Metformin Contraindications
The biguanide metformin (dimethylbiguanide) was initially introduced for use in the treatment of type 2 diabetes mellitus in the late 1950s. Today this drug is considered to be the first-choice agent and the “gold standard” for most people with type 2 diabetes. It has been estimated that the annual number of people receiving prescriptions for metformin worldwide is more than 120 million. The efficacy and benefits of metformin treatment in type 2 diabetes have been confirmed by large-scale studies and recognized by many consensus statements. Still, a large list of contraindications may increase the incidence of serious adverse effects, which precludes many patients from taking metformin. Intolerance and contraindications to metformin Three particular contraindications to the use of metformin have been suggested. They include renal impairment with elevated serum creatine levels (i.e. more than 136 mmol/l in men and 124 mmol/l in women) or abnormal creatinine clearance, congestive heart failure requiring pharmacologic treatment and advanced age (more than 80 years of age). Renal impairment represents a contraindication to metformin usage due to the increased risk of lactic acidosis (a form of metabolic acidosis due to the inadequate clearance of lactic acid from the blood). Although lactic acidosis linked to metformin is a rare condition, with an estimated prevalence of one to five cases per 100 000 population, it has a reported mortality of 30-50%. However, recent studies have suggested that metformin can be used safely, unless the estimated glomerulal filtration rate (the volume of fluid that is filtered from the capillaries of the glomeruli into the kidney tubules per unit time) falls below 30 ml/min, with a dose reduction advised at 45 ml/min. Congestive heart fail Continue reading >>
Metformin, Heart Failure, And Lactic Acidosis: Is Metformin Absolutely Contraindicated?
Many patients with type 2 diabetes are denied treatment with metformin because of “contraindications” such as cardiac failure, which may not be absolute contraindications Treatment with metformin is not associated with an increased risk of lactic acidosis among patients with type 2 diabetes mellitus who have no cardiac, renal, or liver failure Despite increasing disregard of contraindications to metformin by physicians, the incidence of lactic acidosis has not increased, so metformin may be safe even in patients with “contraindications” The vast majority of case reports relating metformin to lactic acidosis report at least one other disease/illness that could result in lactic acidosis Use of metformin in patients with heart failure might be associated with lower mortality and morbidity, with no increase in hospital admissions and no documented increased risk of lactic acidosis Further studies are needed to assess the risk of lactic acidosis in patients with type 2 diabetes and traditional contraindications to metformin Metformin first became available in the United Kingdom in 1957 but was first prescribed in the United States only in 1995.w1 The mechanism of action has been extensively reviewed.w2 w3 The UK prospective diabetes study showed that metformin was associated with a lower mortality from cardiovascular disease than sulphonylureas or insulin in obese patients with type 2 diabetes mellitus.1 It was also associated with reduced all cause mortality, which was not seen in patients with equally well controlled blood glucose treated with sulphonylureas or insulin.1 Despite the evidence base for the benefits of metformin, concerns remain about its side effects and especially the perceived risk of lactic acidosis in the presence of renal, hepatic, respiratory, Continue reading >>
Review Article Metformin In Heart Failure Patients
Summary The use of metformin was considered a contraindication in heart failure patients because of the potential risk of lactic acidosis; however, more recent evidence has shown that this should no longer be the case. We reviewed the current literature and the recent guideline to correct the misconception. Continue reading >>
Metformin May Reduce All-cause Mortality In Patients With Congestive Heart Failure
A systematic review of 17 observational studies found that metformin was associated with a reduction in all-cause mortality in patients with type 2 diabetes and chronic kidney disease, congestive heart failure or chronic liver disease with hepatic impairment. Metformin was also associated with fewer heart failure readmissions in patients with chronic kidney disease or congestive heart failure. Lead researcher Matthew J. Crowley, MD, MHS, of Duke University and the Durham Veterans Affairs Medical Center in North Carolina, and colleagues published their results online Jan. 2 in the Annals of Internal Medicine. The U.S. Department of Veterans Affairs funded the study. When the FDA approved metformin in 1994, the drug became the initial treatment option for many people with type 2 diabetes in the U.S., according to the researchers. However, the FDA required a label warning against using metformin in patients with chronic kidney disease and recommended caution for patients with congestive heart failure and chronic liver disease. The researchers noted that the FDA in 2006 removed congestive heart failure as a contraindication to metformin use, although the agency still cautions against the drug’s use in patients with acute or unstable congestive heart failure. They also noted that the FDA in April 2016 revised its warning regarding metformin use in patients with chronic kidney disease. By switching to a more inclusive criteria based on estimated glomerular filtration rate, an estimated one million additional patients with moderate chronic kidney disease are eligible to receive metformin, although the drug remains contraindicated in patients with severe chronic kidney disease. For this analysis, the researchers searched databases, the ClinicalTrials.gov website and other pub Continue reading >>
Metformin Linked To Decreased Mortality In Ckd, Chf, And Liver Disease
Metformin is associated with lower all-cause mortality in patients with moderate chronic kidney disease (CKD), congestive heart failure (CHF) and chronic liver disease (CLD), according to a study published in the February issue of the Annals of Internal Medicine.1 “Although data were limited, we found no evidence to suggest that metformin's benefits do not extend to patients with moderate CKD, CHF, or CLD with impaired hepatic function. Together with reports regarding the safety of metformin with respect to lactic acidosis, our findings support the FDA's recent actions,” wrote first author Matthew Crowley, MD, of Durham Veterans Affairs Medical Center (Durham, NC) and Duke University, and colleagues.2 When metformin was first approved in 1994, it was contraindicated in patients with CKD and CLD, due to concerns over lactic acidosis. Several years later, the US Food and Drug Administration (FDA) also advised against its use in CHF. These warnings were motivated, in part, by concerns for lactic acidosis with use of phenformin, a related drug that was pulled from the market in 1977.1,2 Over the years, the FDA has relaxed some of the restrictions over metformin’s use. In 2006, the agency removed CHF as a contraindication for the drug, though still cautioned about its use in acute or unstable CHD.2 In April 2016, the FDA changed metformin’s boxed warning, expanding its use to patients with mild kidney impairment and some patients with moderate renal impairment.3 Collectively, these changes will likely increase metformin use in patients who would have had contraindications in the past. Effective in more patients? To evaluate whether metformin use improves outcomes in an expanded population of patients, researchers searched Medline from January 1994 to September 2016, Continue reading >>
Does Metformin Increase The Risk Of Fatal Or Nonfatal Lactic Acidosis?
WILLIAM E. CAYLEY, JR., MD, MDiv, University of Wisconsin Department of Family Medicine, Eau Claire, Wisconsin Am Fam Physician. 2010 Nov 1;82(9):1068-1070. Clinical Scenario A 70-year-old woman with type 2 diabetes mellitus who is in otherwise good health is experiencing gradually increasing glucose levels. Her physician considers starting her on an oral diabetes agent, but is concerned that her age may put her at risk for adverse effects if she is treated with metformin (Glucophage). Clinical Question Does metformin increase the risk of fatal or nonfatal lactic acidosis? Evidence-Based Answer In patients without standard contraindications to metformin therapy, metformin does not increase the risk of lactic acidosis.1 (Strength of Recommendation = B, based on inconsistent or limited-quality patient-oriented evidence) Practice Pointers The first-line treatments recommended for type 2 diabetes are lifestyle changes and metformin, which is a biguanide antihyperglycemic agent.2 Demonstrated benefits of metformin include lower cardiovascular mortality than other oral diabetes medications3 and a reduced risk of death or myocardial infarction in overweight patients with type 2 diabetes.4 However, because an earlier biguanide, phenformin, was removed from the market after being linked to several cases of lactic acidosis, there have been concerns that metformin may predispose patients to lactic acidosis as well. In light of this, metformin is considered contraindicated in patients with chronic renal insufficiency, pulmonary disease, or hypoxic conditions; abnormal hepatic function; peripheral vascular disease; and in those older than 65 years. The use of metformin in patients with heart failure continues to be controversial.1 The authors of this Cochrane review found no cases o Continue reading >>
Metformin And Heart Failure: Never Say Never Again
Metformin represents the cornerstone of treatment for type 2 diabetes mellitus. Traditionally, heart failure (HF) was considered a contraindication to its use. However, more recent evidence has shown that this should no longer be the case. Indeed, studies have demonstrated that metformin may even reduce the risk of incident HF and mortality in diabetic patients, while improving up to 2-year survival rates in those with HF. In addition, it appears to exert cardioprotective actions. Although longer follow-up data and more explicit information about the situation in patients with very advanced HF are needed, the cardiac safety of metformin has profound clinical implications and may be anticipated to further encourage its widespread use. 1. Introduction Metformin has long been established as the mainstay of treatment for type 2 diabetes mellitus (T2DM) [1,2] Nathan DM, Buse JB, Davidson MB, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203 Papanas N, Maltezos E, Mikhailidis DP. Metformin: diamonds are forever. Expert Opin Pharmacother 2009;10:2395-7. Not only does it reduce hyperglycaemia but it is not associated with unwanted hypoglycaemia (unless used along with insulin or excessive exercise), and it has favourable actions on body weight and serum lipids [3]. More importantly, based on an observational study of participants in a large randomised controlled trial (RCT), it confers long-term protection from all T2DM-related endpoints, myocardial infarction and death from any cause [4]. Traditionally, the use of metformin has been subject to contraindications Continue reading >>
Drugs That Should Be Avoided Or Used With Caution In Patients With Heart Failure
INTRODUCTION A number of medications that are in common clinical use are relatively or absolutely contraindicated in patients with heart failure (HF), either because they can cause exacerbations of HF or because there is a higher risk of adverse reactions in such patients (table 1) [1]. Drug-induced exacerbation or decompensation of established HF is a relatively common occurrence. Its prevention requires frequent reassessment and meticulous management of often complex medication regimens. Utilization of these drugs is common in patients with HF. In a study from Denmark, 34 percent of patients received at least one nonsteroid anti-inflammatory agent or cyclooxygenase-2 inhibitor after discharge for first hospitalization for HF [2]. Use of some of these drugs may be increasing. As an example, a review of Medicare beneficiaries hospitalized with the diagnoses of HF and diabetes mellitus found that the proportion using metformin and/or a thiazolidinedione increased from 13.5 percent in 1998 to 1999 to 24.4 percent in 2000 to 2001 [3]. Management of patients with HF is discussed separately. (See "Overview of the therapy of heart failure with reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction".) GENERAL PRINCIPLES General principles for avoiding drug-induced worsening of HF include the following: Recognition of the basic mechanisms by which drugs can exacerbate HF including: TI CONTEXT: According to package inserts, metformin is contraindicated in diabetic patients receiving drug treatment for heart failure therapy, and thiazolidinediones are not recommended in diabetic patients with symptoms of advanced heart failure. Little is known about patterns of use of these antihyperglycemic drugs in diabetic patients with heart Continue reading >>
Metformin And Heart Failure
Innocent until proven guilty Throughout the world and for many years, metformin has been a mainstay of therapy for patients with type 2 diabetes. This highly effective and usually well-tolerated oral agent is, to date, the only one demonstrated to reduce cardiovascular disease (CVD) complications in newly diagnosed type 2 diabetic patients (1). It's precise mechanism of action remains enigmatic, although it clearly results in a reduction of endogenous glucose production, primarily hepatic gluconeogenesis, most likely involving the stimulation of AMP-activated protein kinase activity (2). A peripheral insulin-sensitizing effect in skeletal muscle has also been demonstrated by some, but not all, investigators (3). In small studies, metformin appears to exert benefit on various other fundamental biological processes that influence atherogenesis, such as lipid metabolism, inflammation, and vascular endothelial function (4). Another insulin sensitizer category, the thiazolidinediones (TZDs), has also been proposed to reduce CVD risk, but that class carries with it concerns of weight gain and fluid retention. As a result, TZDs remain more popular in combination therapy regimens. Perhaps of greatest import to clinicians is the recognition that metformin is the only oral antidiabetic agent associated with weight loss. Accordingly, metformin remains, in the eyes of many authorities, the optimal initial drug choice in most type 2 diabetic patients if diet and exercise have not succeeded in adequately reducing blood glucose levels (5). Approval of metformin in the U.S. was delayed because of previous experience with phenformin, which was associated with lactic acidosis. Although the risk of such metabolic decompensation with metformin was known to be significantly lower than with Continue reading >>
Metformin Use In Patients With Diabetes And Heart Failure: Cause For Concern?
Patients with type 2 diabetes are 2.5 times more likely to develop heart failure than those without diabetes,1 and > 30% of patients with heart failure have concurrent diabetes.2 Biguanides, namely phenformin and metformin, have been used for the treatment of diabetes for decades. In certain clinical situations, however, the use of biguanides can result in an accumulation of lactic acid, which may result in a rare condition known as acute lactic acidosis (ALA), which is fatal in ∼ 50% of cases.3,4 In most instances, the development of ALA arises secondary to conditions predisposing patients to hemodynamic compromise and overt tissue hypoxia, such as acute myocardial infarction (MI), acute uncompromised heart failure, or sepsis.5,6 Phenformin was removed from the market in 1976 because of reports of both fatal and nonfatal phenformin-associated lactic acidosis (PALA).7 The incidence of PALA at the time was estimated to be between 40 and 64 cases per 100,000 patient-years, or four to six times that seen in patients with diabetes who were not on phenformin.8,9 Unlike phenformin, which is metabolized through the liver via hydroxylation, metformin is excreted unchanged in the urine.10 Therefore, metformin is less likely to inhibit hepatic lactate clearance and lead to ALA. The estimated incidence of metformin-associated lactic acidosis (MALA) in patients with diabetes is between 3 and 9 cases per 100,000 patient-years, roughly the same as that reported in patients with diabetes who are not taking a biguanide.4,7,11–13 Epidemiological data reveal that metformin is often used in patients with heart failure. Prospective and retrospective cohort studies have evaluated health care databases of hospitalized and outpatient diabetic populations to determine metformin usage in pa Continue reading >>
Clinical Outcomes Of Metformin Use In Populations With Chronic Kidney Disease, Congestive Heart Failure, Or Chronic Liver Disease: A Systematic Review
Abstract Background: Recent changes to the U.S. Food and Drug Administration boxed warning for metformin will increase its use in persons with historical contraindications or precautions. Prescribers must understand the clinical outcomes of metformin use in these populations. Purpose: To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment. Data Sources: MEDLINE (via PubMed) from January 1994 to September 2016, and Cochrane Library, EMBASE, and International Pharmaceutical Abstracts from January 1994 to November 2015. Study Selection: English-language studies that: 1) examined adults with type 2 diabetes and CKD (with estimated glomerular filtration rate less than 60 mL/min/1.73 m2), CHF, or CLD with hepatic impairment; 2) compared diabetes regimens that included metformin with those that did not; and 3) reported all-cause mortality, major adverse cardiovascular events, and other outcomes of interest. Data Extraction: 2 reviewers abstracted data and independently rated study quality and strength of evidence. Data Synthesis: On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF. Limitations: Strength of evidence was low, and data on multiple outcomes of interest were sparse. Available studies were observational and varied in follow-up duration. Conclusion: Metformin use in patients with moderate CKD, CHF, or CLD with hepatic impairment is associated with improvements in key c Continue reading >>
(pdf) Metformin In Heart Failure Patients
Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called "Diabetic Cardiomyopathy" (DCM) is becoming a well- known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined. BackgroundMetformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use.ObjectiveThe aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF.MethodsA total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data.ResultsWe obse Continue reading >>
Wrongfully Accused: Metformin Use In Heart Failure
Expert Rev Cardiovasc Ther.2011;9(2):147-150. Metformin has long been the cornerstone of therapy for glycemic control in patients with Type 2 diabetes worldwide. It is recommended as first-line therapy by all major diabetes clinical practice guidelines owing to its efficacy, favorable tolerability profile and beneficial effects in limiting weight gain. Moreover, metformin is the only oral anthyperglycemic agent shown in randomized controlled trials to reduce mortality in newly diagnosed patients with Type 2 diabetes. However, the use of metformin has not been without controversy, in particular in patients with heart failure. This article will review a recent observational study by Aguilar et al. published in Circulation Heart Failure that reported improved outcomes associated with metformin therapy in patients with diabetes and heart failure. Heart failure is a very common comorbidity present in 2540% of all adults with diabetes.[ 1 ] Diabetes also portends poorer outcomes in patients with heart failure and hyperglycemia is associated with increased risk of hospital admission.[ 2 ] Historically, the use of metformin in patients with comorbid heart failure was considered 'absolutely' contraindicated owing to the perceived increased risk of lactic acidosis. Recently, regulatory bodies in both Canada (Health Canada) and the USA (US FDA) have removed the heart failure contraindication from product labeling for metformin, although a 'black box' warning for the cautious use of metformin in this population still exists. How best to control blood glucose in patients with diabetes and heart failure still remains controversial owing to the lack of randomized controlled trial evidence. Indeed, except for one small randomized controlled trial (n = 222),[ 3 ] patients with heart fa Continue reading >>
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Metformin, Heart Failure, And Lactic Acidosis: Is Metformin Absolutely Contraindicated?
Many patients with type 2 diabetes are denied treatment with metformin because of “contraindications” such as cardiac failure, which may not be absolute contraindications Summary points Treatment with metformin is not associated with an increased risk of lactic acidosis among patients with type 2 diabetes mellitus who have no cardiac, renal, or liver failure Despite increasing disregard of contraindications to metformin by physicians, the incidence of lactic acidosis has not increased, so metformin may be safe even in patients with “contraindications” The vast majority of case reports relating metformin to lactic acidosis report at least one other disease/illness that could result in lactic acidosis Use of metformin in patients with heart failure might be associated with lower mortality and morbidity, with no increase in hospital admissions and no documented increased risk of lactic acidosis Further studies are needed to assess the risk of lactic acidosis in patients with type 2 diabetes and traditional contraindications to metformin Metformin first became available in the United Kingdom in 1957 but was first prescribed in the United States only in 1995.w1 The mechanism of action has been extensively reviewed.w2 w3 The UK prospective diabetes study showed that metformin was associated with a lower mortality from cardiovascular disease than sulphonylureas or insulin in obese patients with type 2 diabetes mellitus.1 It was also associated with reduced all cause mortality, which was not seen in patients with equally well controlled blood glucose treated with sulphonylureas or insulin.1 Despite the evidence base for the benefits of metformin, concerns remain about its side effects and especially the perceived risk of lactic acidosis in the presence of renal, hepatic Continue reading >>
Metformin Reduces Mortality In Ckd, Chf, And Cld
FDA label update will increase drug use in persons with historical contraindications or precautions. From 1950 to 1995, we only had 1 class of drugs for type 2 diabetes. Then in 1994, metformin was approved. And it has become the cornerstone therapy for patients with type 2 diabetes. There was and still is a warning of possible lactic acidosis. However, because phenformin was withdrawn due to lactic acidosis in 1977, the FDA put a boxed warning on metformin stating that it should not be used in patients with chronic kidney disease (CKD), to avoid accumulation of the drug, which could possibly lead to lactic acidosis. There was also a warning concerning individuals who may accumulate lactate such as patients with congestive heart failure (CHF) and chronic liver disease (CLD). However, over the years, individuals who had CKD, CHF, or CLD were on metformin. This present study looked at these patients to see if metformin conferred any benefit relative to their chronic diseases. The researchers reviewed five observational studies with a total of 33,442 patients with moderate to severe CKD. In the metformin-treated groups, all-cause mortality was reduced by 33% (HR, 0.77). They looked at 11 observational studies with 35,410 patients with CHF. All-cause mortality was reduced by 22% (HR, 0.78) in the metformin-treated groups. In the three studies on CLD, there was a trend toward benefit with metformin; however, the numbers were small they did not reach statistical significance. This article nicely shows that there was no increased harm in using metformin in patients with CKD, CHF, or CLD; in fact, there was a significant reduction in death in CKD and CHF patients. Therefore, the new FDA label for metformin that was just updated in April 2016 seems to be a step in the right dire Continue reading >>
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