Effect of linagliptin on glucose metabolism and pancreatic beta cell function in patients with persistent prediabetes after metformin and lifestyle

Mildred Fátima de la Luz Alvarez-Canales, Sara Stephania Salazar-López, Diana Farfán-Vázquez, Yosceline Estrella Martínez-López, Jessica Noemí González-Mena, Lilia Marisela Jiménez-Ceja, Katya Vargas-Ortiz, María Lola Evia-Viscarra, María Luisa Montes de Oca-Loyola, Franco Folli, Alberto Aguilar-García, Rodolfo Guardado-Mendoza, Mildred Fátima de la Luz Alvarez-Canales, Sara Stephania Salazar-López, Diana Farfán-Vázquez, Yosceline Estrella Martínez-López, Jessica Noemí González-Mena, Lilia Marisela Jiménez-Ceja, Katya Vargas-Ortiz, María Lola Evia-Viscarra, María Luisa Montes de Oca-Loyola, Franco Folli, Alberto Aguilar-García, Rodolfo Guardado-Mendoza

Abstract

The goal of the study was to evaluate the effect of adding linagliptin to metformin and lifestyle on glucose levels and pancreatic β-cell function in patients with persistent impaired glucose tolerance (IGT) after 12 months of metformin and lifestyle. A single center parallel double-blind randomized clinical trial with 6 months of follow-up was performed in patients with persistent IGT after 12 months of treatment with metformin and lifestyle; patients were randomized to continue with metformin 850 mg twice daily (M group, n = 12) or linagliptin/metformin 2.5/850 mg twice daily (LM group, n = 19). Anthropometric measurements were obtained by standard methods and by bioelectrical impedance; glucose was measured by dry chemistry, insulin by chemiluminescence, and pancreatic β-cell function was calculated with the disposition index using glucose and insulin values during oral glucose tolerance test (OGTT) and adjusting by insulin sensitivity. The main outcomes were glucose levels during OGTT and pancreatic β-cell function. Patients in the LM group had a reduction in weight (-1.7 ± 0.6, p < 0.05) and body mass index (BMI, -0.67 ± 0.2, p < 0.05). Glucose levels significantly improved in LM group with a greater reduction in the area under the glucose curve during OGTT (AUCGluc0_120min) as compared to the M group (-4425 ± 871 vs -1116 ± 1104 mg/dl/120 min, p < 0.001). Pancreatic β-cell function measured with the disposition index, improved only in LM group (2.3 ± 0.23 vs 1.7 ± 0.27, p 0.001); these improvements persisted after controlling for OGTT glucose levels. The differences in pancreatic β-cell function persisted also after pairing groups for basal AUCGluc0_120min. The addition of linagliptin to patients with persistent IGT after 12 months of treatment with metformin and lifestyle, improved glucose levels during OGTT and pancreatic β-cell function after 6 months of treatment.Trial registration: Clinicaltrials.gov with the ID number NCT04088461.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Study profile.
Figure 2
Figure 2
Glucose levels during OGTT at basal and after 6 months (a); change in glucose levels (b), HbA1c (c), insulin sensitivity (d), and pancreatic β-cell function (e) from 0 to 6 months between the study groups. * p˂0.05 for comparisons in LM group between basal and 6 months, # p˂0.05 for inter-group comparisons at basal (0 months).

References

    1. Saeedi P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019;157:107843. doi: 10.1016/j.diabres.2019.107843.
    1. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21:1414–1431. doi: 10.2337/diacare.21.9.1414.
    1. Alegre-Diaz J, et al. Diabetes and cause-specific mortality in Mexico City. N. Engl. J. Med. 2016;375:1961–1971. doi: 10.1056/NEJMoa1605368.
    1. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med24, 137–144. 10.1111/j.1464-5491.2007.02043.x (2007).
    1. Cho NH, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 2018;138:271–281. doi: 10.1016/j.diabres.2018.02.023.
    1. Cosentino F, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 2020;41:255–323. doi: 10.1093/eurheartj/ehz4865556890[pii].
    1. Prattichizzo F, de Candia P, De Nigris V, Nicolucci A, Ceriello A. Legacy effect of intensive glucose control on major adverse cardiovascular outcome: systematic review and meta-analyses of trials according to different scenarios. Metabolism. 2020;110:154308. doi: 10.1016/j.metabol.2020.154308.
    1. Edelstein SL, et al. Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes. 1997;46:701–710. doi: 10.2337/diab.46.4.701.
    1. Abdul-Ghani MA, Williams K, DeFronzo R, Stern M. Risk of progression to type 2 diabetes based on relationship between postload plasma glucose and fasting plasma glucose. Diabetes Care. 2006;29:1613–1618. doi: 10.2337/dc05-1711.
    1. Classification and Diagnosis of Diabetes Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42:S13–S28. doi: 10.2337/dc19-S00242/Supplement_1/S13[pii].
    1. Bergman M, et al. Review of methods for detecting glycemic disorders. Diabetes Res. Clin. Pract. 2020;165:108233. doi: 10.1016/j.diabres.2020.108233.
    1. den Biggelaar LJ, et al. Discriminatory ability of simple OGTT-based beta cell function indices for prediction of prediabetes and type 2 diabetes: the CODAM study. Diabetologia. 2017;60:432–441. doi: 10.1007/s00125-016-4165-310.1007.
    1. Tripathy D, et al. Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW. J. Clin. Endocrinol. Metab. 2016;101:2056–2062. doi: 10.1210/jc.2015-4202.
    1. Ferrannini E, et al. beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J. Clin. Endocrinol. Metab. 2005;90:493–500. doi: 10.1210/jc.2004-1133.
    1. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes. 2006;55:1430–1435. doi: 10.2337/db05-1200.
    1. Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130–1139. doi: 10.2337/diacare.2951130.
    1. Federici M, et al. High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes. 2001;50:1290–1301. doi: 10.2337/diabetes.50.6.1290.
    1. Folli F, et al. Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus. Diabetes Obes. Metab. 2018;20(Suppl 2):137–144. doi: 10.1111/dom.13380.
    1. Guardado Mendoza R, et al. Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas) Diabetologia. 2015;58:1814–1826. doi: 10.1007/s00125-015-3625-5.
    1. Guardado-Mendoza R, et al. Islet amyloid polypeptide response to maximal hyperglycemia and arginine is altered in impaired glucose tolerance and type 2 diabetes mellitus. Acta Diabetol. 2017;54:53–61. doi: 10.1007/s00592-016-0904-710.1007.
    1. Guardado-Mendoza R, et al. Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons. Proc. Natl. Acad. Sci. USA. 2009;106:13992–13997. doi: 10.1073/pnas.0906471106.
    1. Vilchis-Flores LH, et al. Pancreatic beta-cell dysfunction in normoglycemic patients and risk factors. Acta Diabetol. 2019;56:1305–1314. doi: 10.1007/s00592-019-01411-910.1007.
    1. Campos-Nonato I, Ramirez-Villalobos M, Flores-Coria A, Valdez A, Monterrubio-Flores E. Prevalence of previously diagnosed diabetes and glycemic control strategies in Mexican adults: ENSANUT-2016. PLoS ONE. 2020;15:e0230752. doi: 10.1371/journal.pone.0230752PONE-D-19-29166[pii].
    1. Basto-Abreu, A. et al. [Prevalence of diabetes and poor glycemic control in Mexico: results from Ensanut 2016.]. Salud Publica Mex62, 50–59. 10.21149/10752 (2020).
    1. Vatcheva KP, Fisher-Hoch SP, Reininger BM, McCormick JB. Sex and age differences in prevalence and risk factors for prediabetes in Mexican-Americans. Diabetes Res. Clin. Pract. 2020;159:107950. doi: 10.1016/j.diabres.2019.107950.
    1. Huang Y, et al. Associations of prediabetes with all-cause and cardiovascular mortality: a meta-analysis. Ann. Med. 2014;46:684–692. doi: 10.3109/07853890.2014.955051.
    1. Gong Q, et al. Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol. 2019;7:452–461. doi: 10.1016/S2213-8587(19)30093-2.
    1. Perreault L, et al. Regression from prediabetes to normal glucose regulation and prevalence of microvascular disease in the diabetes prevention program outcomes study (DPPOS) Diabetes Care. 2019;42:1809–1815. doi: 10.2337/dc19-0244dc19-0244[pii].
    1. Perreault L, et al. Regression from prediabetes to normal glucose regulation is associated with reduction in cardiovascular risk: results from the Diabetes Prevention Program outcomes study. Diabetes Care. 2014;37:2622–2631. doi: 10.2337/dc14-0656dc14-0656[pii].
    1. Knowler WC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403. doi: 10.1056/NEJMoa012512346/6/393[pii].
    1. Tuomilehto J, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 2001;344:1343–1350. doi: 10.1056/NEJM200105033441801.
    1. Vargas-Ortiz K, et al. Effect of a family and interdisciplinary intervention to prevent T2D: randomized clinical trial. BMC Public Health. 2020;20:97. doi: 10.1186/s12889-020-8203-110.1186/s12889-020-8203-1[pii].
    1. Foretz M, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 2010;120:2355–2369. doi: 10.1172/JCI4067140671[pii].
    1. Ahren B, Foley JE. Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism. Diabetologia. 2016;59:907–917. doi: 10.1007/s00125-016-3899-210.1007/s00125-016-3899-2[pii].
    1. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr. Rev. 2014;35:992–1019. doi: 10.1210/er.2014-1035.
    1. Kaku K, et al. Sitagliptin improves glycaemic excursion after a meal or after an oral glucose load in Japanese subjects with impaired glucose tolerance. Diabetes Obes Metab. 2015;17:1033–1041. doi: 10.1111/dom.12507.
    1. McGuire DK, et al. Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA. Circulation. 2019;139:351–361. doi: 10.1161/CIRCULATIONAHA.118.038352.
    1. Rosenstock J, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321:69–79. doi: 10.1001/jama.2018.182692714646[pii].
    1. Guardado-Mendoza R, et al. The combination of linagliptin, metformin and lifestyle modification to prevent type 2 diabetes (PRELLIM), A randomized clinical trial. Metabolism. 2020;104:154054. doi: 10.1016/j.metabol.2019.154054.
    1. Hernandez-Avila M, et al. Validity and reproducibility of a food frequency questionnaire to assess dietary intake of women living in Mexico City. Salud Publica Mex. 1998;40:133–140. doi: 10.1590/s0036-36341998000200005.
    1. Utzschneider KM, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009;32:335–341. doi: 10.2337/dc08-1478dc08-1478[pii].
    1. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–1470. doi: 10.2337/diacare.22.9.1462.
    1. Martinez-Gonzalez MA, Lopez-Fontana C, Varo JJ, Sanchez-Villegas A, Martinez JA. Validation of the Spanish version of the physical activity questionnaire used in the Nurses' Health Study and the Health Professionals' Follow-up Study. Public Health Nutr. 2005;8:920–927. doi: 10.1079/PHN2005745.
    1. DeFronzo RA, et al. Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study. Diabetologia. 2010;53:435–445. doi: 10.1007/s00125-009-1614-2.
    1. DeFronzo RA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 2011;364:1104–1115. doi: 10.1056/NEJMoa1010949.
    1. the Diabetes Prevention Program Outcomes Study Diabetes Prevention Program Research, G. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up. Lancet Diabetes Endocrinol. 2015;3:866–875. doi: 10.1016/S2213-8587(15)00291-0.
    1. Daniele G, et al. Effects of treatment with metformin and/or sitagliptin on beta-cell function and insulin resistance in prediabetic women with previous gestational diabetes. Diabetes Obes Metab. 2020;22:648–657. doi: 10.1111/dom.13940.
    1. Nahon KJ, et al. Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial. Diabetologia. 2018;61:2386–2397. doi: 10.1007/s00125-018-4716-x10.1007/s00125-018-4716-x[pii].
    1. Wang Z, et al. Effects of saxagliptin on glucose homeostasis and body composition of obese patients with newly diagnosed pre-diabetes. Diabetes Res. Clin. Pract. 2017;130:77–85. doi: 10.1016/j.diabres.2017.05.012.
    1. Defronzo RA, et al. Actos Now for the prevention of diabetes (ACT NOW) study. BMC Endocr. Disord. 2009;9:17. doi: 10.1186/1472-6823-9-17.
    1. Armato JP, DeFronzo RA, Abdul-Ghani M, Ruby RJ. Successful treatment of prediabetes in clinical practice using physiological assessment (STOP DIABETES) Lancet Diabetes Endocrinol. 2018;6:781–789. doi: 10.1016/S2213-8587(18)30234-1.
    1. le Roux CW, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389:1399–1409. doi: 10.1016/S0140-6736(17)30069-7.
    1. Ahren B. Beta- and alpha-cell dysfunction in subjects developing impaired glucose tolerance: outcome of a 12-year prospective study in postmenopausal Caucasian women. Diabetes. 2009;58:726–731. doi: 10.2337/db08-1158.
    1. Faerch K, et al. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes. 2015;64:2513–2525. doi: 10.2337/db14-1751db14-1751[pii].
    1. Kishimoto S, et al. Effects of the dipeptidyl peptidase 4 inhibitor alogliptin on blood pressure in hypertensive patients with type 2 diabetes mellitus. Am. J. Hypertens. 2019;32:695–702. doi: 10.1093/ajh/hpz0655482513[pii].
    1. Liu H, et al. The protective role of DPP4 inhibitors in atherosclerosis. Eur. J. Pharmacol. 2020;875:173037. doi: 10.1016/j.ejphar.2020.173037.
    1. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Incretin-based therapies and renin-angiotensin system: Looking for new therapeutic potentials in the diabetic milieu. Life Sci. 2020;256:117916. doi: 10.1016/j.lfs.2020.117916.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever