Thread by @fernandbteich

1/ Diabetes mellitus is one of the most active areas of drug development. Fascinating advances have occurred in the past decade, leading to easier-to-administer medications and reductions in cardiovascular mortality.

2/ I saw a young patient with T2DM & obesity (BMI 62 kg/m2). She was being treated with high-dose insulin glargine at night, lispro sliding scale & metformin. Her morning BS were ~140 and her pre-meal levels ~150 mg/dL. Despite these numbers, her A1c was 8.6%. Next step?

3/ A reasonable A1c goal for a young patient is ~7%. A ⬆️ A1c with reasonable morning and pre-prandial BS levels suggests post-prandial excursions poorly covered by lispro.
The ideal drug to add is one that is potent (⬇️ A1c >1%), is easy to administer and does not further ⬆️Wt.

4/ GLP-1 receptor agonists seem to ✅ all the right marks on this list. I was fortunate enough to follow the evolution of this class of drugs after their advent on the market in 2005. From daily injections with low efficacy to once weekly drugs with improvements in A1c of ~1.5%!

5/ If you're not familiar with this relatively new class of anti-diabetics, this #Tweetorial will help you get to know more about them.
GLP-1 RA use supraphysiologic levels of GLP-1 to saturate receptors in the gut, the brain and the heart.

6/ GLP-1 (glucagon-like peptide 1) and GIP (gastric inhibitory polypeptide) are both incretin hormones secreted by the small intestine in response to oral glucose loads. They lower glucose levels and increase satiety.

https://twitter.com/fernandbteich/status/1103466027638243333?s=20

7/ Here's a list of the GLP1-RAs on the market. Liraglutide is short-acting and is injected daily. Exenatide (first to market) has both a twice-daily formulation (Byetta) and a long-acting one meant to be injected every week (Bydureon).

8/ The "SUSTAIN" series of RCTs demonstrated the potency of semaglutide (latest GLP-1 RA to market). The highest dose (1mg) decreases A1c by up to 1.6-1.8%.

Diabetes & Metabolism. (2019) doi:10.1016/j.diabet.2018.12.001

9/ Weight loss was also prominent with semaglutide (as high as 6kg or 13lbs). Maximal effect on glycemia is reached ~10-16wks after starting treatment. Weight loss plateau is reached after ~10wks.

N Engl J Med 2016; 375:1834-1844 DOI:10.1056/NEJMoa1607141 ⬇️

10/ Most common side effects with GLP-1 RAs include nausea, vomiting and diarrhea.
Pancreatitis and hypoglycemia are uncommon.
Slightly increased risk of developing medullary thyroid cancer (GLP-1 RA stimulates thyroid C cells). ncbi.nlm.nih.gov/pubmed/23471186

11/ In 2019, an ORAL formulation of semaglutide (Rybelsus) made it to the market. Initially thought to be degraded in the stomach by proteases, semaglutide was coupled with SNAC, an absorption enhancing excipient acting as a carrier molecule that keeps it stable in the stomach.

12/ This proof-of-concept oral formulation of a peptide drug will likely open the door for new avenues in both diabetes and non-diabetes oral drug development. nature.com/articles/s4157…

13/ The future is even more promising!
During the #ADA2019 meeting, #EliLilly demonstrated that its dual-incretin-agonist tirzepatide (GIP/GLP-1 RA) is even more potent than pure GLP-1 RA. A1c ⬇️~1.9% and Wt ⬇️up to 25 lbs!

https://twitter.com/drpatrickholmes/status/1137537134330408960?s=20

14/ Take-home points:
- Incretin mimetics are powerful new anti-diabetics that help achieve better glycemic control, lose weight and ⬇️CV events.
- New oral formulations are starting to appear on the market.
- Think of them as a multi-pronged treatment for metabolic syndrome.

15/ When adding a once-weekly GLP-1 RA to an insulin-based regimen, decrease basal insulin by 10-20% and prandial insulin dose by 30% in order to avoid hypoglycemia.
Titrate GLP-1 RA dose up over 2-4 wks (body adaptation).
Maximal effect of medication will be reached in ~8 wks.