Metformin and renal impairment

At what stage should a patient with renal dysfunction stop medication using Metformin? To act too conservatively, does it mean to keep the patient away from the benefits of first-line medicine like metformin? What are the ideas of international diabetes associations in this regard? Or what are we going to give as an alternative?

​​In recent years, it has begun to be mentioned that cutt-off values ​​that have been used in America for a long time (serum creatinine> 1.5 mg / dL [> 133 mmol / L] or 1.4 mg / dL [124 mmol / L] are extremely limiting.

In the NICE guideline, in 2010, the cut-off value of creatinine determined for metformin was 150 μmol / L (1.7 mg / dL) or the calculated GFR was <30 mL / min / 1.73 m 2.

In the Canadian guideline published in the same year, it was suggested that if the calculated GFR <60 mL / min / 1.73 m 2, it should be used with caution and warnings, and should be cut if the calculated GFR <30 mL / min / 1.73 m 2.

In the same year, the Australian Diabetes Association recommends stopping the drug when the calculated GFR <30 mL / min / 1.73 m2. Careful use of metformin has been suggested when the calculated GFR is 45-60 mL / min / 1.73 m2 (3).

EMA (European Medicines Agency) has informed that about one year ago, considering the European-based considerations, the limits of renal function for metformin use could be relaxed a little more.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have briefly addressed this issue in 2015 (4).

In the article, if the calculated GFR is between 45-60 mL / min / 1.73 m2, it has been argued that the prescription of metformin is not contraindicated. Even in the same article, there are considerations for using metformin by careful follow up until the calculated GFR <30 mL / min / 1.73 m2.It is emphasized that DPP-4 inhibitors may be an option but dose adjustment should be considered (except for linagliptin) for renal insufficiency.

Eventually in August 2016, the FDA made a safety announcement for metformin. The FDA announced that metformin could be used for mild and moderate renal insufficiency in the light of accumulated data in the literature.

REFERANCES

1. National Institute for Health and Clinical Excellence.The Management of Type 2 Diabetes: 2010 NICE Guidelines [Internet]. London, U.K., National Institute for Health and Clinical Excellence, 2010. Available fromhttp://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf. Accessed 21 October 2010

2. Canadian Diabetes Association. Clinical practice guidelines [Internet]. 2008. Available fromhttp://www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed 5 December 2010

3. National evidence based guidelines for blood glucose control in type 2 diabetes. [Internet]. Available fromhttp://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/di19-diabetes-blood-glucose-control.pdf. Accessed 5 December 2010.

4. Diabetes Care. 2015;38:140-149



Some other topics in INTERNALISM

• Treatment of hypercalcemia,
• Metformin and renal impirment, 
• PBC - Primary biliary cirrhosis,
• Giant cell arteridis:Clinical features,
• Vancomycin Resistant Enterococcus: a current overview of diagnosis, prevention and treatment,
• PAN -Diagnosis,
• Cateter Releated Bloodstream Infections-diagnosis,
• Exercise-induced hematuria

TREATMENT OF HYPERCALCEMIA

Patients with mild hypercalcemia (<12 mg / dL) have no indications for immediate treatment. It may be advisable to increase fluid intake to reduce the risk of nephrolithiasis.

Intermediate hypercalcemia (12-14 mg / dL) may not require immediate treatment. An acute rise in serum calcium can cause significant impairment in mental status and requires urgent treatment.

Severe hypercalcemia (> 14 mg / dL) should be treated;

The isotonic saline should be given at a rate of 200-300 mL / h and a rate of 100-150 mL / h urine output. If there is no heart / kidney failure, it is not necessary to give loop diuretics.

Calcitonin (4 IU / kg) should be given and serum calcium measured after hours. If hypocalcemic response is observed, this can be repeated every 6 to 12 hours (4-8 IU / kg).

Zolendronic acid (4 mg i.v., over a 15 minute period) should be started concurrently with treatment. The other alternative is pamidronate.

Administration of saline with calcitonin will cause a reduction in calcium in 12 to 48 hours. The bisphosphonate reduces serum calcium within 2 to 4 days.

Donesumab is an alternative drug in a patient with malignant, Zolendronic acid-resistant, severe hypercalcemia.

Hemodialysis.

The most common cause of hypercalcemia in non-hospitalized patients is HYPERPARATHYROIDISM.

Hydration with isotonic NaCl

Hypovolemia causes hypercalcemia by impairing renal clearance of calcium.

With saline treatment, hypercalcemia on a moderate level often does not become normal. Simultaneous bisphosphonates should also be initiated. If necessary calcitonin can be started.

Calcitonin

At pharmacological doses, calcitonin acts by increasing renal calcium excretion and, more importantly, by impairing osteoclast function and reducing bone resorption. Nasal form is not successful in hypercalcemia treatment.

Calcitonin is safe and does not have major toxicities. The effect is fast despite the weakness. It starts in six hours and reduces calcium up to 1-2 mg / dL maximum. Probably due to receptor down-regulation, tachyphylaxis develops within 48 hours.

Bisphosphonates

Bisphosphonates are nonhidrolizable analogs of inorganic phosphate adsorbing to the surface of bone hydroxyapatite. It disrupts osteoclast-mediated bone resorption and impairs calcium release.

Although zoledronic acid has the potential to cause osteonecrosis of the jaw, it is a side effect that is more commonly seen in chronic use.

The efficacy of zolendronic acid 4 mg and 8 mg doses were similar. 8 mg was associated with more renal toxicity.

Pamidronate is more effective than etidronate or clodronate.

Ibandronate 2mg / 4mg / 6mg is also effective in hypercalcemia. The efficacy is greater at 4 mg and 6 mg, but duration of action is dose independent.

Ibandronate appears to be as effective as pamidronate.

Clodronate and etidronate are relatively low-impact first-generation bisphosphonates. If the other bisphosphonates are not aviable, these two agents can be used.

Glucocorticoids

Where absorption of vitamin D-related dietary calcium is increased, glucocorticoids reduce the production of calcitriol within 2-5 days.

Denosumab

DenoSumab has a 60 mg injector and is used weekly.

It can also be used in chronic kidney failure. Optimal dosing is not clear in renal failure. The risk of hypocalcemia seems to be more in chronic kidney disease.

If the first dose is as low as 0.3 mg / kg, and if the target is not reached within 1 week, the second injection may be recommended as a prudent approach, considering the risk of hypocalcemia.

Measuring vitamin D levels prior to denosumab may also be warranted, because those with vitamin D deficiency are more susceptible to hypocalcemia. Even if the measurement of vitamin D levels is delayed, give vitamin D 50000 IU 1-2 days before donesumab; If the result is Vitamin D deficiency you will continue treatment; If there are no deficiencies, you will end up giving vitamin D. Some authors advocate this view.

Calcimimetics

Sinekalset

Dialysis

It is the approach to be considered in the last stage.