Metformin Use And Risk Of All
- 1Department of Medicine Renal Division, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
- 2Department of Medicine Renal Division, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China
- 3Department of Medicine Renal Division, West China Hospital, West China School of Medicine, Sichuan University, Kidney Research Institute, Chengdu, China
Background: To evaluate whether metformin use assuredly alters overall all-cause death in patients with type 2 diabetes mellitus and chronic kidney disease .
Methods: Pubmed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to Feb. 29, 2020 with no language restriction. All related articles comparing all-cause death of T2DM and CKD patients after metformin use versus non-metformin treatment were identified. Pooled risk ratios and 95% confidence intervals were computed using random-effects models regardless of the heterogeneity quantified by Cochrane 2 and I2 statistics.
Results: Totally 13 studies involving 303,540 patients were included. Metformin-based treatments relative to any other measure displayed significantly lower risks of all-cause mortality and cardiovascular events in CKD patients at stage G1-3, with substantial heterogeneity. Metformin use was not significantly related with these end points in advanced CKD patients.
Preventing Diabetic Kidney Disease: 10 Answers To Questions
Diabetic kidney disease is a decrease in kidney function that occurs in some people who have diabetes. It means that your kidneys are not doing their job as well as they once did to remove waste products and excess fluid from your body. These wastes can build up in your body and cause damage to other organs.
Common Diabetes Drug Found Safe For Most Diabetics With Kidney Disease
Acidosis related to use of metformin seen only in those with severely decreased kidney function
Oral diabetes drug metformin is safe for most diabetics who also have chronic kidney disease .Credit: Johns Hopkins Medicine
A report on the study appeared online June 4 in JAMA Internal Medicine.
Metformin is the first-line medication for treatment of type 2 diabetes in adults and the fifth most commonly used drug in the United States. However, there has been a longstanding concern in the medical community about prescribing metformin for people with both diabetes and CKD because it may cause lactic acidosis, says senior study author Morgan Grams, M.D., Ph.D., M.H.S., an associate professor of medicine and epidemiology at the Johns Hopkins University School of Medicine. Lactic acidosis is a rare but serious complication, occurring when lactatea product of glucose breakdownbuilds up in the bloodstream, producing symptoms such as severe muscle pain, cramps, nausea and weakness. Because patients with CKD may be at increased risk of metformin-associated lactic acidosis, health care providers historically avoided prescribing metformin in this population.
The research team used computer-based statistical models to analyze the risk of developing acidosis among metformin users compared with nonusers. The researchers adjusted for conditions such as cardiovascular disease and smoking status.
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History Of Biguanide Use
Metformin is a type of biguanide, a class of oral anti-hyperglycemic drugs that have been utilized in the treatment of diabetes mellitus for many years. In medieval times, Galega officinalis, also known as French lilac or goat’s rue, was used for the treatment of diabetes . In the 1920s, it was discovered that the active ingredient in French lilac extracts, which lowered blood glucose levels was guanidine 2). By the 1950s and 1960s, 3 biguanide compounds became available for clinical use, namely, phenformin, buformin, and metformin. However, in 1976, phenformin was withdrawn from the US market and other countries due to high rates of fatal lactic acidosis. While buformin was never available in the United States, it was also removed from many industrialized nations due to lactic acidosis. In 1995, metformin use was approved by the FDA with the stipulation that it would be contraindicated in kidney disease or kidney dysfunction, defined by a creatinine of 1.5 and 1.4 mg/dl in men and women, respectively, or an abnormal creatinine clearance, and it should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates normal kidney function . Notably, the aforementioned cutoff for kidney dysfunction was based upon conservative estimates of the threshold at which 3 g of metformin is removed at steady state levels in 24-48 h .
Whos At High Risk Of Serious Side Effects
Because of the risk of serious problems, your doctor will probably recommend a different medication if you:
- Have had an allergic reaction to metformin or other medicines
- Have diabetes that isnât under control
- Have liver or kidney problems
- Have a severe infection
- Recently had a heart attack or heart failure
- Have breathing or blood flow problems
- Drink a lot of alcohol
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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.
Can Metformin Extend Life Expectancy
A number of news articles have recently addressed the rise in popularity of metformin and other drugs that might extend the length of your life. In the early 2000s, research showed that metformin extended life expectancy in mice, but its impact on human life expectancy is currently unknown. Some researchers believe that metformin may be effective in anti-aging, though research is ongoing and nothing is definitive at this time.
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Effect Of Metformin On All
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.
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 .
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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Can Metformin Cause Kidney Problems
Actually, metformin is usually not the original cause of kidney problems. However, metformin is eliminated by the kidneys and when a patient has poor kidney function, the metformin can build up in the blood and cause a rare but serious condition called lactic acidosis. Lactic acidosis affects the chemistry balance of your blood and can lead to kidney failure and other organ failure. The risk of lactic acidosis is very low and most often occurs in patients with poor kidney function â so for most patients, the benefits of metformin outweigh the risks of treatment. Most doctors will regularly perform kidney function tests to make sure the kidney is working well in patients who are taking metformin. With that said, if you are taking metformin, contact your doctor immediately if you experience unexplained weakness, muscle pain, difficulty breathing, or increased drowsiness â these can be early signs of lactic acidosis. Also, if you are taking metformin and going to receive a radiocontrast dye study or have surgery, tell your doctors that you are taking metformin â in most cases, your doctor will instruct you to temporarily stop taking metformin during these procedures to help decrease the risk of lactic acidosis.
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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.
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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 .
What Other Injectable Medicines Treat Type 2 Diabetes
Besides insulin, other types of injected medications are offered. These medications assist keep your blood sugar level from going expensive after you consume. They might make you feel less hungry and help you lose some weight. Other injectable medications are not alternatives to insulin.
What should I learn about adverse effects of diabetes medicines?Side effects are issues that arise from a medicine. Some diabetes medications can trigger hypoglycemia, also called low blood glucose, if you dont balance your medications with food and activity.Ask your doctor whether your diabetes medicine can trigger hypoglycemia or other side results, such as indigestion and weight gain. Take your diabetes medications as your healthcare specialist has advised you, to assist prevent side effects and diabetes issues.
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Taking insulin or other diabetes medications is often part of treating diabetes Together with healthy food options and physical activity, medication can assist you manage the disease. Some other treatment alternatives are also available.
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Demographic Medical And Laboratory Data Collection
Demographic and medical data including age, gender, comorbid conditions involving hypertension, ischemic heart disease, heart failure, cerebrovascular disease, peripheral arterial occlusive disease, and liver cirrhosis, and medications including anti-hypertensive agents, anti-diabetic agents, lipid-lowering agents, non-steroidal anti-inflammatory drugs, and selective COX-2 inhibitors were obtained from the research database of KMUH. Baseline laboratory data including blood fasting glucose, serum triglycerides, serum total cholesterol, serum LDL-C, serum high-density lipoprotein cholesterol, HbA1c, eGFR, serum creatinine, serum uric acid, and UACR were also collected. eGFR was calculated using the four-variable equation in the Modification of Diet in Renal Disease study.
How To Tolerate Metformin
Some patients may have gastrointestinal intolerance to metformin such diarrhea and bloating. In these patients, slower titration, ensuring that the patient is taking the medication with food, or switching to an extended-release formulation may improve tolerability. Extended-release metformin Extended-release metformin, typically taken once daily with the evening meal, is available in 500 and 750 mg tablets. For our patients having tolerance problems, we sometimes give the entire dose up to 2000 mg at once at the dinner meal. Because patients take metformin with meals, the ability to administer the whole treatment once daily typically improves adherence.
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Metformin And Vitamin B12 Deficiency
The association between long-term use of metformin and low vitamin B12 levels in type 2 diabetes mellitus patients is well-established. This is thought to be due to changes in the production of intrinsic factor in the stomach, which decreases vitamin B12 absorption in the intestine. Vitamin B12 deficiency is more pronounced if the patient is also taking a proton pump inhibitor such as omeprazole or histamine H2 receptor antagonist such as famotidine, which are medications used to treat acid reflux. Since diabetes can cause peripheral neuropathy, as well as vitamin B12 deficiency can cause peripheral neuropathy, it can be confusing for diabetic patients on metformin and their practitioners.
Therefore, patients using metformin for a prolonged period should be screened initially and periodically for vitamin B12 deficiency. In addition, there is also growing evidence that other B vitamins, vitamin D, and magnesium can be impacted by metformin.
Metformin Causes Scary Lactic Acidosis
The risk of metformin causing lactic acidosis of the blood is exceedingly rare. A Cochrane systematic review of 70,490 patients with type 2 diabetes on metformin did not report a single case of metformin-induced lactic acidosis. The risk of metformin causing lactic acidosis appears to be no greater than that of non-metformin therapies.
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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 .
Can Metformin Can Cause Nerve Damage
Along with increasing your risk for anemia, low vitamin B12 levels may also contribute to nerve damage , which can cause chronic nerve pain. However, uncontrolled diabetes can also lead to neuropathy. If youre taking metformin to treat type 2 diabetes and experience neuropathy, it could be a symptom of your diabetes rather than a side effect of the drug.
Research on metformin causing nerve damage is mixed overall and suggests that while the neuropathy concern is relevant, its unlikely that its a side effect of metformin.
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