1. + Metformin and other antidiabetic agents in renal failure patients Kidney International (2015) 87, 308–322 Jean-Daniel Lalau,Paul Arnouts, Adnan Sharif and Marc E. De Broen

2. + METFORMIN THERAPY AND THE FEAR OF LACTIC ACIDOSIS Lactic acidosis (lactate level>45 mmol/l and serum pH<7.35), unrelated to metformin

3. + The pharmacokinetics and pharmacodynamics of metformin -99.9% of the molecules exist as cations -Fractional oral bioavailability is 50–60% -Mean renal clearance in subjects with normal renal function was reported as 510ml±130ml/min -t1/2 is 20 h

4. + Kinetic parameters (mean±s.e.m.) for metformin in plasma and erythrocytes in six healthy subjects after a single oral dose of 0.85 g (from Robert et al.22) Plasma Erythrocytes P-value Time of maximal concentration (h) 3.0±0.3 4.7±0.5 NS (0.068) Maximal concentration (mg/l) 1.7±0.1 0.3±0.0 0.028 Elimination half-life (h) 2.7±0.2 23.4±1.9 50.001 Area under the curve (mg h/l) 8.9±0.4 7.5±1.5 NS Distribution volume (l) 146±11 — —

5. + Metformin’s mechanism of action an insulin sensitizer and reduces hepatic glucose output from gluconeogenesis

6. + Anti-hyperglycemic effects of metformin and the corresponding mechanisms Intestine; Increase in glucose utilization,Activation of the incretin axis. Conversion of glucose into lactate in the splanchnic bed. Modulation of several components of the incretin axis. Liver; Inhibition of gluconeogenesis and (to a lower extent) glycogenolysis. Decrease in substrate availability.Decrease in hepatic energy state (through inhibition of fatty acid oxidation and direct inhibition of oxidative phosphorylation). Antagonism of glucagon. Insulin-dependent peripheral tissues (muscle, adipose tissue); Increased insulin-mediated glucose uptake.Decreased release of free fatty acids from adipose tissue. Enhanced insulin receptor expression and tyrosine kinase activity. Non insulin-dependent peripheral tissues; Enhanced glucose disposal. Stimulation of non-insulin-dependent glucose transport.

7. + Metformin-induced lactic acidosis

8. + Metformin-associated lactic acidosis (MALA) 1. Metformin-unrelated lactic acidosis, when metformin is not detectable in the blood; 2. Metformin-induced lactic acidosis (rare), when causal factors other than marked metformin accumulation (such as cardiovascular failure, sepsis, hemorrhage, hepatic failure, and pulmonary failure) are absent; 3. Metformin-associated lactic acidosis (less rare), with detectable metformin and the presence of other disease conditions (listed above) to varying extents.

9. + Metformin therapy and renal failure serum creatinine thresholds (generally >1.5mg/dl in male patients and >1.4mg/dl in female patients),

10. + Advantages and limitations of measuring the metformin concentration in blood in metformin-associated lactic acidosis Advantages -Differentiation between (i) true, excessive metformin acquisition in cells (such as erythrocytes) and (ii) a plasma peak after a recent metformin intake. -Assessment of the risk, extent or duration of metformin accumulation. -Assessment of a patient’s compliance with metformin therapy. -Help for distinguishing between metformin-unrelated, metformin- induced and metformin-associated lactic acidosis. -Retrospective establishment of a link between metformin use and the development of lactic acidosis (especially in an emergency context, when a metformin assay is not the top priority). -Detection of metformin accumulation in special cases of metformin accumulation that is unrelated to kidney disease (i.e., intestinal occlusion) -Monitoring of the elimination of accumulated metformin.

11. + Advantages and limitations of measuring the metformin concentration in blood in metformin-associated lactic acidosis Limitations -Unavailability of the measurement of metformin (both in plasma and in erythrocytes). -Inability to define a blood metformin concentration as a threshold for metformin accumulation. -High blood metformin concentrations are not necessarily linked to hyperlactatemia or lactic acidosis. -Does not provide information on factors predisposing to and/or triggering hyperlactatemia (other than metformin accumulat -Measurement of the metformin concentration with a long time lag or lack of information of when the blood samples were collected (particularly for plasma samples) - Measurement of metformin concentration after treatments that may affect its value (i.e., dialysis and vasoactive drugs).

12. + Lactic acidosis occurring in patients treated with metformin: toward a global approach Distinguis h different profiles Retain main factors for lactic acidosis Characterize the link between metformin and lactic acidosis Estimate the mortality rate Pathologies – Metformin accumulation + Pathologies + Metformin accumulation + Pathologies + Metformin levels normal Pathologies + Metformin levels undetectable Metformin Pathologi es Metformi n -induced (rare Metformin -associated Metformin -unrelated Metformin -unrelated No mortality? Lowered by metformin? Lowered by metformin ? High

13. + RENAL TRANSPLANTATION New-onset diabetes after kidney transplantation (NODAT) NODAT Consensus guidelines from 2003 do not recommend metformin as the first-line anti-glycemic agent insulin therapy is the most appropriate glucose-lowering therapy

14. +

15. + ANTIDIABETIC AGENTS OTHER THAN METFORMIN

16. + A: Sulfonylureas Chlorpropamide,acetohexamide, tolbutamide, and tolazamide Glibenclamide Glimepiride Gliclazide Glipizide Gliquidone

17. + B: Nonsulfonylurea insulin secretagogues (glinides Repaglinide Nateglinide

18. + C: Insulin

19. + D: Incretin-based insulin secretagogues 1. DPP4 inhibitors Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin 2. Incretin mimetics Exenatide, Liraglutide

20. + E: Thiazolidinediones (glitazones) Pioglitazone

21. + F: Alpha-glucosidase inhibitors Acarbose Miglitol

22. + G: SGLT2-inhibitors (sodiumglucose co-transport inhibitors) Canaglifozin dapagliflozin

23. + CONCLUSION Metformin should itself be no longer considered a paradox. After more than half a century of experience, clinical studies continue to shed new light on the multiple beneficial effects of this drug. In addition, it will probably be clinically feasible in the near future to continue metformin therapy in cases of severe CKD.

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