Why lactic acidosis with metformin

There were hospitalizations with acidosis over a median follow-up of 5. Compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall adjusted hazard ratio [HR], 0. Regulatory and professional society guidelines suggest that metformin may be an option in patients with mild to moderate CKD. We aimed to investigate the relationship between metformin therapy and acidosis across the full spectrum of eGFR in a large, integrated electronic medical record cohort, accounting for time-dependent eGFR stage, and for potential confounding from multiple variables, including concomitant insulin use.

We sought to replicate findings in a separate nationwide cohort derived from private health systems. In both cohorts, we compared acidosis risk during metformin use with the risk during alternative management of DM, hypothesizing that acidosis would be no more common among metformin users within categories of eGFR. We studied a community-based cohort of patients with a diagnosis of DM and a postdiagnosis serum creatinine measurement between January 1, , and January 20, , receiving primary care in Geisinger Health System.

Deidentified individual patient data from inpatient and outpatient encounters, including problem lists, prescriptions, diagnostic codes, and laboratory measurements, were used.

We censored patient time at death or at the end of study follow-up February 2, Metformin use and daily dose were ascertained from electronic prescription records. Start time was defined as the date of electronic prescription, and stop time was the end date of the prescription, or the date that a clinician discontinued the medication, whichever came earlier.

A gap between prescriptions of less than 60 days was not considered a medication discontinuation to allow for the possibility of stockpiling of medications. Each time a participant changed eGFR stage, the variable was updated and subsequent follow-up time was categorized accordingly. Other covariates included age, sex, race, smoking status, body mass index BMI, calculated as weight in kilograms divided by height in meters squared , serum bicarbonate, hemoglobin A 1c HbA 1c , comorbid cardiovascular disease, heart failure, hypertension, and medication use.

We categorized patients as ever or never cigarette smokers, and determined comorbid cardiovascular disease coronary artery disease, stroke, or peripheral arterial disease , heart failure, and hypertension by the presence of relevant diagnostic codes at any time prior to cohort inclusion eTable 1 in the Supplement. We abstracted serum bicarbonate and HbA 1c from outpatient laboratory data within 1 year prior to index date.

We recorded baseline and time-dependent use of statins, renin-angiotensin system inhibitors, diuretics, nonsteroidal anti-inflammatory drugs, insulin, sulfonylureas eg, glimepiride, glyburide, glipizide , and other hypoglycemic medications in a manner similar to metformin use. We determined deaths by linkage to the National Death Index. We compared baseline characteristics of patients according to baseline eGFR stage. Differences across categories were determined using linear regression for continuous variables and logistic regression for binary variables on the median eGFR value within each eGFR category.

We analyzed risk of acidosis in metformin use, compared with no metformin use, using Cox proportional hazards regression. We used a model in which metformin use and eGFR category were captured as time-dependent variables. In other words, values were allowed to change over time, with metformin use initiated or discontinued with prescription start and stop time, and eGFR category updated when outpatient eGFR changed.

Models were run unadjusted, demographic-adjusted, and fully adjusted for baseline covariates demographic characteristics, eGFR, serum bicarbonate level, smoking status, BMI, cardiovascular disease, heart failure, hypertension, and medication use. A linear spline was used for bicarbonate level, with a knot at the mean We tested for modification of the association between metformin and acidosis by eGFR stage by including a product term with eGFR stage modeled as an ordinal variable.

In secondary analysis, we also captured the use of other medications as time-dependent variables. First, we performed an active comparator study, in which new first-time metformin users were compared with new sulfonylurea users without accounting for time-dependent eGFR.

Second, we constructed propensity-matched cohorts for prevalent metformin users within each category of eGFR, censoring at metformin discontinuation for cases, metformin initiation for controls, or eGFR category change. The propensity score was created using logistic regression of metformin status on the aforementioned covariates.

Cases metformin users and controls non—metformin users were matched using nearest-neighbor matching on a basis within each category of eGFR using a caliper of one-fifth the standard error 0. Fourth, we included baseline HbA 1c in the fully adjusted model. Fifth, we replicated the analysis in persons with a new diagnosis of DM after January 1, Finally, to address the possibility of incomplete capture of metformin discontinuation and thus overestimation of metformin exposure during which no events occurred, we censored all metformin users without acidosis events 90 days earlier.

We replicated active comparator results in the MarketScan database, an individual-level inpatient and outpatient claims data source from private health systems, linked to outpatient laboratory test results for some patients.

Medication use was sourced from pharmacy dispensing claims. Covariates, laboratory values, and acidosis outcomes were determined from diagnostic codes in a parallel manner to Geisinger Health System.

Time at risk began at prescription for either metformin or sulfonylurea after January 1, , and ended at hospitalization with acidosis, use of the opposite medication class, cessation of medication use, death, or end of study follow-up on December 31, , whichever came first. Cessation of medication use was recorded as the date of last prescription, plus days of supply.

We compared risk of acidosis in metformin users with sulfonylurea users using Cox proportional hazards regression, adjusted for baseline age, sex, eGFR, cardiovascular disease, heart failure, hypertension, and use of insulin, renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs.

All calculations were performed using statistical software Stata, version Patients were not involved in the design or implementation of the study. Mean SD age at baseline was Median follow-up duration was 5. The median number of creatinine measurements per year was 2. The median duration of metformin use was 2. Of these events, only 29 had an acidosis diagnostic code in the primary position.

The adjusted hazard ratio HR of acidosis during metformin use compared with nonuse was 0. In both metformin users and nonusers, lower eGFR itself was associated with a higher incidence of acidosis. Sulfonylurea use was more common at lower eGFR. Compared with sulfonylurea use, metformin use had similar associations with acidosis overall adjusted HR, 0. Metformin users were slightly younger and more often female compared with sulfonylurea users eTable 3 in the Supplement.

Median follow-up of metformin users was There were acidosis events among metformin users, and 94 among sulfonylurea users. The incidence of acidosis was 2. Lower eGFR was a risk factor for acidosis in both metformin and sulfonylurea users. The risk of acidosis associated with metformin use was slightly lower overall adjusted HR, 0. Our findings support results from smaller cohorts that assessed lactic acidosis through medical record review, 16 , 24 and using a wide range of diagnostic codes.

The 1 trial that randomized participants with moderate CKD serum creatinine level, 1. Our results partially contradict a large cohort study investigating the association between metformin use and acidosis at low eGFR. However, this study was limited by sparse eGFR data and did not account for changes in eGFR over time, leaving the possibility of confounding by GFR, which we show is itself a strong risk factor for acidosis. From a public health perspective, the potential benefits of using metformin for patients with DM and CKD are vast, given the increasing number of people affected with both diseases worldwide.

Metformin may also have pleiotropic health benefits beyond its effect on glycemic control. The present study, while benefiting from a large sample size, has certain limitations. First, as with all observational studies, residual confounding is possible.

Patients receiving metformin could have different acidosis risk than those who did not receive metformin, for reasons other than their metformin use. However, we observed consistent results in propensity-matched analyses, with multivariable adjustment, and when excluding insulin users and directly comparing with alternative therapies. On the other hand, the diagnostic code maintains consistency with earlier epidemiological studies, 26 , 29 and allows for the possibility that metformin may contribute to acidosis from other metabolic factors such as malnutrition, liver disease, sepsis, and drug toxicity, which are all clinically relevant for patients.

Third, if the effect of metformin use on lactic acidosis were mediated by decline in eGFR, the use of time-dependent eGFR in our analyses could bias results to the null. However, we found similar results when only adjusting for baseline eGFR in active comparator analyses. People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly.

Talk to your doctor about the best way to treat low blood sugar. Hyperglycemia high blood sugar may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

This medicine may interact with the dye used for an X-ray or CT scan. Your doctor should advise you to stop taking it before you have any medical exams or diagnostic tests that might cause less urine output than usual. You may be advised to start taking the medicine again 48 hours after the exams or tests if your kidney function is tested and found to be normal.

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The plasmatic peak level is quickly reached 1 to 2 hours after ingestion, and the plasmatic half-life is 4 to 8. Aggressive therapy should be initiated as soon as possible. Extrarenal epuration is the first-line treatment, with the aim of decreasing metformin concentration and allowing the physiological lactate clearance. Indeed, endogenous lactate clearance is probably superior to hemofiltration [ 16 ]. Thus, the most appropriate method for emergency elimination is hemodialysis.

Nevertheless, CVVH may be considered if hemodialysis is unavailable [ 17 ]. Although drug clearance by CVVH was less than generally reported by conventional dialysis, some authors did not find differences between both techniques [ 6 ]. Sustained low-efficiency dialysis SLAD is an intermittent hybrid renal replacement modality halfway between conventional intermittent hemodialysis and continuous renal replacement therapy.

This prolonged diffusive technique may be a valuable option in case of hemodynamic instability [ 18 ]. After absorption, metformin is rapidly distributed in a tissue compartment with high volume distribution [ 19 ]. According to a two-compartment model, metformin shows a biphasic pattern of elimination.

Therefore, it is necessary to proceed over a long filtration period due to recirculating metformin from an extraplasmatic compartment. In case of CVVH use, renal replacement therapy of over approximately 30 hours has been reported. Hemodialysis has the additional benefit of correcting the acidosis while removing toxins.

Even though cases report the use of regional citrate anticoagulation RCA in extracorporeal treatment for metformin intoxication without complication [ 18 , 20 ], using RCA could be controversial. Citrate is metabolized in the cytoplasm of hepatocytes by ATP citrate lyase which cleaves the citrate into acetyl-CoA and oxaloacetate in the cytoplasm [ 21 ]. This ATPase does not seem affected by metformin.

Theoretically, the safety of citrate accumulation could be critical, especially in patients with liver failure. However, it is demonstrated that despite substantial accumulation of citrate in serum, RCA-CVVH seems feasible in patients with severely impaired liver function [ 22 , 23 ].

It is important to identify patients at risk and assess careful monitoring of electrolyte status, especially calculating the calcium ratio [ 24 ]. Current recommendations from the Extracorporeal Treatments in Poisoning Workgroup do not contraindicate the use of regional citrate anticoagulation [ 17 ].

Second-line treatment is supportive care. Administration of vasopressor agents is mandatory to restore hemodynamic conditions. In some cases, the use of vasopressin demonstrated effectiveness [ 25 ]. Authors recommend the use of vasopressin when the patient is unresponsive to catecholamines [ 26 ]. There is no relevant correlation between metformin blood level and survival rate [ 27 ].

The outcome of metformin acute lactic acidosis is mainly influenced by the occurrence of multiple organ dysfunction and patient comorbidity [ 19 ]. The factor that seems crucial is the time to start extrarenal epuration which allows removal of metformin and correction of metabolic abnormalities. It is the only way to stop the vicious circle from lactic acidosis to multiple organ failure. We present the case of a voluntary metformin intoxication resulting in the highest metformin concentration ever described.

It is capital to rapidly initiate extrarenal epuration in order to remove toxins and lead to acidosis correction. It is the only way to avoid fatal multiple organ failure due to major lactic acidosis. The authors declare that there is no conflict of interest regarding the publication of this article. Technical description of the metformin quantification method used in this case. Supplementary Materials.

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Received 12 Dec Revised 01 Aug Accepted 14 Oct Published 21 Oct Abstract Metformin is an oral antidiabetic largely prescribed in the treatment of type II diabetes.

Introduction In , metformin was the 7 th most frequently prescribed generic drug in the United States [ 1 ]. Figure 1. References A. Protti, P. Properzi, S. Magnoni et al. Wang and C. Contargyris, C. Mcnamara and G. Hess, M. Unger, B.