Should diabetes be considered for curative surgery in primary hyperparathyroidism?

Primary hyperparathyroidism (PHPT) is a common endocrine disorder that is rising in incidence, with recent estimates suggesting annual rates of 233 per 100,000 of women and 85 per 100,000 of men affected in the United States (1). Parathyroidectomy remains the definitive option for symptomatic PHPT, but it is also indicated for asymptomatic patients who meet specific criteria (2,3). Currently, society guidelines from the Fifth International Workshop recommend surgical treatment for patients who have significant hypercalcemia (>1 mg/dL above the upper limit of normal), are less than 50 years old, or present with skeletal (osteoporosis or fragility fracture) or renal involvement (reduced creatinine clearance (<60 mL/min), nephrolithiasis, or hypercalciuria) (2).

In cases of asymptomatic PHPT, curative surgery has been advocated based on high rates of biochemical cure and evidence for improved postoperative outcomes. Parathyroidectomy at an earlier age is intended to mitigate the harmful effects from delaying definitive surgery in younger patients (4). Based on a systematic review that included several randomized controlled and prospective cohort studies, bone mineral density improves and fracture risk is reduced following surgery (5). Parathyroidectomy may also impede the PHPT-related decline in renal function and development of kidney stones, although this is largely reinforced by observational data and expert consensus (6,7).

Beyond these traditional target organ indications, untreated PHPT has been associated with other neuropsychiatric, cardiovascular and metabolic effects (8,9). Consensus guidelines at present do not support parathyroidectomy solely for these indications due to limited evidence of reversibility, though there has been a recent push to expand criteria (10,11).

Higher-than-expected rates of diabetes mellitus (DM) in the PHPT population, which range from 8% to 15%, has generated interest in the PHPT-glucose metabolism relationship (12,13). Of clinical relevance is whether parathyroidectomy can improve or alleviate the insulin resistant state, a finding first described in an early patient series by Walsh et al. (14). Several prospective studies have reproduced these results, demonstrating post-operative improvements in fasting glucose and biomarkers of insulin resistance (15-17). In contrast, others have found no significant changes in peri-procedural insulin requirements or corrections in insulin resistance (18,19). And while a retrospective review by Richards and Thompson did show improved glycemic control in 37% of patients after parathyroidectomy, the remaining cohort had no change (40%) or worsening (23%) glucose levels, respectively (20). These heterogeneous results are further limited by small study populations and lack of direct comparisons with non-operative controls.

Liu and colleagues offer the largest analysis to date evaluating the relationship between PHPT and diabetes (21). This multicenter population-based retrospective study compared 596 patients with PHPT treated with parathyroidectomy and 2,539 managed non-operatively over a 17-year study period. After assessing the primary outcome of incident diabetes between groups, parathyroidectomy was found to be associated with lower overall rates [hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.65–0.71, P<0.001] relative to the non-surgical group. Furthermore, Kaplan-Meier analysis showed that those who underwent surgery were significantly more likely to remain non-diabetic compared to their non-operative counterparts over a 10-year follow-up period.

The authors provide robust evidence for the potential metabolic benefits following parathyroidectomy while addressing issues with previously published data (relatively smaller sample sizes, missing comparators) (15-20). A 32% overall reduction in diabetes risk is notable and suggests an additional benefit to parathyroidectomy beyond the known skeletal and renal improvements. Some may argue the retrospective study design limits this conclusion, although it’s noteworthy that there have been no randomized PHPT trials to date evaluating glucose metabolism. Additionally, the results are strengthened by a sensitivity analysis that gauged the impact of unmeasured confounders: with an E-value of 2.3, any unobserved factors would need to have an at least 2.3 times greater association to the outcomes to nullify the study’s findings.

One key weakness from prior literature was the absence of population stratification, which may have provided insights into the varied glycemic responses to parathyroidectomy (22). For example, while Rudman’s pilot study of 22 patients with PHPT showed no overall metabolic benefit following surgery, a follow-up analysis of those specifically with higher insulin resistance indices did show improvement (19). Similarly, Nomine-Criqui et al. found that the greatest post-parathyroidectomy improvement occurred in patients with higher insulin resistance markers and in those with pre-diabetes (23). Subgroup analysis by Liu showed that patients ≤65 years and those with more severe PHPT (defined as serum parathyroid hormone >2 times the upper limit of normal or serum calcium >2.8 mmol/L) had a 36% and 42% lower risk of incident diabetes compared to older patients (32%, P<0.001) and those with milder PHPT (27%, P<0.001), respectively (21). Together, these results suggest the metabolic benefit of surgery would be especially beneficial in younger patients with more severe disease.

We commend the authors for this excellent study that further elucidates the potential metabolic benefits of parathyroidectomy in patients with PHPT. This study adds to the accumulating data on whether curing PHPT grants a metabolic advantage, specifically highlighting younger patients with marked biochemical disease. While the results are consistent with several studies linking PHPT and higher rates of insulin resistance and diabetes, the findings conflict with others published in the literature. We suspect that heterogeneity in study populations and methodologies may be a large contributor, factors that are reinforced by Liu and colleagues’ comprehensive analysis. Further prospective and randomized studies are ultimately needed to clarify the metabolic impact of parathyroidectomy and to inform potential expansion of guidelines to include metabolic indications.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article has undergone external peer review.

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-550/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-550/coif). G.R.V. has received consulting fees from Veracyte, Inc. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Minisola S, Arnold A, Belaya Z, et al. Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism. J Bone Miner Res 2022;37:2315-29. [Crossref] [PubMed]
2. Bilezikian JP, Khan AA, Silverberg SJ, et al. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. J Bone Miner Res 2022;37:2293-314. [Crossref] [PubMed]
3. Stephen AE, Mannstadt M, Hodin RA. Indications for Surgical Management of Hyperparathyroidism: A Review. JAMA Surg 2017;152:878-82. [Crossref] [PubMed]
4. Lorenz FJ, Beauchamp-Perez F, Manni A, et al. Analysis of Time to Diagnosis and Outcomes Among Adults With Primary Hyperparathyroidism. JAMA Netw Open 2022;5:e2248332. [Crossref] [PubMed]
5. Kongsaree N, Thanyajaroen T, Dechates B, et al. Skeletal Effect of Parathyroidectomy on Patients With Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 2024;109:e1922-35. [Crossref] [PubMed]
6. Liang CC, Yeh HC, Lo YC, et al. Parathyroidectomy slows renal function decline in patients with primary hyperparathyroidism. J Endocrinol Invest 2021;44:755-63. [Crossref] [PubMed]
7. Mollerup CL, Vestergaard P, Frøkjaer VG, et al. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ 2002;325:807. [Crossref] [PubMed]
8. Lightle WR, Zheng F, Makris KI, et al. Objectively measured cognitive dysfunction in patients with primary hyperparathyroidism improves after parathyroidectomy. Surgery 2024;175:161-5. [Crossref] [PubMed]
9. Pepe J, Minisola S, Ettorre E, et al. Cardiovascular Involvement In Primary Hyperparathyroidism. J Clin Endocrinol Metab 2025;dgaf625. [Crossref] [PubMed]
10. Bartz-Kurycki MA, Dream S, Yen TW, et al. Older Patients With Asymptomatic Primary Hyperparathyroidism: Should Criteria for Surgery Be Expanded? J Endocr Soc 2023;7:bvad098. [Crossref] [PubMed]
11. Romero-Velez G, Khan LZ, Jin J. Should I refer my patient for a parathyroidectomy? Cleve Clin J Med 2024;91:279-80. [Crossref] [PubMed]
12. Taylor WH, Khaleeli AA. Coincident diabetes mellitus and primary hyperparathyroidism. Diabetes Metab Res Rev 2001;17:175-80. [Crossref] [PubMed]
13. Cardenas MG, Vigil KJ, Talpos GB, et al. Prevalence of type 2 diabetes mellitus in patients with primary hyperparathyroidism. Endocr Pract 2008;14:69-75. [Crossref] [PubMed]
14. Walsh CH, Soler NG, Malins JM. Diabetes mellitus and primary hyperparathyroidism. Postgrad Med J 1975;51:446-9. [Crossref] [PubMed]
15. Khaleeli AA, Johnson JN, Taylor WH. Prevalence of glucose intolerance in primary hyperparathyroidism and the benefit of parathyroidectomy. Diabetes Metab Res Rev 2007;23:43-8. [Crossref] [PubMed]
16. Karakose M, Caliskan M, Arslan MS, et al. The impact of parathyroidectomy on serum ADAMTS1, ADAMTS4 levels, insulin resistance, and subclinical cardiovascular disease in primary hyperparathyroidism. Endocrine 2017;55:283-8. [Crossref] [PubMed]
17. Duran C, Sevinc B, Kutlu O, et al. Parathyroidectomy Decreases Insulin Resistance Index in Patients with Primary Hyperparathyroidism. Indian J Surg 2017;79:101-5. [Crossref] [PubMed]
18. Bannon MP, van Heerden JA, Palumbo PJ, et al. The relationship between primary hyperparathyroidism and diabetes mellitus. Ann Surg 1988;207:430-3. [Crossref] [PubMed]
19. Rudman A, Pearson ER, Smith D, et al. Insulin resistance before and after parathyroidectomy in patients with primary hyperparathyroidism--a pilot study. Endocr Res 2010;35:85-93. [Crossref] [PubMed]
20. Richards ML, Thompson NW. Diabetes mellitus with hyperparathyroidism: another indication for parathyroidectomy? Surgery 1999;126:1160-6. [Crossref] [PubMed]
21. Liu X, Lui DTW, Xiong X, et al. Parathyroidectomy and Risk of Incident Diabetes in Patients With Primary Hyperparathyroidism. JAMA Surg 2025;160:1125-32. [Crossref] [PubMed]
22. Barnett MJ. Association Between Primary Hyperparathyroidism and Secondary Diabetes Mellitus: Findings From a Scoping Review. Cureus 2023;15:e40743. [Crossref] [PubMed]
23. Nomine-Criqui C, Bihain F, Nguyen-Thi PL, et al. Patients with prediabetes improve insulin resistance after surgery for primary hyperparathyroidism. Surgery 2024;175:180-6. [Crossref] [PubMed]