An Analysis of Characteristics of Subjects Examined for Incretin Effects on Pancreatic Pathology

Abstract

A recent autopsy analysis asserted that incretin drugs have the potential of increasing the risk for pancreatic cancer and for pancreatic neuroendocrine tumors. We examined the Network for Pancreatic Organ Donors with Diabetes (nPOD) database from which that analysis was derived. Our findings raise important questions about the comparability of the two groups of diabetes patients used for the analysis. Our review of the data available on the nPOD Web site and our reading of the earlier article lead us to the conclusion that the data, and the implications of the data, as expressed by the authors of the autopsy analysis are vastly overstated and are a misrepresentation of the information available.

Introduction

I ncretin-based therapies for type 2 diabetes mellitus (DM) have been available since the introduction of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in 2005 and the introduction of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in 2006.¹ Subsequently, several additional drugs in each of these classes have been introduced. These have been shown to be effective glucose-lowering agents that minimize the risk of hypoglycemia.² Moreover, meta-analyses suggest that these two classes of agents may have a beneficial effect on cardiovascular outcomes,^3,4 and thus there are large ongoing randomized controlled trials with each of them, designed to determine whether there is indeed a cardiovascular benefit. Both classes of agents are included in current treatment guidelines of the American Diabetes Association and the European Association for the Study of Diabetes⁵ and of the American Association of Clinical Endocrinologists.⁶ Nonetheless, there have been reports to the U.S. Food and Drug Administration Adverse Event Reporting System of cases of pancreatitis, which has resulted in warnings being added to the label of GLP-1 receptor agonists. The original report and label change may have led to a “notoriety” bias in reporting, as several analyses of insurance company databases have failed to confirm such a risk. The evidence about this has recently been reviewed.⁷ Yet, the potential risks of incretin-based therapies have been continually emphasized by Butler and colleagues.^8,9 Recently, Butler et al.¹⁰ presented an autopsy analysis in which they asserted that these drugs have a potential of increasing the risk for pancreatic cancer and for pancreatic neuroendocrine tumors. An accompanying commentary by Kahn¹¹ raised important questions about the analyses reported. Because the specimens and material came from the Network for Pancreatic Organ Donors with Diabetes (nPOD),¹² an open-access network funded by the JDRF, and because nPOD users have access to the nPOD Web site and may review online both the subject characteristics and the pathology, we decided to review the data in detail, particularly in view of the contrasting commentary by Kahn.¹¹

Materials and Methods

The nPOD Web site (http://path-aperio.ahc.ufl.edu) was accessed. Using the case numbers reported by Butler et al.,¹⁰ each case was retrieved, and the data available on the Web site were tabulated. Age at diagnosis was calculated by subtracting duration of DM from age. Although we relied primarily on the information tabulated for each case in the nPOD Web site, a few selected pathology sections were reviewed by one of us (J.L.), a pathologist. The human leukocyte antigen (HLA) types reported were reviewed to determine whether subjects had high-risk type 1 diabetes alleles,¹³ reconciling high-risk HLA with current nomenclature.¹⁴ The groupings of subjects were the same as that used by the authors of the original report¹⁰ (i.e., DM subjects treated with incretins [DM-incretin] [n=8], DM subjects not treated with incretins [DM-other] [n=12], and control subjects without DM [Control] [n=14]). Pancreas weight was obtained from Supplementary Table 1 of Butler et al.¹⁰

Results

Clinical characteristics of individual subjects are shown in Table 1, which is similar in construct to Table 1 of Butler et al.,¹⁰ but our Table 1 includes all fields available on the nPOD Web site and thus provides all available data tabulated on the nPOD Web site. The last six columns summarize key pathological findings, enabling one to see at a glance which subjects had which findings. These findings are taken directly from the Web site and do not involve our own review of the pathology.

Table 1.

Review of Clinical and Pathological Features from the Network for Pancreatic Organ Donors with Diabetes Database

Group, case number	Age (years)	Duration (years)	Age (years) at diagnosis	Gender	Race	BMI (kg/m²)	Treatments	Cause of death	HLA	Autoantibodies	C-peptide (ng/mL)	HbA1c (%)	Histopathology	β-Cell hyperplasia	α-Cell hyperplasia	Pancreatitis	Amyloid	Ductal dysplasia	Other
DM-incretin group
6157	74	1	73	F	African American	39	Sitagliptin	ICH/stroke	A01/02, B08/51, DR04/09, DQ07/09	Negative	2.74	6.9	Few islets; islet amyloid; no α-cell hyperplasia				Amyloid
6185	46	15	31	M	African American	41	Sitagliptin, metformin	Anoxia	A03/74, B42/53, DR18/11, DQ04/06	Negative	26.42	NA	Neuroendocrine tumor; α-cell hyperplasia (follicular); β-cell hyperplasia (follicular)	β-Cell hyperplasia	α-Cell hyperplasia
6186	68	5	63	M	White	21	Sitagliptin, metformin	ICH/stroke	A11/20, B07/49, DR07/15, DQ02/02	Negative	2.98	NA	Chronic pancreatitis; exocrine atrophy; α-cell hyperplasia (follicular); islet amyloid		α-Cell hyperplasia	Pancreatitis
6189	49	26	23	F	White	36	Exenatide, metformin, glipizide	Stroke	A11/-, B27/35, DR103/-, DQ05/-	IAA-positive	1.85	NA	Chronic pancreatitis; exocrine atrophy; α-cell hyperplasia (follicular); β-cell hyperplasia (follicular)	β-Cell hyperplasia	α-Cell hyperplasia	Pancreatitis
6199	53	20	33	M	African American	30	Sitagliptin, insulin	ICH/stroke	A03/30 B44/63 DR01/12 DQ05/-	Negative	8.87	NA	Islet amyloid; α-cell hyperplasia (follicular); fibrosis		α-Cell hyperplasia		Amyloid
6194	47	13	34	M	White	24	Sitagliptin, insulin	ICH/stroke	A02/03, B55/57, DR04/07, DQ08/09	Negative	0.16	7.3	α-Cell hyperplasia; β-cell hyperplasia; PP-cell hyperplasia; acinar atrophy	β-Cell hyperplasia	α-Cell hyperplasia				Renal transplant; acinar atrophy
6203	68	5	63	M	White	33	Sitagliptin, metformin	Stroke	A24/33, B35/65, DR0/11, DQ05/07	Negative	6.24	NA	Exocrine atrophy; α-cell hyperplasia (follicular); β-cell hyperplasia; PP-cell hyperplasia	β-Cell hyperplasia	α-Cell hyperplasia				Exocrine atrophy
6206	59	10	49	M	White	42	Sitagliptin, metformin	Stroke	A02/26, B38/62, DR04/13, DQ06/08	Negative	11.15	8.5	Chronic pancreatitis; ductal hyperplasia; microadenoma pan-tail; α-cell hyperplasia (tail only); β-cell hyperplasia (tail only)	β-Cell hyperplasia	α-Cell hyperplasia	Pancreatitis		Ductal dysplasia
DM-other group
6028	33	17	16	M	African American	30	Insulin	Gunshot	A02/-, B44/45, DR14/-, DQ05/-	Negative	22.4	NA	α-Cell hyperplasia (head, body); some β-cell hyperplasia (tail); few β-cells in head and body; kidney complications	β-Cell hyperplasia	α-Cell hyperplasia		Amyloid
6059	18	0.3	17.7	F	Hispanic	39	None	CVD	A02/11, B35/50, DR07/08, DQ02/0	Negative	10.68	NA	α-Cell hyperplasia (follicular; especially in tail and body); β-cell hyperplasia (head, body, and tail)	β-Cell hyperplasia	α-Cell hyperplasia
6108	57	2	55	M	Asian	30	Metformin	ICH/stroke	A11/24, B38/-, DR15/-, DQ05/-	Negative	1.25	NA	Islet amyloid (tail); pancreatic stone; no obvious β- or α-cell hyperplasia				Amyloid
6110	20	0.2	19.8	F	African American	40	None	ICH/stroke, DKA	A23/34, B65/53, DR18/15, DQ04/06	Negative	0.58	NA	Few β-cells; α-cell hyperplasia (follicular; especially in tail and body)		α-Cell hyperplasia
6109	48	-		F	Hispanic	33	None	ICH/stroke, DKA	A02/68, B35/39, DR14/16, DQ07/-	mIAA+	<0.05	8	Islet amyloid; no obvious β- or α-cell hyperplasia (maybe mild for α-cell in tail); PP-cell hyperplasia (head)				Amyloid
6114	42	2	40	M	White	31	Metformin (noncompliant)	Asphyxiation	A03/31, B07/62, DR07/15, DQ06/09	Negative	0.58	7.8	Islet amyloid; fibrosis; α-cell hyperplasia (follicular; especially tail and body); β-cell hyperplasia follicular in tail); few β-cells in head	β-Cell hyperplasia	α-Cell hyperplasia		Amyloid
6124	62	3	59	M	White	34	Metformin	ICH/stroke	A29/-, B27/45, DR04/15, DQ06/07	Negative	2.85	NA	Islet amyloid; hypertrophied islets, some with massive α-cell hyperplasia (tail and body, also follicular in head); some β-cell hyperplasia (tail and body), but few β-cells in head	β-Cell hyperplasia	α-Cell hyperplasia		Amyloid
6127	44	10	34	F	White	30	Insulin	ICH/stroke	A01/02, B08/56, DR04/17, DQ02/08	mIAA+	0.08	NA	Few β-cells, but in big islets (with amyloid?); α-cell hyperplasia (follicular, head, body, and tail)		α-Cell hyperplasia
6133	45	20	25	F	White	40	Insulin	CVD	A02/03, B37/60, DR10/15, DQ05/06	Negative	0.84	NA	Pancreatitis; severe exocrine atrophy; marked islet amyloid; few β- or α-cells and, when detected, in big amyloid-ridden islets; PP-cell hyperplasia (follicular, head)			Pancreatitis	Amyloid
6139	37	1.5	35.5	F	Hispanic	45	None	Seizure	A02/30, B60/57, DR04/15, DQ08/06	Negative	0.6	NA	Pancreatic duct with dysplasia and numerous α-cells (body); some islet amyloid; β-cell numbers appear near normal; marked α-cell hyperplasia (head, body, and tail)		α-Cell hyperplasia		Amyloid	Ductal dysplasia
6142	29	14	15	F	Hispanic	34	None	Bacterial meningitis	A24/80, B39/58, DR14/01, DQ07/05	mIAA+	0.19	NA	β-Cells reduced; moderate acinar atrophy, fibrosis, and ductular dysplasia; some islet amyloid; one lobe (body) with marked β- and α-cell hyperplasia (38712; 38387)		α-Cell hyperplasia		Amyloid	Ductal dysplasia
6149	39	20	19	F	African American	29	Insulin	ICH/stroke	A30/66, B07/53, DR09/15, DQ02/06	GAD+	11.55	NA	Some acinar atrophy; islet amyloid; increased ductal Ki67 (head); few β-cells, possible LADA; α-cell hyperplasia (follicular; head, body, and tail); massive islet in duct cell mass very Glgn+, but some Ins + too (41521 and 41434)		α-Cell hyperplasia		Amyloid
Control group
6009	45	NA		M	White	31	NA	Anoxia	A11/29; B50/57, DR07/15, DQ06/-	Negative	11.32	NA	Numerous islets; seemingly normal β-/α-cell distribution
6015	39	NA		F	White	32	NA	Anoxia	A02/02, B14/51, DR01/04, DQ/	Negative	1.99	NA	Gastric bypass 6 years previously; marked PP-cell hyperplasia in one lobe (46176); odd ductal-like structure with Ins + cells and CD3 infiltrate (14221 and 1458)				Amyloid		Gastric bypass
6012	64	NA		F	White	31	NA	Cerebrovascular/stroke	A02/31, B07/60, DR15/04, DQ06/08	Negative	2.97	NA	Chronic pancreatitis (head); many islet β-cells (tail); Ins+ cells in ducts (no α-cell staining available); islets seem OK in head			Pancreatitis
6016	42	NA		M	White	31	NA	Cerebrovascular/stroke	A02/03, B07/60, DR13/15, DQnot tested		NA	NA	α-Cell hyperplasia (follicular; tail, 26401); β-cell hyperplasia (follicular; tail, 50711); islets appear normal in head except one lobe where many PP-cells and few β-cells (45608)	β-Cell hyperplasia	α-Cell hyperplasia		Amyloid
6019	68	NA		F	White	24	NA	Head trauma	A01/03, B08/35, DR01/17, DQnot tested	Negative	0.47	NA	Area of marked α-cell (not β-cell) hyperplasia in head (duct region) 18805, 18932, and 18660; tail seems OK with many islets		α-Cell hyperplasia
6020	60	NA		M	White	30	NA	Cerebrovascular/stroke	DRB107:01/13:01 DQA101:03/02:01…	Negative	2.82	NA	Chronic pancreatitis; fibrosis; acinar atrophy; area of marked α-cell hyperplasia in tail (37252 duct region; 14476 and 14484 Ins adjacent sections); same in head (14224)		α-Cell hyperplasia	Pancreatitis
6022	75	NA		M	White	31	NA	Cerebrovascular/stroke	A02/03, B44/60, DR04/-, DQ03/-	Negative	4.99	NA	Severe acinar atrophy; islet amyloid; few β-cell; many α-cells; indications of α-cell hyperplasia (tail, 57570); β-cell hyperplasia follicular (tail, 45583)		α-Cell hyperplasia		Amyloid		Acinar atrophy
6034	32	NA		F	White	25	NA	Head trauma	A03/-, B07/62, DR01/08, DQ05/04	Negative	3.15	NA	Seems normal
6060	23	NA		M	White	33	NA	Head trauma	A03/24, B51/39, DR01/11, DQ05/07	Negative	13.63	NA	Pancreatitis, chronic and acute; seems normal; more β-cells than α-cells in most lobes
6097	43	Preclinical T2D		F	White	36	NA	Cerebrovascular/stroke	A02/11, B44/55, DR01/14, DQ05/-	Negative	16.76	7.1	Exocrine atrophy; Interesting area of β- and α-cell hyperplasia in body (22825 and 22887) and in tail; islet numbers low in head	β-Cell hyperplasia	α-Cell hyperplasia				Preclinical T2D
6099	14	NA		M	White	30	NA	Head trauma	DR13/15, DQ06/06	Negative	5.37	NA	Some pancreatitis; CD3+ infiltrates; islets seem normal			Pancreatitis			CD3 infiltrate
6102	45	NA		F	White	35	NA	Cerebrovascular/stroke	DR04/17, DQ02/0	Negative	0.55	6.1	Islets mostly OK except for interesting area of β- and α-cell hyperplasia in tail (23982 and 23638)	β-Cell hyperplasia	α-Cell hyperplasia
6158	40	NA		M	White	30	NA	Head trauma	A03/24, B149/62, DR04/13, DQ06/07	GAD+/mIAA+	0.51	5.6	Exocrine atrophy; mild ductular dysplasia; focal chronic pancreatitis; massive PP-cell hypertrophy (head); few β- and α-cells there; few islets on body and tail			Pancreatitis		Ductal dysplasia	PP staining
6165	45	NA		F	White	25	NA	Cerebrovascular/stroke	A01/02, B08/38, DR13/15, DQ06/-	Negative	4.45	5.6	Ductular dysplasia and metaplasia in head and tail (many Ins+ cells there); islets seem OK otherwise					Ductal dysplasia

CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DM, diabetes mellitus; GAD, glutamic acid decarboxylase; Glgn, glucagon; HbA1c, glycated hemoglobin; IAA, insulin autoantibodies; ICH, intracerebral hemorrhage; Ins, insulin; LADA, latent autoimmune diabetes; mIAA, multiple insulin autoantibodies; NA, not available; PP, pancreatic polypeptide producing; T2D, type 2 diabetes.

Table 2 summarizes by group the frequency of several parameters noted in Table 1 and also includes mean pancreas weight for each group.

Table 2.

Tabulation of Different Features Among the Three Groups

	Group
	DM-incretin	DM-other	Control
n	8	12	14
Age (years)	58	40	45
DM mean (years)	46.9
Gender	6 M:2 F	4 M:8 F	7 M:7 F
HLA T1D	2 (25%)	1 (8%)	1 (7%)
Islet autoantibodies	1 (13%)	4 (33%)	1 (7%)
T1D HLA or ABS	3 (38%)	4 (33%)	1 (7%)
T1D HLA or ABS or age at diagnosis <20 years	3 (38%)	7 (58%)	1 (7%)
Pancreas weight (g)	113.3	79.3	91^a
β-Cell hyperplasia	5 (63%)	4 (33%)	3 (21%)
α-Cell hyperplasia	7 (88%)	9 (75%)	6 (43%)
Pancreatitis	3 (38%)	1 (8%)	4 (29%)
Islet amyloid	2 (25%)	9 (75%)	3 (21%)
Ductal dysplasia	1 (13%)	2 (17%)	2 (14%)

Weight not available for seven patients.

ABS, antibodies; DM, diabetes mellitus; F, female; HLA, human leukocyte antigen; M, male; T1D, type 1 diabetes.

It can be seen that there is an 18-year difference in mean age of the two DM groups, with the DM-incretin group having a mean age of 58±4 years and the DM-other group having a mean age of 40±4 years. Moreover, the age range for the DM-incretin group was 46–74 years, whereas the age range for the DM-other group was 18–62 years, with only three subjects in the DM-other group being as old as the youngest subject in the DM-incretin group. Thus, the ages were essentially nonoverlapping. Five of the subjects in the DM-other group were diagnosed prior to 20 years of age, in contrast to none of the subjects in the DM-incretin group. The mean age at diagnosis in the DM-other group was 20.7 years, in contrast to a mean age at diagnosis of 46.1 years in the DM-incretin group. Mean duration of diabetes in the DM-other group was 6.4 years, in contrast to the DM-incretin group, in which it was 11.9 years. Unfortunately, the duration of incretin therapy is not stated on the nPOD Web site. In the DM-incretin group 75% of the subjects were male, whereas only 33% of the DM-other subjects were male. Five of the subjects in the DM-other group were on no diabetes therapy, and four subjects were being treated only with insulin; in the DM-incretin group, seven subjects were treated with sitagliptin, one subject was treated with exenatide, and two of the subjects also were being treated with insulin. Two subjects in the DM-other group died in diabetic ketoacidosis. Only one (13%) of the DM-incretin subjects had a diabetes autoantibody, in contrast to four (33%) of the DM-other subjects. High-risk HLA was present in two subjects in the DM-incretin group (subject #6194 and subject #6206) and one subject in the DM-other group (subject #6127). In total, three (38%) subjects in the DM-incretin group had either high-risk HLA or autoantibodies, whereas in total seven (58%) subjects in the DM-other group had either high-risk HLA or autoantibodies or age at diagnosis of less than 20 years, and an additional subject (diagnosed at 25 years of age) had been treated only with insulin, raising the possibility that as many as 67% of subjects in the DM-other group could have had type 1 DM.

Pancreas weight differed between the groups, as seen in Table 2. However, it should be noted that seven (50%) of the subjects in the control group without DM did not have their pancreas weight noted, thus making the control group number unreliable.

Based on the descriptions on the nPOD Web site, β-cell hyperplasia was more often noted in the DM-incretin group, being found in five (63%) subjects in comparison with four (33%) of the DM-other subjects. In contrast, α-cell hyperplasia was noted in a large number of subjects in both groups with diabetes: seven (88%) DM-incretin subjects and nine (75%) DM-other subjects. Pancreatitis was noted to be present in three (38%) DM-incretin subjects and only one (8%) DM-other subject but was also noted in four (29%) control subjects. Islet amyloid was noted in only two (25%) DM-incretin subjects but in nine (75%) DM-other subjects. Ductal dysplasia was noted more or less equally in all three groups.

Discussion

There is a clear and unambiguous difference between the DM-incretin and DM-other groups. Butler et al.¹⁰ asserted that “pancreata were also obtained from 14 non diabetic (ND) controls matched by age, sex and BMI [body mass index] with the two DM treatment groups” and in the abstract asserted “examination of pancreata from age matched organ donors with type 2 diabetes (DM) treated by incretin therapy (n=8) or other therapy (n=12) and non diabetic controls (n=14).” Although it is true that if you add the two DM groups together the mean age is 46.9 years, versus 45 years in the control group, most of the comparisons and the thrust of the article was comparison of the two DM groups, which were not matched for age, with mean age being 40 years in the DM-other group and 58 years in the DM-incretin group and with little overlap of age between the DM groups. Likewise, it is true that 50% of all DM subjects were male, as were 50% of control subjects, but again 75% were male in the DM-incretin group, and only 33% were male in the DM-other group. Thus, we find the statements about matching to be misleading.

Other findings also raise some questions about comparability of the groups. Because pancreas weight was not available in seven (50%) of control subjects and because the large increase in β-cell mass in the DM-incretin group was calculated by Butler et al.¹⁰ as the β-cell area×the pancreas weight, it is important to carefully examine the impact of pancreas weight on the calculations. Could it be that the crucial finding is a decrease of pancreatic weight in the DM-other group, rather than an increase in the DM-incretin group? If the DM-other group has a substantial number of subjects with covert type 1 DM, that may be playing a role, as there is a well-known decrease in weight in type 1 DM.^15,16 If type 1 DM is present, that might also account for the decrease in β-cell area in the DM-other group compared with the control group. And, the accuracy of the control group β-cell mass might be questioned in that four of the control subjects with the highest percentage of β-cell area lacked pancreas weight, by which β-cell mass is calculated. Thus, at the very least, there is an incomplete dataset for control subjects.

Another potentially important difference between the two DM groups is that in the nPOD Web site tabulation, amyloid was noted in nine (75%) of the DM-other subjects but only two (25%) of the DM-incretin subjects. Because islet amyloid may reflect β-cell apoptosis, this could contribute to the differences in β-cell area and mass reported. The presence of amyloid in a higher proportion of the DM-other subjects may be indicative that this group has more apoptosis and/or that the DM-incretin group has less amyloid because incretins are diminishing apoptosis.

In Butler et al.,¹⁰ the authors noted “glucagon immunoreactive cells were frequently found in long linear groups or solid nests of cells either within the duct itself or in the immediate periductal location.” However, they either did not detect or did not note that such staining could also be found in at least one control subject without DM (subject #6020), as shown in Figure 1.

FIG. 1.

A section from a control subject without diabetes shows staining for glucagon, including evidence of glucagon cells within pancreatic ducts. This figure was downloaded and enlarged from the Network for Pancreatic Organ Donors with Diabetes Web site at http://path-aperio.ahc.ufl.edu

The authors also claimed that there is an increase in pancreatic intraepithelial neoplasia (PanIN) cells in the DM-incretin group but failed to note that previous studies have shown an age-related increase in PanIN cells.¹⁷ The nearly 20-year difference in age between the two DM groups could completely account for any difference in PanIN frequency. Butler et al.¹⁰ asserted that GLP-1 receptors may be responsible for increase in exocrine pancreas and in PanIN cells but failed to note that there is controversy as to whether GLP-1 receptors are expressed in such tissues, depending on which antibody is used to measure GLP-1 receptors, with multiple GLP-1 receptor antibodies, including several used to localize GLP-1 receptor expression in the pancreas, failing to exhibit appropriate sensitivity or specificity.¹⁸

Another point to note is that the authors argued that there is “α-cell hyperplasia, abnormal α-cell distribution and predisposition to glucagon expressing neuroendocrine tumors previously reported with suppressed glucagon secretion or signaling.” However, the three articles cited include one in receptor knockout mice, one in receptor-deficient mice, and one in an individual with a mutation in the glucagon receptor.^19
–21 No example is cited of such abnormalities in the setting of suppressed glucagon secretion, a known biological effect of GLP-1.

Butler et al.¹⁰ also argued that β-cell function has not been shown to be improved on incretin therapies and used the continued presence of diabetes a year after treatment has commenced to conclude that the therapies have no effect. In fact, β-cell function has been carefully measured during therapy with incretins—both GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors—and has been found to be increased.^22
–24 It is true that diabetes has not been reversed, but improved glycemic control is maintained.

This critique describes our review of the data available on the nPOD Web site and our reading of the article by Butler et al.¹⁰ From this, we conclude that the data and the implications of the data, as expressed by Butler et al.,¹⁰ are vastly overstated and seemingly irresponsibly articulated. Their analysis seems to be more of an alarmist perspective, creating controversy rather than a neutral and fact-based approach. At the core of the discussion are limited numbers and many confounders related to subject history, presentation, and other subject-specific factors that make their conclusions invalid. We believe that a much larger sample needs to be examined, with appropriately matched subjects, including matching of DM subjects treated with incretins in comparison with DM subjects treated with other agents. Until such is accomplished, no conclusions can be made. In the interim, we note that the American Diabetes Association has launched a complete review of all industry data pertaining to the subject.²⁵ We also note that while our present critique was under review, the European Medicines Agency issued a statement that it had concluded its review prompted by the article of Butler et al.¹⁰ and indicated “no new concerns for GLP-1 therapies identified on the basis of available evidence.”²⁶

A fundamental premise of all medical interventions is the calculation of benefit versus risk. In the case of the report by Butler et al.,¹⁰ the beneficial clinical effects of the incretin drugs were ignored. Every drug should have aggressive pharmacovigilance to understand the full effects in heterogeneous populations. That often requires extensive experience with the drugs after approval by regulatory agencies. The irresponsible indictment of two classes of drugs that are used by millions of people, in our opinion, is reprehensible.

Footnotes

Acknowledgments

This research was performed by use of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF. in this manuscript was provided by the nPOD online pathology site. Organ Procurement Organizations partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php.

Author Disclosure Statement

E.H. declares no competing financial interests exist. J.L. reports serving on the Board of Directors of Dexcom and Steracycle and serving as a consultant to Anthelio Health Care and Serco UK. J.S.S. reports having served on the Board of Directors of Amylin Pharmaceuticals until the company was sold in August 2012 and is currently on the Board of Directors of Dexcom, Moerae Matrix, Paean Therapeutics, and VasoPrep Surgical, has consulted with BD Technologies, Bristol-Myers Squibb/Astra-Zeneca, Cebix, DiaVacs, Exsulin, Gilead, Halozyme, Ideal Life, Intarcia, MannKind, Mellitech, Merck, Orgenesis, Sanofi, Sekris, Takeda, Valeritas, and Viacyte, has had research grants (to the University of Miami) from Halozyme, Intuity Medical, Mesoblast, and Osiris Therapeutics, and currently holds stock in Dexcom, Ideal Life, Moerae Matrix, Patton Medical Devices, Tandem Diabetes Care, and VasoPrep Surgical.

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