Inclusion And Exclusion Criteria
Inclusion criteria were: RCT, p-h/sa of RCTs, or OSs provision of endpoints for all-cause mortality and cardiovascular events in patients with T2DM and CKD with or without metformin use. The tested outcomes were assured by physical tests and hospital records, or recognized from links of administrative records. The exclusion criteria were: kidney transplant case report, comment, editorial, letter, quasi-experiment , or unpublished study abstract or conference proceeding. Of two or more articles from the same team or organization, only the one with latest publication or largest sample size was selected.
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What Medicines Might I Consider Diabetes
The medication you take will vary by your type of diabetes and how well the medicine controls your blood sugar levels, likewise called blood sugar level. Other factors, such as your other health conditions, medication expenses, and your daily schedule might contribute in exactly what diabetes medication you take.
Medications That Can Harm The Kidneys
No matter what kind of medicine you take, whether OTC or prescription, it is destined to take a trip through your kidneys. Taking a drug the wrong way or in excessive amounts can damage these vital, bean-shaped organs and lead to serious complications. In the worst-case scenario, it could necessitate a kidney transplant.
Compared with 30 years ago, patients todayhave a higher incidence of diabetes and cardiovascular disease, take multiple medications, and are exposed to more diagnostic and therapeutic procedures with the potential to harm kidney function, according to Cynthia A. Naughton, PharmD, senior associate dean and associate professor in the department of pharmacy practice at North Dakota State University. All of these factors are associated with an elevated risk of kidney damage.
An estimated 20% of cases of acute kidney failure are due to medications. The technical term for this scenario is nephrotoxicity, which is growing more common as the aging population grows, along with rates of various diseases.
The kidneys get rid of waste and extra fluid in the body by filtering the blood to produce urine. They also keep electrolyte levels balanced and make hormones that influence blood pressure, bone strength and the production of red blood cells. When something interferes with the kidneys, they cant do their job, so these functions can slow down or stop altogether.
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The Egfr Slope Determinants
eGFR was recorded in the metformin continuation group until the point of the metformin interruption or the end of the study period. In the metformin interruption group, eGFR was measured from at least 100 days after discontinuing metformin until the point of re-starting metformin treatment or December 31, 2013. The rate of renal function decline was determined according to the eGFR slope, and defined as the regression coefficient between eGFR and time in units of mL/min/1.73 m2/year, representing the change in the eGFR over time. At least four eGFR values were required to calculate the eGFR slope using regression coefficients between eGFR and time. A faster decline in renal function was indicated by a higher negative eGFR slope.
Metformin Is A Useful Drug In T2dm
Metformin increases insulin sensitivity, reduces glucose absorption from the intestine, increases peripheral glucose uptake in cells, reduces hepatic gluconeogenesis in the liver and reduces weight, all highly desirable goals in T2DM . Further advantages are a reduction in blood pressure and plasma lipids, plasminogen activator inhibitor, and insulin, and an increase in fibrinolytic activity. In addition, hypoglycemia is a rare complication of treatment. Sulfonylurea and insulin both have hypoglycemia as a major and common side effect. The risk of hypoglycemia doubles in the presence of CKD . Metformin is the only drug demonstrated to significantly reduce the risk of mortality and myocardial infarction , by 36% and 39% respectively , this effect being independent of glycemic control. For these reasons, metformin is the first line drug of choice in obese T2DM.
Metformin was previously contraindicated in heart failure. However, a meta-analysis of performed trials showed a significantly reduced risk for mortality and hospital admission related to metformin , with no risk of LA. Use of the drug in the presence of heart failure is now so common that a randomized controlled trial is no longer possible .
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Glycaemic Control After Metformin Discontinuation In Diabetic Patients With A Declining Renal Function
Chin Meng Khoo
1Department of Medicine, National University Hospital, Singapore
2Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3Higher Education Department, Centre for International Education, Cebu, Philippines
Abstract
1. Introduction
The rising prevalence of type 2 diabetes mellitus is considered one of the most challenging public health problems. More than 400 million people will be affected by T2DM by the year 2030, with the greatest increase expected in Asian populations . Metformin is the recommended first-line antidiabetic therapy for all patients in addition to lifestyle change. Metformin is a very effective antidiabetic agent, widely available and affordable. Its most common side effect is gastrointestinal irritation. T2DM is associated with dismal micro- and macrovascular complications. One of the most dreadful microvascular complications is diabetic nephropathy, which is often characterised by declining estimated glomerular filtration rate and proteinuria. Declining renal function prohibits many medications for fear of potential side effects from lower renal clearance. As such, it is recommended that metformin should be discontinued when the eGFR falls to 30ml/minute/1.73m2 or below , in anticipation of a higher risk of lactic acidosis. Other antidiabetic agents including sulfonylureas, meglitinides, dipeptidyl peptidase-4 inhibitors, and insulin have been shown to be safe in patients with declining renal function .
3. Results
| N |
Kidney Impairment Can Be Costly
Although renal impairment is often reversible if the offending drug is discontinued, the condition can be costly and may require multiple interventions, including hospitalization, Dr. Naughton explained. To help you avoid getting to that point, we learned about medications that commonly cause kidney damage from Rebekah Krupski, PharmD, RPh, pharmacy resident at the Cleveland Clinic and clinical instructor of pharmacy practice at Northeast Ohio Medical University.
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Metformin Clearance By The Kidneys
Metformin does not undergo metabolism in the body, and it is eliminated unchanged in the urine. It is mainly cleared by tubular secretion in the kidneys. Metformin clearance is proportional to creatinine clearance. Therefore, although metformin can be used in patients with advanced kidney disease the dose of metformin should be decreased. The following table shows the recommended doses of metformin according to kidney function.
| Kidney function |
Study Participants And Design
We performed a retrospective observational cohort study of patients with type 2 diabetes who were followed at the nephrology clinics of two tertiary hospitals in South Korea . Deidentified patient data retrieved from electronic medical records were used, including the date of birth, sex, BMI, diagnostic codes according to the ICD-10-Clinical Modification, drug prescriptions, and laboratory results. The follow-up period for each patient was defined as the interval between the first and last dates of creatinine measurements. From 1 January 2001 to 31 December 2016, 11,677 patients were investigated . We excluded patients with missing serum creatinine levels , patients with short follow-up periods and patients who received renal replacement before or within 30 days of the first visit . Finally, 10,862 patients were included .
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How To Monitor Diabetes On Metformin
For patients taking metformin, we measure A1C every three to six months, serum creatinine annually, vitamin B12 annually. B12 deficiency is more common in especially in individuals, especially in individuals who took metformin for many years. Those people who are at risk are patients on a vegetarian diet or problems with absorption, such as after gastric bypass surgery. We know that 5 to 10% of patients taking metformin more than five years have a B12 deficiency.
Emerging Data On Additional Metformin Benefits
Among type 2 diabetic patients who were newly prescribed metformin vs. other anti-diabetic drugs from the National Health Insurance reimbursement database in Taiwan, the incidence of kidney cancer among metformin users was substantially lower compared to non-users: 80 vs. 190 cases per 100,000 person-years, respectively . Furthermore, metformin use was associated with 72, 40, 72, and 90% lower risk of developing kidney cancer after < 14.5, 14.5-45.8, and > 45.8 months of follow-up compared to non-metformin users. These findings may have particular relevance in diabetic kidney disease patients, given the heightened risk of kidney cancer associated with CKD . Given the relatively low event rate of MALA observed in the aforementioned Hung et al. study, further studies are needed to determine whether the risks of metformin outweigh its potential benefits upon cancer risk and cardiovascular outcomes as shown in the UKPDS 34 study .
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There Is No Epidemiological Evidence That Metformin Use Increases The Risk Of La
A Cochrane analysis of 347 controlled studies covering 70,490 patient-years of metformin use revealed no cases of LA and no significant change in p-lactate . There is no correlation between metformin and lactate controls . In 43% of these studies, CKD was not a contraindication. In a population of T2DM patients with no access to biguanide therapy, the incidence of LA was 9.7-16.9/100,000 patient-years . In all cases, proximal medical causes were identified in the form of hypotension, sepsis, or congestive heart failure, and can thus be classified as Type A LA. Thus, all diabetic patients, regardless of treatment, have an increased risk of LA when faced with circulatory challenge, and the risk of MALA should be compared with this intrinsic risk. The quoted incidence of MALA varies from 0-9.7 and is thus comparable with this figure. Indeed, in two studies where this was investigated, the incidence of sulphonylurea-associated LA was higher than MALA . One might argue that this low incidence was the result of pedantic attention to contraindications in reality, stated contraindications, mainly CKD, are widely ignored in general practice, with a contraindication prevalence varying from 19-94% of treated patients . In one center over 1,000 patients with CKD have been treated without any cases of MALA .
Bonus: Metformins Impact On The Gut Microbiome
Because of metformins actions on the gut, it can also alter the intestinal microbiota for the better. Studies showed that metformin can enhance the growth of Akkermansia muciniphila, Butyrivibrio, Bifidobacterium, and Lactobacillus. In addition, it decreases the levels of some other bacteria like Intestinibacter. Metformin also promotes the production of the short-chain fatty acids that protect the intestinal barrier. In fact, some authors attribute some of metformins actions to its favorable impact on the gut microbiota and integrity.
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Effect Of Metformin On All
Mild/Moderate CKD
Six studies reported the effect of metformin use versus any other measure on all-cause mortality in patients with T2DM and mild/moderate CKD . The pooled RR was 0.71 in a random-effects model, with severe heterogeneity .
Figure 2 Forest plot of the risk of all-cause mortality in patients with type 1 diabetes mellitus and chronic kidney disease .
Sensitivity analysis uncovered that heterogeneity did not disappear after the deletion of single studies. Significant publication bias was found by Eggers test , but not by funnel plot inspection or Begg test . During publication bias exploration based on the trim-and-fill approach, the probable missing data were not replaced, so the results were basically equal to a remarkably less risk of all-cause death after metformin treatment . The GRADE determined a low-quality evidence that metformin prevented all-cause death in mild/modest CKD patients.
Advanced CKD
Six trails reported all-cause mortality in advanced CKD patients . Metformin use had no significant therapeutic effect on all-cause death , with heavy between-study heterogeneity . The effect was still insignificant in the stratified analysis by study design . The heterogeneity did not disappear after the exclusion of any single study.
The funnel plots showed no evident systematic bias between all-cause death and advanced CKD .
Moderate CKD
How Are The Kidneys Kept Working As Long As Possible
The kidney doctor, called a nephrologist, will plan your treatment with you, your family and your dietitian. Two things to keep in mind for keeping your kidneys healthy are controlling high blood pressure in conjunction with an ACE inhibitor and following your renal diabetic diet. Restricting protein in your diet also might be helpful. You and your dietitian can plan your diet together.
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Sensitivity Analysis Of Glycemic Control
Because glycemic control can affect patient outcomes, we conducted two sensitivity analyses of glycemic control. First, we adjusted HbA1c levels as a time-varying covariate based on a fully adjusted multivariate Cox regression model. Metformin users with an eGFR > 30 mL/min/1.73 m2 still had low all-cause mortality and low ESRD incidence .
Second, we investigated severe hypoglycemic events that caused an emergency department visit. A total of 535 events were recorded in the whole cohort, and 294 events were recorded in the PSM cohort. Metformin did not increase the number of severe hypoglycemic events for either the whole population or the PSM cohort .
Can A Person With Diabetes Have A Kidney Transplant
Yes. Once you get a new kidney, you may need a higher dose of insulin. Your appetite will improve so your new kidney will break down insulin better than your injured one. You will use steroids to keep your body from rejecting your new kidney. If your new kidney fails, dialysis treatment can be started while you wait for another kidney. Learn more about kidney transplant.
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Medical Therapy In Dialysis And Post
There are a few oral agents that can be used safely in patients on dialysis, particularly if the diabetes is fairly mild. Most others, however, will need insulin for glycemic control.
Patients receiving hemodialysis can have different clearance rates of insulin that may be affected by the timing of dialysis. We have done continuous glucose monitoring on patients undergoing HD and found that patients glycemic responses during HD are quite idiosyncratic and their insulin regimens need to be individualized to avoid both hyper-and hypoglycemia during and after HD. Patients who are on peritoneal dialysis have exposure to large amounts of glucose in the dialysate that can lead to uncontrolled hyperglycemia. In patients receiving PD continuously, a standard basal/bolus insulin regimen is best. However, with overnight PD using a cycler, coverage of the increased glucose load may best be accomplished using a fixed mixture insulin combination, such as 70/30 or 75/25 insulins, given at the onset of PD. The nephrologist prescribing the PD will often change the glucose concentration of the dialysate because of the need for more or less fluid removal and such changes need to be discussed with the endocrinologist so that the insulin doses may be appropriately changed.
Renal Disease Impact On Long
Editor: Steve Freed, R.PH., CDE
As we are all familiar with how metformin can impact patients with existing renal disease, researchers aimed to study how far the limitations can be pushed.
Chronic kidney disease is well known to be caused by diabetes. As scientists have studied the disease for years and novel treatments can assist in the management of it, metformin is still considered a first-line treatment for type 2 diabetes. Metformin is not expensive, has excellent efficacy, is weight neutral, and has benefits regarding cardiovascular outcomes. However, if a patient has chronic kidney disease, metformin is not recommended as a first-line treatment due to the risk of lactic acidosis. Historically, the risk of this fatal adverse effect has resulted in the withdrawal of biguanide, phenformin, and buformin off the market. The purpose of this study was to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease.
In conclusion, this retrospective study found metformin use decreased the risk of all-cause mortality and incident end-stage renal disease in patients with advanced chronic kidney disease, especially those with chronic kidney disease 3B. Also, metformin use did not increase the risk of lactic acidosis. Although these findings are promising, there are remaining biases after patient-specific mortality that warrant the need for further randomized controlled trials to change real-world practice.
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Current Guidelines And Future Implications
These studies highlight the lack of randomised clinical trials to test the specific hypothesis that metformin is safe in patients with mild to moderate CKD. Randomised trials would help to better inform evidence-based guidelines. Nevertheless, given the rarity of LA in the setting of metformin therapy, a study would need to examine hundreds of thousands of patients for many years to demonstrate noninferiority compared with other hypoglycaemic agents, which might not be feasible. National patient registries might be a reasonable alternative however, for regulatory bodies at this time, the best available evidence is limited to meta-analyses, retrospective studies, and smaller mechanistic investigations reported herein.
Other non-American guidelines considered the use of eGFR to determine the safety of metformin. The National Institute for Health and Care Excellence recommends using metformin with caution in patients58 for whom serum creatinine > 130 mol/L or eGFR < 45 mL/min. Doses should be lower and prescribed with increased frequency of monitoring. In patients already taking metformin, the drug should be discontinued if the serum creatinine > 150 mol/L or GFR < 30mL/min.
Metformin Intoxication Is Not Usually The Cause Of Mala
Virtually all cases of MALA occur in individuals with severe conditions that in themselves cause LA. In a study of 20 MALA cases, only 7 had raised concentrations of p-metformin , and in another series of 47 cases of MALA, only 13 could be ascribed to metformin . Metformin concentration is not correlated to plasma lactate in MALA .
Lalau & Race have suggested that, since many cases of MALA are unrelated to metformin, the term MALA should be divided into metformin-unrelated LA and metformin-induced LA , the latter being defined by a raised metformin concentration. While MULA, being primarily caused by Type A LA, bears a very high mortality of 50%, the risk of mortality from MILA is only about 10% .
Accepting that metformin is sometimes a cause of MALA, the question then arises whether this contraindicates metformin in CKD. Assuming a mortality of 50%, the death rate from MALA is 3/100,000 patient-years. This is on a level with the risk of death from anaphylactic shock during penicillin therapy and compares favorably with the risk of dying in a traffic accident in the USA . The calculated corresponding figures for hypoglycemia-related death of patients treated with sulphonylurea and insulin are 43 and 77, respectively . The potential benefits on death and myocardial infarction mentioned above far outweigh this risk. It remains, however, to be demonstrated that these benefits also apply to the CKD population.
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