Comment

that the patient cohorts include those with large ranges about the use of GLP-1 receptor agonists in patients
of eGFR and albuminuria, this arguably allows for a with, or at risk of, diabetic kidney disease.
better understanding of the effects of semaglutide at SB reports personal fees from Boehringer Ingleheim; conference fees from
Sanofi Aventis; personal fees and trial investigator fees from Novo Nordisk;
different stages of diabetic kidney disease and degrees and personal fees from MSD, AstraZeneca, Napp, and Lilly. AAT reports grants,
of severity of diabetic kidney disease. Additionally, the personal fees, and non-financial support from Sanofi and Novo Nordisk; non-
financial support from MSD, Philips Resporinics, Impeto medical, ANSAR, and
finding that semaglutide was not associated with an Aptiva; personal fees and non-financial support from Boehringer Ingelheim;
increase in kidney adverse events, particularly acute personal fees from Lilly, AstraZeneca, Bristol-Myers Squibb, and Janssen;
non-financial support and equipment and travel support from Resmed; and
kidney injury or urinary disorders, provides reassurance grants and non-financial support from Napp. AHB has received personal fees for
about its use for its primary indications. advisory work and lectures from Novo Nordisk, MSD, Boehringer-Ingelheim,
Janssen, and Napp in the past 3 years.
Although these findings can be seen as highly relevant
in the context of management of type 2 diabetes *Srikanth Bellary, Abd A Tahrani, Anthony H Barnett
s.bellary@aston.ac.uk
and specifically in the prevention and progression of
School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK
associated diabetic kidney disease, important questions (SB); University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
remain. Reductions in albuminuria and haemodynamic (SB, AAT, AHB); Institute of Metabolism and Systems Research, University of
Birmingham, Birmingham, UK (AAT, AHB); and Centre for Endocrinology
changes affecting glomerular function are recognised Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham,
markers of kidney protection, but diabetic kidney UK (AAT)

disease progresses over many years and there is little 1 Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges,
progress, and possibilities. Clin J Am Soc Nephrol 2017; 12: 2032–45.
evidence that these improvements will translate into 2 Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes.
Diabetes Spectr 2017; 30: 202–10.
delayed progression to end-stage kidney disease.
3 Mann JFE, Hansen T, Idorn T, et al. Effects of once-weekly subcutaneous
Ongoing kidney outcome studies of semaglutide, semaglutide on kidney function and safety in patients with type 2 diabetes:
a post-hoc analysis of the SUSTAIN 1–7 randomised controlled trials
such as FLOW (NCT03819153), aim to answer these Lancet Diabetes Endocrinol 2020; published online Sept 21.
questions. https://doi.org/10.1016/S2213-8587(20)30313-2
4 Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular
Another question relates to establishing the outcomes in patients with type 2 diabetes. N Engl J Med 2016;
role and positioning of GLP-1 receptor agonists in 375: 1834–44.
5 Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal
the management of diabetic kidney disease. For outcomes in type 2 diabetes: an exploratory analysis of the REWIND
randomised, placebo-controlled trial. Lancet 2019; 394: 131–38.
example, an agent from a different class of anti- 6 Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal
diabetes therapies, the SGLT2 inhibitor canagliflozin, outcomes in type 2 diabetes. N Engl J Med 2017; 377: 839–48.
7 Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes
effectively improves all kidney outcomes9 and studies in patients with type 2 diabetes and acute coronary syndrome: an
of dapagliflozin have indicated similar benefits.10 To exploratory analysis of the ELIXA randomised, placebo-controlled trial.
Lancet Diabetes Endocrinol 2018; 6: 859–69.
more clearly define the place of GLP-1 receptor agonists 8 Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the
in the management of diabetic kidney disease, an potential for renal protection in diabetic nephropathy.
Curr Opin Nephrol Hypertens 2015; 24: 96–103.
understanding of the exact mechanisms through 9 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in
type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–306.
which SGLT2 inhibitors and GLP-1 receptor agonists
10 AstraZeneca. Farxiga Phase III DAPA-CKD trial will be stopped early after
exert their kidney effects needs to be elucidated. overwhelming efficacy in patients with chronic kidney disease.
March 30, 2020. https://www.astrazeneca.com/media-centre/press-
If the mechanisms are different, could they have a releases/2020/farxiga-phase-iii-dapa-ckd-trial-will-be-stopped-early-after-
complementary role? Finally, despite the limitations overwhelming-efficacy-in-patients-with-chronic-kidney-disease.html
(accessed Aug 12, 2020).
of post-hoc analyses, these findings by Mann and
colleagues3 offer some reassurance and confidence

Understanding the epidemiology of adrenal tumours

As clinicians, we try to make the best decision that including how often and under what circumstances a See Articles page 894

is personalised for each patient depending on their condition occurs, the probability of false positive and
individual history, physical examination, blood and false negative test results, and the treatment options.
urine tests, and imaging studies. To properly interpret We need to know the prevalence of a condition (pretest
clinical information, we need a broader view of diseases, probability) to interpret the test results (positive or

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 Comment

negative predictive values). As clinicians, we care for resection of incidentalomas of more than 20 Hounsfield
our patients as individuals, but epidemiological studies units lead to more patient morbidities and unwise
provide a broader perspective and context that allows us use of resources?3 We learned a lesson not to overtreat
to treat each patient appropriately. papillary thyroid microcarcinoma incidentally found on
Andreas Ebbehoj and colleagues1 studied the ultrasound.4 What lesson will we learn from diagnosing
epidemiology of adrenal tumours in Olmsted County, and treating the increasing number of incidentalomas?
MN, USA, from 1995 to 2017, using the data from the Only one in seven patients with adrenal tumours
Rochester Epidemiology Project. Many of their findings had sufficient hormonal workup. How many patients
Shutterstock

parallel our clinical impressions, including increasing with subclinical hormone secreting adrenal tumours
incidence of adrenal tumours because of an increasing could have benefited from a more definitive diagnosis
use of imaging studies and a low rate of hormonal and more targeted medical or surgical treatment? The
workup in these patients. The size and depth of the most common discovery of pheochromocytoma is as
study provide useful quantitative data that will help an incidentaloma (eight cases) rather than for clinical
sharpen our clinical decisions when treating patients suspicion (five cases).1,5 Subclinical hypercortisolism
with adrenal tumours. Their study contains a large might be underdiagnosed and undertreated especially in
amount of valuable data; analysis of which will helps us patients with metabolic syndrome.6 Many patients with
interpret the literature and will inform future studies. primary aldosteronism are inappropriately treated for
The categorisation of adrenal tumours according to their essential hypertension.7 With the underdiagnosis of the
mode of discovery allows us to appreciate the intent of hormone secreting adrenal tumours, are we missing the
the clinicians who found these tumours; poor knowledge opportunity to treat some of these patients definitively
regarding clinical intent is a common weakness of large with laparoscopic adrenalectomy, which is safe and
database studies. By separating the patients by the effective?8 Because more adrenal metastases are being
method of tumour discovery (incidentaloma, staging diagnosed, would some of these patients benefit
for cancer, and workup for hormonal excess), clinicians from adrenalectomy, especially if they have solitary or
can interpret the data appropriately. The increase in oligo metastases from lung cancer, renal cell cancer, or
the incidence of adrenal tumours by ten-times over melanoma?9
two decades was accounted for by an increasing use of Large long-term epidemiological studies, such as the
abdominal imaging, leading to incidental discovery of Rochester Epidemiology Project, are costly to replicate.
small, non-functioning, benign tumours, especially in However, with broader use of standardised electronic
people aged 60 years or older. The lower overall incidence health record and increased availability of health
of adrenocortical cancer, pheochromocytoma, and insurance, perhaps similar studies can be done using
steroid hormone secreting tumours in this study is likely data from larger and more representative populations.
because of both an expanding denominator of small non- I declare no competing interests.
functioning adenomas and incomplete hormonal workup Quan-Yang Duh
of some patients with subclinical disease. quan-yang.duh@ucsf.edu
The two main clinical concerns for adrenal tumours University of California, San Francisco, Mount Zion Medical Center, Department
of Surgery, San Francisco, CA 94115, USA
are cancer and hormone hypersecretion. My impression
1 Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of adrenal tumours in Olmsted
from this study is that the risk of cancer in the increasing County, Minnesota, USA: a population-based cohort study.
number of incidentalomas has been overemphasised, Lancet Diabetes Endocrinol 2020; 8: 894–902.
2 Rossfeld KK, Maithel SK, Prescott J, et al. The prognostic significance of
but some people with hormone hypersecretion have adrenocortical carcinomas identified incidentally. J Surg Oncol 2018;
118: 1155–62.
been missed. 3 Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal
With only four patients with adrenocortical cancer incidentalomas: European Society of Endocrinology Clinical Practice
Guideline in collaboration with the European Network for the Study of
diagnosed in Olmsted county over 20 years, is it likely Adrenal Tumors. Eur J Endocrinol 2016; 175: G1–34.
that a population level effort would substantially 4 Ahn HS, Kim HJ, Welch HG. Korea’s thyroid-cancer “epidemic”—screening
and overdiagnosis. N Engl J Med 2014; 371: 1765–67.
improve the overall care of these patients? 5 Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and
Adrenocortical cancers presenting as incidentalomas are paraganglioma: an endocrine society clinical practice guideline.
J Clin Endocrinol Metab 2014; 99: 1915–42.
associated with better prognosis,2 but would increasing

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 Comment

6 Di Dalmazi G, Pasquali R, Beuschlein F, Reincke M. Subclinical 8 Chen Y, Scholten A, Chomsky-Higgins K, et al. Risk Factors associated with
hypercortisolism: a state, a syndrome, or a disease?. Eur J Endocrinol 2015; perioperative complications and prolonged length of stay after
173: M61–71. laparoscopic adrenalectomy. JAMA Surg 2018; 153: 1036–41.
7 Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of 9 Drake FT, Beninato T, Xiong MX, et al. Laparoscopic adrenalectomy for
primary aldosteronism: a cross-sectional study. Ann Intern Med 2020; metastatic disease: retrospective cohort with long-term, comprehensive
173: 10–20. follow-up. Surgery 2019; 165: 958–64.

Diabetes, like COVID-19, is a wicked problem

Diabetes has long been mistaken as a tame problem. A wicked problem persists in perpetuity because
Following a recipe, playing chess, and doing open- of incomplete information, multiple (often selfish)
heart surgery are tame problems. Tame problems can stakeholder interests, a large economic burden, and a
be solved by having engineers, clinicians, and scientists ripple effect whereby every action triggers a reaction
develop guidelines, algorithms, and systems that with other wicked problems. For example, during the
achieve easily measured outcomes that matter to these COVID-19 pandemic, the exclusion of undocumented
same stakeholders. For example, the longstanding and residents from the funding given to US taxpayers by the
accepted approach in diabetes has been to empower federal government reduced their purchasing power

Shutterstock
experts to create algorithms, therapies, technologies, amid a looming recession, contributing further to both
and models to manage glucose within controlled the public health and economic crises in US states such
conditions, which are then offered to people with as California.4 COVID-19 is also a wicked problem for Published Online
October 1, 2020
diabetes and their clinicians. Invariably, there is little telehealth. COVID-19 has caused us to move away from https://doi.org/10.1016/
effort to understand much about the anticipated in-person healthcare toward virtual visits. However, for S2213-8587(20)30312-0

users beyond their biology. This quantified approach telehealth to be successful, it is important that people
also mistakenly assumes that if a variable cannot be have access to the technology required for virtual visits.
measured, it is probably not important.1 These attempts In reality, in the USA one in four adults with Medicare do
to solve the problem of diabetes have, so far, been not have digital access (whether via a desktop or laptop
authoritative (eg, authorising self-proclaimed experts computer with a high-speed internet connection, or
to develop clinical guidelines that are assumed to be via a smartphone with a wireless data plan) at home,
adopted widely, or economic rationing of access to making it unlikely that these people can participate in
new devices and therapies by payers) or on the basis of telehealth video visits with doctors. The proportion of
free-market competition (eg, allowing pharmaceutical people without digital access is notably higher among
and medical device industries to develop independent people of colour than among other populations.5 As the
approaches without collaboration). Needless to say, COVID-19 example shows, there is no single, correct,
diabetes has not been solved, and that is because definite answer to a wicked problem. A wicked problem
diabetes is not a tame problem. cannot be solved, merely resolved.
Diabetes, like COVID-19, is a wicked problem. The When considering diabetes as a wicked problem, the
concept of a wicked problem arose in the 1960’s, based aim should be a resolution with the least bad outcome
on the realisation that purely scientific solutions to for the majority. Now there are efforts to personalise
societal problems are doomed to fail.2 Wicked problems diabetes care, allowing for the categorisation of
are impossible to solve because of contradictory and subpopulations on the basis of biological and genetic
changing requirements, the absence of equality, and variables.6 This approach allows identification of
ever-evolving social complexities. Poverty, crime, clusters of people with different characteristics and
and climate change are wicked problems. COVID-19 risks that could be responsive to targeted therapeutic
is also a classic wicked problem, as evidenced by the interventions. However, beyond using genetic and
unanticipated and disproportionate effect of the biological factors to identify these subgroups, it is
virus on minority racial and ethnic populations and now recognised that sociocultural influences are also
individuals who have experienced health disparities.3 important factors in determining risk of progression

www.thelancet.com/diabetes-endocrinology Vol 8 November 2020 873