Diabetes treatment in patients with renal disease: Is the landscape clear enough?

Table of Contents

METFORMIN

Metformin is globally accepted as the first choice in practically all therapeutic algorithms for diabetic subjects. The advantages of metformin are low risk of hypoglycaemia, modest weight loss, effectiveness and low cost. Data of UKPDS indicate that treatment based on metformin results in less total as well cardiovascular mortality.

Many diabetologists as well as practitioners are fear to use metformin in patients with renal problems even if they have only albuminuria. There is a lot of confusion about the real restriction of its use in patients with CKD[11].

Metformin is slowly absorbed when administered orally. The bioavailability of the drug is low (50%-60%).

Metformin achieves a maximum plasma concentration one to three hours after ingestion, if taken in the form of immediate release or in 4-8 h with the extended release form. Metformin is not connected with albumin or any other protein in plasma. This results in a high volume of distribution up to 1000 even after the first dose[12].

In patients with moderate and severe CKD Cmax is increased 173% and 390%, respectively, compared with patients with normal renal function.

In normal pH metformin remains as hydrophilic cation. Less than 0.01% of the drug is unionized in blood. Lipid solubility of metformin is low. So, metformin can not diffuses through cell membranes. Phenformin, another member of antidiabetic drug class biguanides, which is no longer in the market, is more lipophilic than metformin due to different side chain. Metformin is not metabolized in the liver. Metformin is actively excreted by the urinary tube and found unchanged in the urine. After 24 h, if renal function is normal, metformin is not detected in the blood after administration of a single dose. The half-life of metformin is plasma is about 6 h[13].

Read more  Treating and Managing Diabetes Mellitus in Dogs

The absorption of metformin in the intestine is mediated by a transporter known as plasma membrane monoamine transporter. Several metformin transporters are implicated in its intestinal absorption as well as in its hepatic uptake and renal excretion. These transporters are either Organic Cation Transporters (OCTs) or multidrug and toxin extrusion proteins (MATEs).

The kidneys also actively excrete metformin. Metformin enters renal cells of the renal tubule from circulation. This procedure takes place on the basolateral membrane of the cells and is mediated by OCT2.

Then, metformin is excreted into the lumen. This excretion is facilitated by MATE (1 and 2-K). These extrusion proteins are located in the apical membrane of renal proximal tubule cells.

Metformin is also reabsorbed in renal tubules and this action is mediated by OCT1, which is located also in proximal and distal tubules.

The molecular mechanisms underlying metformin action appear to be complex. Metformin entries into the hepatic cell and facilitate phosphorylation and activation of AMP-activated protein kinase (AMPK). Activation of this key-kinase (energy status sensor) lead to many effects related to metabolism of glucose and lipids. Metformin inhibits hepatic neoglycogenesis also in a direct manner. Metformin inhibits complex I of the mitochondrial respiratory chain. This inhibition, leads to an incretion of AMP:ATP ratio, which activate AMPK. This inhibition leads also to increased anaerobic metabolism of glucose in cytoplasm and the production of lactic acid. Thus, metformin is related with increased risk of lactic acidosis when renal elimination of lactic acid is decreased (renal disease, reduced GFR) or hepatic function is severely damaged (lactic acid is used in hepatocytes to produce glucose-neoglycogenesis-). The risk of lactic acidosis is also increased in patients with tissue hypoxia (shock, severe heart failure, sepsis, surgery related hypotension, etc.)[14].

Read more  Is Sugar-Free Candy Good or Bad for You?

Risk of lactic acidosis was greater with phenformin because it’s a more potent inhibitor of mitochondrial respiration. Phenformin has hepatic metabolism with an inactive metabolite. The enzyme CYP2D6 metabolizes phenformin into an inactive metabolite. A small ratio of patients (about 2.8%) has a polymorphism of the enzyme that makes them poor metabolizers. In these patients the risk of lactic acid is even greater (due to higher levels of phenformin).

Nevertheless, analysis of data from may trials (347 comparative trials and cohort studies) from Cochrane Database systematic review in 2010, showed no cases of lactic acidosis in 70490 patient-years of metformin.

Statistical analysis of these data suggested that the upper limit for the incidence of lactic acidosis per 100000 patient-years was 4.3 cases (lower than 5.4 cases in the non-metformin group).

In this analysis also, levels of lactic acid seems to be no different in the two groups.

In most studies however lactic acidosis was not a pre specified end point and there were no data about lactic acid levels.

In the Table ​Table11 we summarize the current recommendations about the use of metformin in CKD.

All diabetic subjects at risk of acute renal failure must discontinue at least temporally metformin. Clinical situations related to increase of acute renal failure includes hepatic insufficiency and use of radiocontrast agents and antimicrobial drugs. Fluid substitution as well as support of cardiac output is useful in certain clinical conditions. Monitoring of urine output and serum creatinine lack sensitivity and specificity in acute renal failure, they remain the most used parameters in clinical practice.

Read more  Top 5 Snacks for Gestational Diabetes

At last, when we change the dose of drugs affecting blood pressure and potentially renal perfusion we have to monitor renal function closely and to reduce the dose of metformin (use of diuretics or increase of their dose, start of use of ACEIs and ARBs, unstable heart failure with frequent hospitalizations, etc.).

References

Recommended For You

About the Author: Tung Chi