. is supported by a National Heart Foundation of Australia Future Leader Fellowship (107323). The funding sources had no role in study design, data collection, analysis, interpretation, or manuscript preparation.

Vadsholt D., Kvist A. V., Sandiramoorthy C., et al., “Dose–Response Association Between Systemic and Dermatologic Glucocorticoid Use and Type 2 Diabetes Mellitus: A Nationwide Case–Control Study,” Diabetes, Obesity and Metabolism
28, no. 9 (2026): 8094–8102, 10.1111/dom.71001.

Handling Editor: Richard Donnelly

Data from this study were presented as an oral presentation at the EASD Annual Meeting 2025.

Data Availability Statement

Data is stored on secure servers on Statistics Denmark and cannot be shared according to Danish law. Access to Statistics Denmark servers and the associated data can be granted by Statistics Denmark upon adequate permission. SAS and R code used for data management and statistical analyses are available in the associated Figshare repository.

References

Associated Data

Supplementary Materials

Table S1: ICD‐8 and ICD‐10 diagnosis codes used to make Charlson Comorbidity Index (CCI) scores, including weights.

Table S2: Equipotent doses of selected glucocorticoids.

Table S3: ICD‐8 and ICD‐10 diagnosis codes used to identify conditions commonly treated with glucocorticoids.

Data S1: STROBE Statement—checklist of items that should be included in reports of observational studies.

Data Availability Statement

Data is stored on secure servers on Statistics Denmark and cannot be shared according to Danish law. Access to Statistics Denmark servers and the associated data can be granted by Statistics Denmark upon adequate permission. SAS and R code used for data management and statistical analyses are available in the associated Figshare repository.