Work on Metformin

 Metformin has been in use for 60 years to treat diabetes. It has a good safety record and is the first-line treatment for type II diabetes. It works by reducing glucose production in the liver and increasing the body’s sensitivity to insulin. Studies show that metformin extends lifespan and lowers the risk of age-related diseases in experimental mice, worms, and flies. And preliminary results from human observational studies suggest people with diabetes who take metformin may see similar benefits.

Metform is interesting for anti-aging and anti-cancer but anecdotal, situation better after 2016 CDC double randomized study. Interesting questions are

1. How much metformin per day. How many doses. 2550 mg limit, 2000 mg preferred, 1000 mg for non-diabetics. Metformin should be given in divided doses with meals and should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
2. Contraindicated for whom, answers before clinical data from mechanism of digestion and excretion.
   To determine dose, 500 and 1500 mg doses are being tried. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (i.e. shit). Means kidney better be good. Likely in age 80+ or patients before. Ensure adequate urine clearance. Other contraindication on clinical use data. Best wait pioneering use, ie to 2025. I must for use it for diabetes! Fasting means elimination of Teneligliptin.

Special Populations i.e. Patients with Type 2 Diabetes In the presence of normal renal function, there are no differences between single or multiple dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table I), nor is there any accumulation of metformin in either group at usual clinical doses, or race/gender differences in type-2 diabetic effects. Can safely await clinical data.

So major testable contraindication is renal insufficiency. Other common sense no go are congestive heart failures, known allergies to metformin, and metabolic acidosis with insulin emergency fix.

Can people with type 2 diabetes live longer than those without? 

Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes.

METHODS:

retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables.

RESULTS:

We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy, adjusted median survival time was 15% lower in matched individuals without diabetes and 38% lower in diabetic patients treated with sulphonylurea monotherapy.

CONCLUSIONS:

Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.