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Effect of sodium–glucose cotransporter 2 inhibitors on insulin resistance; a systematic review and meta-analysis

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Abstract

Aim

Recent studies have indicated that Sodium–GLucose co-Transporter 2 Inhibitors (SGLT2Is) may increase insulin sensitivity (IS); however, these results are heterogeneous and need to be systematically assessed.

Method

We searched MEDLINE/PubMed, Embase, Web of Science, Scopus, Cochrane Library, Ovid, and ProQuest using a predefined search query. Randomized clinical trials on SGLT2Is with a passive control group or metformin controlled group were included. Risk of bias assessment was performed using the Cochrane risk of bias assessment tool. Meta-analysis was performed separately on studies with type 2 diabetes mellitus (T2DM) population and studies with non-T2DM population and also for passive- and active-controlled studies using standardized mean difference (SMD) as the measure of the effect size. Subgroup analysis was performed according to different types of SGLT2Is. Meta-regression analysis was performed according to the dose and duration of intervention.

Results

Twenty-two studies (6 on non-T2DM population) with a total of 1421 (243 non-T2DM) patients were included. Six studies (3 on T2DM and 3 on non-T2DM) were controlled by metformin, and others were passively controlled. SGLT2Is could significantly increase IS in T2DM patients (SMD = 0.72 [0.32–1.12]). SGLT2Is could reduce insulin resistance in non-T2DM population, but this was not significant. SGLT2Is were not inferior to metformin in reducing insulin resistance. Subgroup analysis indicated that dapagliflozin could significantly increase IS, but empagliflozin was not associated with significant improvement in IS. Meta-regression analysis indicated no effect for dose but duration of SGLT2I administration on IS.

Conclusion

SGLT2Is, particularly dapagliflozin, could increase IS. These results need to be consolidated by further studies.

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Abbreviations

SGLT2Is:

Sodium–glucose cotransporter 2 inhibitors

IS:

Insulin sensitivity

IR:

Insulin resistance

T2DM:

Type 2 diabetes mellitus

SMD:

Standardized mean difference

PRISMA:

Preferred reporting items for systematic reviews and meta-analyses

PROSPERO:

Prospective register of systematic reviews

PCOS:

Polycystic ovarian syndrome

HOMA-IR:

Homeostasis model assessment of insulin resistance

GDR:

Glucose disposal rate

RoB-2:

Cochrane risk of bias tool for randomized trials-2

HEC:

Hyperinsulinemic euglycemic clamp

Akt/PI3K:

Protein kinase B (Akt)/phosphoinositide 3-kinase

JNK/ERk:

C-Jun NH2-terminal kinase/extracellular signal-activated protein kinase

IRSs:

Insulin Receptor Substrates

CoA:

Coenzyme A

CPT1:

Carnitine palmitoyl transferase i

UCP3:

Uncoupling protein 3

CD:

Cluster of differentiation

TNF:

Tumor necrosis factor

IL-6:

Interleukin-1

MCP:

Monocyte chemoattractant protein

ROS:

Reactive oxygen species

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Acknowledgements

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Funding

No funds, grants, or support were received for the submitted work.

Author information

Author notes

  1. Mohammad Fakhrolmobasheri and Amir Parsa Abhari have contributed to this study equally.

Authors and Affiliations

  1. Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

    Mohammad Fakhrolmobasheri, Amir Parsa Abhari, Behrad Manshaee & Davood Shafie

  2. Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Maryam Heidarpour

  3. Student Research Committee, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Ehsan Mohammadbeigi & Sadegh Mazaheri-Tehrani

  4. Medical Library and Information Sciences Department, Health Information Technology Research Center, School of Management and Medical Information Sciences, Isfahan University of Medical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Amir Mohammad Mozafari

  5. Shahrekord University of Medical Sciences, Shahrekord, Iran

    Amir Mohammad Mozafari

  6. Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

    Sadegh Mazaheri-Tehrani

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  1. Mohammad Fakhrolmobasheri
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Contributions

MF was involved in conceptualization, screening entries, data extraction, writing the original draft, writing, reviewing, and editing, and risk of bias assessment. APA was responsible for conceptualization, protocol submission, data extraction, formal analysis, writing the original draft, and writing, review, and editing. BM took part in screening entries, data extraction, investigation, and writing the original draft. MH participated in conceptualization and supervision. DS carried out conceptualization, supervision, and risk of bias assessment. EM and SMT conducted data extraction and investigation. AMM screened the entries.

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Correspondence to Davood Shafie.

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Fakhrolmobasheri, M., Abhari, A.P., Manshaee, B. et al. Effect of sodium–glucose cotransporter 2 inhibitors on insulin resistance; a systematic review and meta-analysis. Acta Diabetol 60, 191–202 (2023). https://doi.org/10.1007/s00592-022-01981-1

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