diabetes: oral semaglutide ?better than subcutaneous liraglutide

The drug company sponsored PIONEER 4 study found that oral semaglutide seems to be at least as good as subcutaneous liraglutide in decreasing hemoglobin A1c and body weight (see dm oral semaglut vs liraglut lancet2019 in dropbox, or doi.org/10.1016/ S0140-6736(19)31271-1).

Details:

-- 711 patients with type 2 diabetes, randomized to once daily oral semaglultide (dose escalated to 14 mg), once daily subcutaneous liraglutide (dose escalated to 1.8 mg), vs placebo and followed for 52 weeks, in 2016-2017

-- patients were from 100 sites in 12 countries, were at least 18 years old, A1c of 7.0-9.5%, and on a stable dose of metformin (at least 1500 mg, or maximally tolerated), with or without an SGLT-2 inhibitor

-- 48% female, mean age 56, A1c=8.0%, duration of DM 7.6 yrs, fasting glucose 167 mg/dL, BMI 33, 73% white/4% black or African-American/13% Asian/6% Latino, eGFR 96, 26% on SGLT-2 at baseline 

-- those with persistent hyperglycemia (basically >200 mg/dL) or A1c >8.5% were given rescue meds

-- primary endpoint was a change from baseline hemoglobin A1c at week 26 in intention-to-treat analysis, and superiority compared to subcutaneous liraglutide

-- secondary endpoint was change in body weight from baseline in 26 weeks

Results:

-- mean change in hemoglobin A1c at week 26:

    -- semaglultide: -1.2%

    -- liraglutide: -1.1%

    -- placebo: -0.2%

        -- so, semaglultide was noninferior to subcutaneous liraglutide, but both were superior to placebo

    -- overall, in the per-protocol analysis (ie those actually taking the meds), the A1c decreased over the first 14 weeks with both liraglutide and semaglutide and then plateaued until 52 weeks, though the liraglutide worked faster in the first 14 weeks

    -- the odds of achieving HgbA1C of <7%  or <6.5% was the same in both groups at 26 weeks, but oral semaglutide did better (43% vs vs 33% had A1c<6.5%) at 52 weeks

-- weight loss at week 26:

    -- semaglultide: -4.4 kg

    -- liraglutide: -3.1 kg

    -- placebo: -0.5 kg

    -- overall, in the per-protocol analysis, the body weight decreased over the first 14 weeks with liragludide and then mostly plateaued, but continued to decrease with semaglutide until about 26 weeks and plateaued until 52 weeks

    -- at 52 weeks, the % of patients who achieved >10 kg wt loss was 16% vs 7%, favoring semaglutide

-- per-protocol analysis at week 26

    -- semaglultide was associated with significantly greater decreases in hemoglobin A1c then subcutaneous liraglutide (-0.2%) and placebo (-1.2%)

    -- semaglultide was associated with more weight loss than liraglutide (-1.5 kg) or placebo (-4.0 kg)

-- there was no breakdown provided comparing those on vs not on SGLT2's

-- very few patients were on rescue medications: total of 10 at the 26 week visit and 20 at 52 weeks; most were on sulfonylureas (5 and 12, respectively) [rescue meds do not include those already on SGLT-2’s]

-- adverse events were more common with oral semaglultide (80%) and subcutaneous liraglutide (74%) than was placebo (67%)  [pretty high rate in placebo group: though i suppose that any 52 week study would find many people with some GI symptom at some time, for example, that might be considered to be associated with a med]   

    -- though 2/3 of adverse events were mild

    -- 1-2% in each group, including placebo, were “severe or blood-glucose confirmed symptomatic hypoglycemic episodes” 

    -- adverse events leading to early discontinuation of meds happened in 11% on semaglutide, 9% liraglutide and 4% placebo (for GI adverse events leading to stopping meds: 8% semaglutide, 6% liraglutide and 2% placebo).

    -- Transient nausea and diarrhea were the most commonly reported adverse events and were considered mild-to-moderate

Commentary:

-- i think this is pretty great, having a really effective medication in the class of meds (GLP-1 agonists) that restores a typical deficiency found in diabetics vs nondiabetics (the "incretin effect"), is physiologically important for moderating appropriate insulin release to meals, is a targeted medication (vs DPP-4 inhibitors, which interfere with many enzyme systems), does not in itself cause hypoglycemia, works extremely well with metformin, has cardio- and reno-protective effects, causes weight loss, and now may ??soon be available as an oral agent (though we'll see what the price tag will be....)

-- The SUSTAIN7 study compared injectable semaglutide 1.8mg to injectable dulaglutide 1.5mg, finding that semaglutide was more effective in both glycemic control and weight loss than dulaglutide, and other studies have found semaglutide to be more effective than exenatide

-- the oral preparation is a coformulation of semaglutide with the absorption enhancer SNAC, sodium N-(8-[2-hydroxylbenzoil] amino) caprylate, a medium chain fatty acid-based system which seems to be pretty safe (see https://www.ncbi.nlm.nih.gov/pubmed/30453465 , andhttps://www.tandfonline.com/doi/pdf/10.1080/21688370.2016.1176822?needAccess=true). though would be interesting to know its effects on the gut microbiome...  SNAC is being used to improve oral absorption of PTH, insulin, calcitonin; and it is already on the market in a combination with vitamin b12

--there have been a slew of prior blogs on GLP1's, many contrasting them to SGLT2's, see the recent blog https://gmodestmedblogs.blogspot.com/2019/06/diabetes-guideline-update-pushing-sglt.html

--it is not surprising that there are more GI symptoms with semaglutides (happens with all GLP-1's), or that there are more with semaglutide (it is apparently the strongest one, and has the most weight loss, probably related to its attendant subclinical or clinical GI sx). though, hopefully, the oral form will be titratable for those unable to tolerate the GI effects (as is injectable semaglutide and most of the others)

--of note, liraglutide does have an FDA indication for obesity therapy, and oral semaglutide seems to be even better!!

so, i think this oral GLP-1 agonist is a great step forward. GLP1's can decrease the use of sulfonylureas and insulin, meds that may well increase cardiac events (see blogs referenced below). and the combo of metformin and GLP1s, made easier for patients with an oral formulation of the latter, really does combine the safest and most effective agents for both diabetes control and prevention of some of the most dreaded diabetic complications

for more on the potentially significant adverse cardiac effects of sulfonylureas or insulin, see:

https://gmodestmedblogs.blogspot.com/2017/11/pioglitazone-vs-sulfonylurea-as-add-on.html, a large Italian study finding that diabetic patients inadequately controlled by metformin, then randomized to pioglitazone vs sulfonylruea therapy, had a significant decrease in ischemic cardiovascular events when assessing on-treatment endpoints

https://gmodestmedblogs.blogspot.com/2018/03/loosening-a1c-goal-is-low-a1c-really.html , which reviews the Am College of Physicians guidance on A1c targets, referencing studies on increased cardiovasc disease with sulfonylureas vs metformin

https://gmodestmedblogs.blogspot.com/2016/08/insulin-vs-glp-1-agonists-for-patients.html, which shows the dramatic superiority of GLP1's vs insulin regarding major adverse cardiovascular events

http://gmodestmedblogs.blogspot.com/2016/08/insulin-vs-glp-1-agonists-for-patients.html , reviews a retrospective large study finding major decreases of cardiovascular events in those on GLP-1's vs insulin

geoff

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