The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes

Frías, Juan P.; Bastyr, Edward J.; Vignati, Louis; Tschöp, Matthias H.; Schmitt, Christophe; Owen, K; Christensen, Rune Haubo Bojesen; DiMarchi, Richard D.

doi:10.1016/j.cmet.2017.07.011

Cited by 254 publications

(197 citation statements)

References 48 publications

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“…257 Dual incretin receptor agonists. [259][260][261] Evolving understanding of the enteroendocrine cell biology, gut microbiota, and endocannabinoid system [125][126][127] A randomized, placebo-controlled and active comparator-controlled Phase II trial was reported for one of these dual incretin receptor agonists, LY3298176, in patients with type 2 diabetes.…”

Section: Safety Issues and Tolerabilitymentioning

confidence: 99%

Incretins in obesity and diabetes

Chia

Egan

2019

Annals of the New York Academy of Sciences

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Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from β cells in a glucose‐dependent manner. Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP‐1, and our current knowledge of the relationships between GIP and GLP‐1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP‐1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells.

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Section: Safety Issues and Tolerabilitymentioning

confidence: 99%

Incretins in obesity and diabetes

Chia

Egan

2019

Annals of the New York Academy of Sciences

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“…It is possible that future drugs targeting these pathways can be designed to have greater lipid-lowering effects. Indeed, a dual agonist for both GLP-1 receptor and the glucose-dependent insulinotropic peptide (GIP) receptor lowers total cholesterol, potentially through the GIP signaling pathway [87]. …”

Section: Impact Of Diabetes On Lipoprotein Metabolismmentioning

confidence: 99%

Unexplained reciprocal regulation of diabetes and lipoproteins

Higuchi

Izquierdo

Haeusler

2018

Current Opinion in Lipidology

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Purpose of review Type 2 diabetes is associated with a characteristic dyslipidemia that may exacerbate cardiovascular risk. The causes of, and the effects of new antihyperglycemia medications on, this dyslipidemia, are under investigation. In an unexpected reciprocal manner, lowering LDL-cholesterol with statins slightly increases the risk of diabetes. Here we review the latest findings. Recent findings The inverse relationship between LDL-cholesterol and diabetes has now been confirmed by multiple lines of evidence. This includes clinical trials, genetic instruments using aggregate single nucleotide polymorphisms, as well as at least eight individual genes – HMGCR, NPC1L1, HNF4A, GCKR, APOE, PCKS9, TM6SF2, and PNPLA3 – support this inverse association. Genetic and pharmacologic evidence suggest that HDLcholesterol may also be inversely associated with diabetes risk. Regarding the effects of diabetes on lipoproteins, new evidence suggests that insulin resistance but not diabetes per se may explain impaired secretion and clearance of VLDL-triglycerides. Weight loss, bariatric surgery, and incretin-based therapies all lower triglycerides, whereas SGLT2 inhibitors may slightly increase HDL-cholesterol and LDL-cholesterol. Summary Diabetes and lipoproteins are highly interregulated. Further research is expected to uncover new mechanisms governing the metabolism of glucose, fat, and cholesterol. This topic has important implications for treating type 2 diabetes and cardiovascular disease.

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“…Unexpectedly, the combined action was observed to lower body weight in obese mice when compared with therapy with either agonist alone . These co‐agonists have advanced to human study where with sustained therapy there is profound lowering of blood glucose, and body weight consistent with what is customarily observed with GLP‐1 therapy . Additionally, there was a reduction in plasma LDL‐cholesterol and circulating leptin.…”

Section: Peptides Purposefully Designed For Multiple Biological Actionsmentioning

confidence: 78%

Max Bergmann award lecture:Macromolecular medicinal chemistry as applied to metabolic diseases

DiMarchi

Mayer

Gelfanov

et al. 2018

Journal of Peptide Science

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This review presents the scope of research presented in an October 2016 lecture pertaining to the award of the 2015 Max Bergmann Medal. The advancement in synthetic and biosynthetic chemistry as applied to the discovery of novel macromolecular drug candidates is reviewed.The evolution of the technology from the design, synthesis, and development of the first biosynthetic peptides through the emergence of peptide-based incretin agonists that function by multiple biological mechanisms is exemplified by the progression of such peptides from preclinical to clinical study. A closing section highlights recent progress made in total chemical synthesis of insulin and related peptides.

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The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes

Cited by 254 publications

References 48 publications

Incretins in obesity and diabetes

Incretins in obesity and diabetes

Unexplained reciprocal regulation of diabetes and lipoproteins

Max Bergmann award lecture:Macromolecular medicinal chemistry as applied to metabolic diseases

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