Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study

DeFronzo, Ralph A.; Okerson, Ted; Viswanathan, Prabhakar; Guan, Xiaodan; Holcombe, John H.; MacConell, Leigh

doi:10.1185/03007990802418851

Cited by 338 publications

(254 citation statements)

References 27 publications

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“…1A) and blood glucose levels (154 Ϯ 9 vs. 147 Ϯ 8 mg/dl) was not different between WT and Glp1r Ϫ/Ϫ mice following an oral NaCl and water load with subsequent quantitative urine collection for 3 h (vehicle groups). Com- pared with vehicle, EX4 (10 g/kg ip), the 39-amino acid naturally occurring GLP-1R agonist (12), which is highly resistant to the proteolytic action of DPP-4 in vivo (3,8), lowered blood glucose levels in WT mice (104 Ϯ 8 vs. 154 Ϯ 9 mg/dl, P Ͻ 0.05) and increased urinary excretion of H 2 O and Na ϩ , whereas K ϩ excretion was not significantly changed (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

125

109

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Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na ϩ reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na ϩ excretion, and renal membrane expression of the Na ϩ /H ϩ exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na ϩ reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.glucagon-like peptide-1; dipeptidyl peptidase-4; NHE3; cAMP; proximal tubule GLUCAGON-LIKE PEPTIDE -1 (GLP-1), an incretin hormone secreted from enteroendocrine L cells in the intestine, stimulates glucose-dependent insulin release and may promote preservation of beta-cell function in patients with type 2 diabetes (9, 10). As a consequence, GLP-1 has been a principal focus of clinical and basic diabetes research in recent years. After secretion, active GLP-1 is rapidly cleaved by the widely expressed enzyme dipeptidyl peptidase-4 (DPP-4, CD26), such that the half-life of bioactive GLP-1 is Ͻ3 min. Therefore, therapeutic manipulation of the GLP-1 system includes strategies that inhibit the degradation of GLP-1 by DPP-4 (i.e., DPP-4 inhibitors) or degradation-resistant GLP-1 receptor (GLP-1R) agonists with a longer half-life, such as exendin-4 (EX4) or liraglutide.In addition to its metabolic effects, GLP-1 affects kidney function. Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6, 30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in...

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Section: Resultsmentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

125

109

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“…DPP-4 inhibitors are known to reduce both FPG and PPG [72]. In particular, DPP-4 inhibitors effectively lower PPG by increasing active GLP-1 and decreasing glucagon levels [73]. We examined whether the efficacy of DPP-4 inhibitors in lowering FPG or PPG differs between Asian-and nonAsian-dominant studies.…”

Section: Discussionmentioning

confidence: 99%

Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis

et al. 2013

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Aims/hypothesis The aim of this work was to compare the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Asian and non-Asian patients with type 2 diabetes. Methods We searched MEDLINE, EMBASE, LILACS, CENTRAL, ClinicalTrials.gov and conference proceedings. Studies were eligible if they were randomised controlled trials with a treatment duration of at least 12 weeks, compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy, had information on ethnicity and HbA 1c values and were published or described in English. A systematic review and meta-analysis with a meta-regression analysis was conducted. Results Among 809 potentially relevant studies, 55 trials were included. A meta-analysis revealed that DPP-4 inhibitors lowered HbA 1c to a greater extent in studies with ≥50% Asian participants (weighted mean difference [WMD] −0.92%; 95% CI −1.03, −0.82) than in studies with <50% Asian participants (WMD −0.65%; 95% CI −0.69, −0.60). The between-group difference was −0.26% (95% CI −0.36, −0.17, p<0.001). The baseline BMI significantly correlated with the HbA 1c -lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA 1c <7.0% (53.0 mmol/mol) was higher in studies with ≥50% Asian participants (3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0]). The fasting plasma glucose-lowering efficacy was higher with monotherapy in the Asiandominant studies, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups. Conclusions/interpretation DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups; this requires further investigation to understand the underlying mechanism, particularly in relation to BMI.

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“…However, head-to-head comparisons of the two therapies are scarce, and only one DPP-4 (sitagliptin) has been so evaluated. Two trials compared sitagliptin 100 mg vs exenatide either twice daily [76] or once weekly [36], and a further trial compared sitagliptin 100 mg with liraglutide once daily [40] (Table 2). …”

Section: Dpp-4 Inhibitors Vs Glp-1 Receptor Agonistsmentioning

confidence: 99%

“…In a trial comparing short-term (2-week) treatment with exenatide (5 µg twice daily for 1 week, then 10 µg twice daily for 1 week) vs sitagliptin 100 mg once daily, the results were better with exenatide treatment, as assessed in terms of lowering postprandial glucose, increasing insulin levels, decreasing glucagon levels and decreasing caloric intakes [76]. A 26-week, randomized, double-dummy superiority trial assessed the safety and efficacy of exenatide 2mg once a week vs sitagliptin 100 mg once a day in patients treated with metformin.…”

Section: Dpp-4 Inhibitors Vs Glp-1 Receptor Agonistsmentioning

confidence: 99%

DPP-4 inhibitors in the management of type 2 diabetes: A critical review of head-to-head trials

Scheen¹

2012

Diabetes & Metabolism

171

121

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Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA 1c reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA 1c reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA 1c when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA 1c and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-tohead trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials. Keywords:Clinical trial-DPP-4 inhibitor; Alogliptin; Linagliptin; Saxagliptin; Sitagliptin; Vildagliptin; Type 2 diabetes mellitus; Review Résumé Les inhibiteurs de la DPP-4 dans le traitement du diabète de type 2 : revue critique des essais cliniques contrôlés.Les inhibiteurs de la dipeptidylpeptidase-4 (DPP-4) offrent de nouvelles options pour le traitement du diabète de type 2. Des comparaisons directes avec d'autres médicaments antidiabétiques chez des patients naïfs de tout traitement ont démontré que les inhibiteurs de la DPP-4 étaient un peu moins puissants pour diminuer ...

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Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study

Cited by 338 publications

References 27 publications

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis

DPP-4 inhibitors in the management of type 2 diabetes: A critical review of head-to-head trials

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