Dulaglutide

1. 01Bloodstream

   Injected, then a slow, long-lasting presence in the blood

   The medicine goes under the skin and slowly moves into the blood. It is joined to part of an antibody, which helps it stay in the body much longer. So it lasts for days, not minutes.

   For experts

   After subcutaneous administration, time to peak concentration at steady state is 24 to 72 hours (median 48 hours); steady state is reached in 2 to 4 weeks with an accumulation ratio of about 1.56 and elimination half-life of about 5 days. The GLP-1 analogue is fused to a modified IgG4 Fc. In animal studies only (rats and cynomolgus monkeys), LY2189265 (the development code for dulaglutide) had a half-life of 1.5 to 2 days, and serum immunoreactivity representing active compound persisted for more than 6 days.[src][src]

2. 02Pancreas

   Switches on GLP-1 receptors in the pancreas

   In the pancreas, dulaglutide fits the same lock as the natural GLP-1 hormone. This tells insulin-making cells to release insulin, mostly when blood sugar is high.

   For experts

   Dulaglutide activates the GLP-1 receptor, a membrane receptor coupled to adenylyl cyclase, on pancreatic beta cells. Intracellular cAMP rises, leading to glucose-dependent insulin release. In patients with type 2 diabetes both first- and second-phase insulin secretion were increased versus placebo.[src]

3. 03Pancreas

   Turns down glucagon

   Another pancreas hormone, glucagon, tells the liver to release sugar. Dulaglutide lowers glucagon, so less sugar is released.

   For experts

   Dulaglutide decreases glucagon secretion. In a monotherapy trial, fasting glucagon fell by 1.71 and 2.05 pmol/L from baseline at week 26 at the two studied doses. In a separate clinical pharmacology study, fasting and 2-hour postprandial glucose were lower than placebo, an effect that can be seen after a single dose and was sustained after 6 weeks of dosing.[src]

4. 04Stomach

   Slows the stomach

   Food leaves the stomach more slowly, so sugar from a meal enters the blood more gradually. This effect is biggest after the first dose and fades a bit over time.

   For experts

   Dulaglutide delays gastric emptying. The delay is dose-dependent, attenuated with adequate dose escalation, largest after the first dose and diminishing with subsequent doses. The most common adverse reactions (5% or more) are nausea, diarrhoea, vomiting, abdominal pain and decreased appetite.[src]

5. 05Heart

   Fewer heart and stroke events in a large trial

   In a large trial of people with type 2 diabetes, those given dulaglutide had somewhat fewer heart attacks, strokes or heart-related deaths than those given placebo. Scientists do not fully know how.

   For experts

   In REWIND (9,901 participants, median 5.4 years), the primary composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death occurred in 12.0% on dulaglutide versus 13.4% on placebo (HR 0.88, 95% CI 0.79-0.99, p=0.026). All-cause mortality did not differ significantly (HR 0.90, 95% CI 0.80-1.01). This is a human outcome result; the trial does not establish the mechanism.[src]

6. 06Elsewhere

   Broken down like any protein

   Dulaglutide is a protein. The body eventually breaks it into amino acids, the small building blocks of all proteins.

   For experts

   Dulaglutide is presumed to be degraded into component amino acids by general protein catabolism. Age, sex, race, body weight and renal or hepatic impairment did not have clinically relevant effects on its pharmacokinetics. Apparent population mean clearance is 0.142 L/h.[src]

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