Non-Insulin Dependent Diabetes and Contrast Media 53
8 Non-Insulin Dependent Diabetes and Contrast Media
Henrik S. Thomsen
H. S. Thomsen, MD
Professor, Department of Diagnostic Radiology 54E2, Copen- hagen University Hospital at Herlev, Herlev Ringvej, 2730 Herlev, Denmark
CONTENTS
8.1 Introduction 53 8.2 Biguanides 53 8.3 Renal Handling 53 8.4 Lactic Acidosis 54
8.5 Iodinated Contrast Media 54 8.6 Gadolinium Contrast Media 54 8.7 Guidelines 55
References 55
8.1
Introduction
Reports of patients developing lactic acidosis fol- lowing intravascular iodinated contrast medium administration have caused concern to many radi- ologists in the last decade. The recommendation of the manufacturers of biguanides that these drugs should be stopped in non-insulin dependent diabetic patients for 2–3 days before intravascular admin- istration of contrast media added to the concern.
Health authorities and professional bodies adopted the recommendation, which created practical dif- ficulties for clinical practice in radiology depart- ments. This chapter provides an overview of the lit- erature on the intravascular use of contrast media and biguanide induced lactic acidosis in non-insulin dependent diabetic patients. In current decade the debate about this topic appears to have stopped.
8.2
Biguanides
The biguanide metformin (dimethylbiguanide) was introduced into clinical practice in 1957. Met- formin and the other biguanide agents phenformin and buformin are structurally related to guani- dine. Metformin differs in its chemical structure and pharmacological profile from both phenformin and buformin (Dunn and Peters 1995). Biguanides lower serum glucose by inducing anorexia, decreas- ing gastrointestinal absorption of carbohydrates, inhibiting hepatic gluconeogenesis, and increas- ing cellular uptake of glucose. They are primarily absorbed by the small intestine. Although there is minimal binding of these drugs to plasma proteins, they have a high affinity for protein binding cells of the gastrointestinal tract and undergo enterohepatic recirculation (Baily and Turner 1996).
The biguanides are used in non-insulin depend- ent diabetes mellitus in three ways: (a) as primary treatment in overweight patients inadequately con- trolled by diet, or (b) as adjunct therapy when sul- phonurea alone fails, or (c) sometimes in combina- tion with insulin (Monson 1993).
8.3
Renal Handling
The different biguanides have different routes of
elimination. Phenformin and buformin undergo
hepatic metabolism and renal excretion. Metformin
is excreted unchanged in the urine. In the absence of
renal or hepatic dysfunction, the half-lives of phen-
formin, buformin, and metformin are 12, 4, and 1.5
h, respectively. Approximately 90% of metformin
is eliminated via the kidneys in 24 h. Metformin
does not cause renal failure. However, metformin
accumulation sufficient to produce lactic acidosis
occurs only in the presence of renal failure (and
rarely hepatic failure) (Wilborn and Myrhed 1993;
54 H. S. Thomsen
LaLau et al. 1994). Renal insufficiency with failure to clear metformin and failure of hepatic metabo- lism and excretion of phenformin lead to accumula- tion of these biguanides and the potential for fatal lactic acidosis (Sirtori and Parsik 1994).
8.4
Lactic Acidosis
Lactic acidosis is generally defined as a metabolic acidosis caused by accumulation of lactic acid in the blood in excess of 5 mmol with an accompanying blood pH of less than 7.25. Acute renal failure is an important causal factor (Assan et al. 1997). Phen- formin was withdrawn from clinical use in many countries in the late 1970s when an association with lactic acidosis was recognized. This tarnished the reputation of biguanides, but lactic acidosis is not a major problem with metformin. The incidence of lactic acidosis associated with metformin is approximately 0.03 cases per 1,000 patients per year, with approximately 50% of cases resulting in death (Dachman 1995). From 1968 to 1991 a total of 110 cases were reported in the literature (Sirtori and Parsik 1994). The incidence is low because lactic acidosis occurs in most patients when one or more contraindications to its use are overlooked, mainly renal insufficiency, leading to high plasma met- formin concentrations (Bailey and Turner 1996).
It is important to realize that blood lactate concen- trations rise in any patient in whom cardiogenic shock or other illness decreases tissue perfusion. In some reported cases the metformin was probably an incidental factor and not responsible for lactic aci- dosis. Nolan (1997) recommended that biguanides are contraindicated when renal function is mark- edly reduced (GFR < 70 ml/min, or serum creatinine
> 140 Pmol/l).
8.5
Iodinated Contrast Media
The use of iodinated contrast media in patients receiving metformin was very controversial in the 1990s (Dachman 1995; Rotter 1995; Rasuli 1996;
Nawaz et al. 1998) but now seems to be less of an issue. The potential danger of lactic acidosis relates to the fact that if renal excretion is reduced, metformin accumulates. There is no evidence of
interaction of contrast media and metformin. In a review of metformin-associated lactic acidosis (Sirtori and Parsik 1994) only seven of the 110 cases reported in the world literature from 1968 to 1991 had received iodinated contrast material before developing lactic acidosis. Dachman (1996) was able to find 13 documented cases of lactic aci- dosis after the administration of iodinated contrast material in patients receiving metformin. Most patients either had renal dysfunction before the procedure or continued to use metformin despite the development of contrast medium induced nephropathy. In 12 of the 13 cases, the patients had elevated creatinine levels or decreased creatinine clearance before administration of the contrast medium.
Patients at risk are those who may develop con- trast medium-induced renal insufficiency. Patients with diabetic nephropathy – insulin and non-insu- lin dependent – have the highest risk of developing contrast medium induced nephropathy (Thomsen and Bush 1998; Morcos et al. 1999). The poorer the renal function the higher the risk and dehydration increases the risk even more. Despite the short half- life of metformin (from 1.5 h dependent on the renal function), it is still present in the body when the renal effects of contrast media occur. They develop instantly after the administration of contrast media, but may not be detected until 24–48 h later (Morcos et al. 1999).
Nawaz et al. (1998) showed that patients with normal serum creatinine and who received met- formin before angiographic procedures did not develop lactic acidosis. Only patients with abnormal serum creatinine before angiography developed this complication.
8.6
Gadolinium Contrast Media
Although the risk of contrast medium induced nephropathy after gadolinium contrast media is very low, it has been reported to occur, even at the doses approved for MRI (Thomsen 2004). None- theless, the possibility of metformin induced lactic acidosis after gadolinium agents is considered to be sufficiently low that determination of serum creati- nine before gadolinium is not considered necessary.
No special precautions appear to be necessary when
gadolinium agents are given in doses recommended
for MR to patients taking metformin.
Non-Insulin Dependent Diabetes and Contrast Media 55
8.7
Guidelines
The drug manufacturers currently recommend that metformin should be stopped 48 h before and for 48 h after the administration of iodinated contrast media. However, there is no firm evidence for this recommendation to be applied to all patients.
Current guidelines (see Appendix) recommend that serum creatinine should be checked before iodinated contrast medium administration in all diabetic patients taking metformin. In patients with a normal serum creatinine, it is recommended that metformin is stopped from the time of iodinated contrast medium administration for 48 h. The serum creatinine should be estimated at 48 h, and met- formin only restarted if serum creatinine remains normal. In patients with abnormal renal function, it is recommended that metformin is stopped 48 h before iodinated contrast medium. The serum creat- inine/renal function should be estimated 48 h after contrast medium and metformin should be restarted only if it is normalized as metformin is not approved for used in patients with abnormal renal function defined as abnormal serum creatinine level.
The parts of the current guidelines which are open to debate are those referring to patients with normal renal function. It is necessary to check the serum creatinine before restarting metformin and does one need to stop the metformin intake 48 h before contrast administration; can one wait until the day of contrast administration? The presence of normal function, defined as a normal serum cre- atinine level, does not totally exclude the possibil- ity of lactic acidosis (Westberg 1995). However, in patients with normal serum creatinine the risk of contrast medium induced nephropathy is less than 0.5% when nonionic iodinated agents are used (Rudnick et al. 1995; Thomsen et al. 2005). The necessity for this additional blood test may cause practical difficulties in Radiology Departments.
Argument sometimes occurs as to whether it is the responsibility of the referring clinician or of the radiologist. With increasing experience of the use of iodinated contrast media in patients taking met- formin, it may be possible to propose that the serum creatinine estimation at 48 h after contrast medium is no longer necessary in patients with normal renal function and that intake of metformin is stopped from the time of and for 48 hours after contrast medium administration.
References
Assan R, Heuclin C, Ganeval D, Bismuth C, George J, Girard JR (1997) Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 13:211–217
Baily CJ, Turner RC (1996) Metformin. N Engl J Med 334:574–
579
Dachman AH (1995) New contraindication to intravascular iodinated contrast material. Radiology 197:545
Dachman AH (1996) Answer. Radiology 290:289
Dunn CJ, Peters DH (1995) Metformin. A review of its pharma- cological properties and therapeutic use in non-insulin dependent diabetes mellitus. Drugs 49:721–749
LaLau JD, Lacroix C, DeGagney B, Fournier A (1994) Met- formin-associated lactic acidosis in diabetic patients with acute renal failure. A critical analysis of its patho- genesis and prognosis. Nephrol Dial Transplant [Suppl]
9:126–129
Mason RA, Arbeit LA, Giron F (1985) Renal dysfunction after arteriography JAMA 253:1001–1004
Monson JP (1993) Selected side-effects. II. Metformin and lactic acidosis. Prescriber J 33:170–173
Morcos SK, Thomsen HS, Webb JAW and members of Con- trast Media Safety Committee of European Society Of Urogenital radiology (ESUR) (1999) Contrast media induced nephrotoxicity: a concensus report. Eur Radiol 9:587–588
Nolan DB (1997) Theophylline option for attenuating contrast media-induced nephrotoxicity in patients on metformin.
Am J Health Syst Pharm 54:587–588
Nawaz S, Cleveland T, Gaines PA, Chan P (1998) Clinical risk associated with contrast angiography in metformin treated patients: a clinical review. Clin Radiol 53:342-344 Rasuli P (1996) New contradiction to intravascular contrast
material. Radiology 290:289
Rotter A (1995) New contraindication to intravascular iodi- nated contrast material. Radiology 197:545–546
Rudnick MR, Goldfarb S, Wexler L et al (1995) Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. Kidney Int 47:254–261
Sirtori CR, Pasik C (1994) Re-evaluation of biguanide, met- formin: mechanism of action and tolerability. Pharmacol Res 30:187–228
Thomsen HS (2004) Gadolinium-based contrast media may be nephrotoxic even at approved doses (case report). Eur Radiol 14:1654–1656
Thomsen HS, Bush WH Jr (1998) Adverse effects of contrast media. Incidence, prevention and management. Drugs Safety 19:313–324
Thomsen HS, Morcos SK, Members of Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR) (2005) In which patients should serum-creatinine be measured before contrast medium administration? Eur Radiol 15:749–754
Westberg G (1995) Metformin (Glucophage) och röntgenkon- trastmedel orsakade njurinsufficiens (in Swedish). Info Från Läkemedelsverket 3:170–171
Wilborn BE, Myrhed M (1993) Metformin-associated lactic acidosis lactic acidosis in Sweden. Eur J Clin Pharmacol 44:589–591
![[Scheda bibliografica di] Aldo Barba, Massimo Pivetti, Il lavoro importato. Immigrazione, salari e Stato sociale, Milano, Meltemi, 2019, pp. 183](data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==)