The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation

(A new metformin drug in the pipe line)

Abstract

OBJECTIVE Delayed-release metformin (Met DR) is formulated to deliver drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks.

RESEARCH DESIGN AND METHODS Study 1 was a Phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, Phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblinded Met XR 1,000 or 2,000 mg (reference).

RESULTS The bioavailability of 1,000 mg Met DR bid was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR qd produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information.

CONCLUSIONS Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.

yoly wrote:(A new metformin drug in the pipe line)

Abstract

OBJECTIVE Delayed-release metformin (Met DR) is formulated to deliver drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks.

RESEARCH DESIGN AND METHODS Study 1 was a Phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, Phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblinded Met XR 1,000 or 2,000 mg (reference).

RESULTS The bioavailability of 1,000 mg Met DR bid was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR qd produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information.

CONCLUSIONS Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.

Metformin is probably the only type two drug I trust. It should be remembered it will reduce HbA1c around one full point at best. Any more reduction required and it's down to our old friend low carb. Low carb higher fat gave me around a 5 point reduction in HbA1c and still works over seven years on.

The ADA used to claim that "Medical Nutrition Therapy" produced something like a 1 - 2% reduction is A1c, most meds are similar.

Yet on their very own forum it was routine to see 5 - 8% reduction, and even 10% or more. It's horrifying to think what an A1c of 16% would be doing to the patient and why they weren't diagnosed far sooner, but then to not be told how to make such an improvement is even more horrifying.

In all these cases it was Test Test Test leading to a massive carb reduction, and often to an equally massive reduction in meds.

chris c wrote:The ADA used to claim that "Medical Nutrition Therapy" produced something like a 1 - 2% reduction is A1c, most meds are similar.

Yet on their very own forum it was routine to see 5 - 8% reduction, and even 10% or more. It's horrifying to think what an A1c of 16% would be doing to the patient and why they weren't diagnosed far sooner, but then to not be told how to make such an improvement is even more horrifying.

In all these cases it was Test Test Test leading to a massive carb reduction, and often to an equally massive reduction in meds.

Could all this be a Black Adder type 'cunning plan' to kill all diabetics off before retirement age and save money the Government has not got? With the rise in retirement age and DUK doing their best to send diabetics to an early grave kapesh.

I'm forced to agree.

Look at it this way, people who cannot eat a high carb low fat diet are not profitable.

Make them obese and they have to eat more, by definition. That makes them profitable again.

Make them diabetic and don't tell them how to control it: thus they need increasing amounts of profitable meds until they go onto insulin for life.

Then they die young anyway so reduce the costs of other medical treatment as well as pensions.

Win win win all the way to the bank.

chris c wrote:I'm forced to agree.

Look at it this way, people who cannot eat a high carb low fat diet are not profitable.

Make them obese and they have to eat more, by definition. That makes them profitable again.

Make them diabetic and don't tell them how to control it: thus they need increasing amounts of profitable meds until they go onto insulin for life.

Then they die young anyway so reduce the costs of other medical treatment as well as pensions.

Win win win all the way to the bank.

Chris I reckon you may be just a tad cynical lol