For GLP1

Abstract

For GLP1

Guillermo Dieuzeide

Doctor of Medicine, University of Buenos Aires (UBA), specialist in Endocrinology and Diabetes, Comprehensive Care Center for Diabetes, Endocrinology and Metabolism, Chacabuco, Province of Buenos Aires, Argentina

The Past

The story began in 1902 with the discovery of secretin by Sarling and Bayliss. In 1932, Le Barre named a substance that lowered blood glucose levels without pancreatic exocrine secretion an “incretin.” In the 1970s, Creutzfeldt defined incretins as intestinal hormones that stimulate insulin secretion. Subsequently, proglucagon was discovered, and in 1980, GLP-1 (Holst, Habener, Drucker). In 1971, Brown described GIP. By 1986, Nauck observed that diabetics had lower incretin secretion. Interestingly, in 1990, a GLP-1-like protein was found in the saliva of the Gila Monster, which spurred its pharmacological development.

The present

The therapeutic leap came with the LEADER study, which demonstrated that GLP-1 analogues not only reduce blood glucose, but also cardiovascular mortality. This was followed by other pivotal studies:

Estudio

N pacientes

Duración (años)

MACE HR

Muerte CV HR

IAM no fatal HR

ACV no fatal HR

Leader

9340

3,8

0,87 (0,78-0,97)

0,78 (0,66-0,93)

0,88 (0,75-1,03)

0,89 (0,72-1,11)

Sustain-6

3297

104 sem

0,74 (0,58-0,95)

0,98 (0,65-1,48)

0,74 (0,51-1,08)

0,61 (0,38-0,99)

Harmony

9901

1,6

0,78 (0,68-0,90)

0,93 (0,73-1,19)

0,75 (0,61-0,90)

0,86 (0,65-1,14)

Rewind

4076

5,4

0,88 (0,79-0,99)

0,91 (0,76-1,06)

0,96 (0,79-1,19)

0,76 (0,61-0,71)

Ampitud

4076

1,81

0,73 (0,58-0,92)

0,72 (0,50-1,03)

0,78 (0,55-1,10)

0,80 (0,48-1,31)

Soul

9650

4,1

0,86 (0,77-0,96)

0,93 (0,80-1,09)

0,74 (0,61-0,89)

0,88 (0,70-1,1)

Furthermore, the FLOW study showed a 24% reduction in serious adverse renal events, and SELECT demonstrated a 53% reduction in cardiovascular death in obese individuals without diabetes.

The Future

The great potential of various combinations is being investigated: dual combinations (GLP-1/GIP: tirzepatide), combinations with glucagon analogs (survodutide), triple combinations (retratutide), combinations with weekly insulins (Icodec + GLP-1A), combinations with amylin analogs (cariglintide), or combinations with oral non-peptide agonists (orforglipron).