Pioglitazone may accelerate disease course of slowly progressive type 1 diabetes

Shimada, Akira; Shigihara, Toshikatsu; Okubo, Yoshiaki; Katsuki, Tsutomu; Yamada, Yoshifumi; Oikawa, Yoichi

doi:10.1002/dmrr.1235

Cited by 16 publications

(7 citation statements)

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“…Metformin was used to treat five of the six patients in the S group at baseline; during the study period, the dosage was increased in two patients and was added in one patient (Table S2). We previously reported that metformin may suppress the disease course of SPIDDM/LADA more effectively than pioglitazone [ 23 ], and we subsequently experienced a patient with SPIDDM/LADA whose β-cell function was maintained for 5 years with treatment of metformin alone [ 37 ]. Metformin increases the GLP-1 level [ 38 ], which regulates lymphocyte proliferation and the maintenance of peripheral regulatory T cells [ 39 ]; given that metformin was recently reported to improve gut microbiome flora in type 2 diabetes patients [ 40 ], metformin treatment for non-insulin-dependent SPIDDM might have exerted immunomodulatory effects through gut flora modification.…”

Section: Discussionmentioning

confidence: 99%

“…Because the inferiority of SU compared to insulin treatment had been revealed in the Tokyo study, pioglitazone, a thiazolidinedione (TZD) approved in Japan, was selected as the comparator. The efficacy of TZD on SPIDDM/LADA has been evaluated in several studies with conflicting results [ 23 , 24 ]. In addition, from an ethical point of view, patients under treatment with metformin were allowed to be enrolled because a possible favorable effect of metformin on SPIDDM/LADA was suggested in our previous study [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

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Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)

et al. 2017

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IntroductionWe tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the β-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA).MethodsIn the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used.ResultsOn average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased.ConclusionThe present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the β-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors.Clinical trial registrationJapanese Clinical Trials Registry UMIN000003693.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-017-0299-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)

et al. 2017

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“…Studies conducted by Shimada et al (18) in adults with slowly progressive T1DM showed progression of disease in subjects treated with pioglitazone when compared to those receiving metformin. At two years post intervention, 3 of the 4 subjects in the pioglitazone group reached a HbA1c of 8% compared to 1 of 5 in the metformin group (18).…”

Section: Discussionmentioning

confidence: 98%

“…At two years post intervention, 3 of the 4 subjects in the pioglitazone group reached a HbA1c of 8% compared to 1 of 5 in the metformin group (18). Shimada et al (18) reported that pioglitazone accelerates disease progression, but this conclusion may have been impacted by the small sample size.…”

Section: Discussionmentioning

confidence: 99%

Effect of Pioglitazone on the Course of New-Onset Type 1 Diabetes Mellitus

Tafuri¹,

Godil²,

Lane³

et al. 2013

JCRPE

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Objective: Type 1 diabetes mellitus (T1DM) is caused by insulin deficiency resulting from progressive destruction of β cells. The histological hallmark of the diabetic islet is mononuclear cell infiltration. Thiazolidinediones (TZDs) activate PPARg and enhance the actions of insulin. Studies in non-obese diabetic and streptocotozin-treated mouse models demonstrated that pretreatment with TZDs prevented the development of T1DM. The purpose of this study was to examine whether pioglitazone, given with insulin, preserved β cell function in patients with new-onset T1DM.Methods: This was a randomized, double-blind, placebo-controlled 24-week study. Subjects received pioglitazone or placebo. Blood sugar, glycated hemoglobin (HbA1c), C-peptide, and liver enzymes were measured at baseline. Boost© stimulated C-peptide responses were measured at baseline and at 24 weeks. Blood sugar, insulin dose, height, weight, and liver enzymes were monitored at each visit. HbA1c was performed every 12 weeks.Results: Of the 15 patients, 8 received pioglitazone, and 7 - placebo. There was no clinical improvement in HbA1c between or within groups at the completion of the study. Mean peak C-peptide values were similar between groups at baseline. Mean peak C-peptide level was slightly higher at 24 weeks in the pioglitazone group compared to the placebo (1.8 vs. 1.5ng/mL) which was considered as clinically insignificant. The interaction of HbA1c and insulin dose (HbA1c* insulin/kg/day), which combines degree of diabetic control and dose of insulin required to achieve this control, showed transient improvement in the pioglitazone group at 12 weeks but was not sustained at 24 weeks.Conclusion: In this pilot study, pioglitazone did not preserve β cell function when compared to placebo.Conflict of interest:None declared.

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“…We need to compare insulin and metformin directly in a future study to confirm whether metformin really reduces the progression to an insulindependent state in SPIDDM patients. Regarding thiazolidinediones, which improve insulin resistance, several previous studies have reported the use of this drug in patients with SPIDDM (16)(17)(18); however, there is no consensus to date. Biguanides also improve insulin resistance and may preserve the insulin secretion capacity, although there are no reports regarding the clinical course of SPIDDM after using this class of drug.…”

Section: Discussionmentioning

confidence: 99%

Slowly Progressive Type 1 Diabetes Treated with Metformin for Five Years after Onset

et al. 2013

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A 52-year-old man was diagnosed with slowly progressive type 1 diabetes (SPIDDM). We expected him to quickly progress to an insulin-dependent state due to a high anti-glutamic acid decarboxylase antibody titer (23.9 U/mL). At SPIDDM diagnosis, he was in a non-insulin-dependent state, with a fasting serum C-peptide immunoreactivity level of 2.5 ng/mL. Therefore, we prescribed metformin. His glycemic control remained stable, and his intrinsic insulin secretion capacity was maintained for five years. Although one case is insufficient to draw firm conclusions, this report suggests that metformin is a therapeutic choice for SPIDDM when the insulin secretion capacity is maintained.

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Pioglitazone may accelerate disease course of slowly progressive type 1 diabetes

Abstract: Pioglitazone may accelerate the disease course of SPIDDM.

Cited by 16 publications

References 20 publications

Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)

Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)

Effect of Pioglitazone on the Course of New-Onset Type 1 Diabetes Mellitus

Slowly Progressive Type 1 Diabetes Treated with Metformin for Five Years after Onset

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