Tag Archives: metformin

FDA Revises Guidelines for Use of Metformin In Those With Kidney Impairment

Conquer Diabetes and Prediabetes

Metformin is the most-recommended drug for type 2 diabetes

Recently the U.S. Food and Drug Administration revised their guidelines for physicians regarding use of metformin in patients with kidney impairment. This may make more patients candidates for the drug.

Physicians have been advised for years that type 2 diabetics with more than minimal kidney impairment should not be given metformin. Why? Metformin in the setting of kidney failure raises the risk of lactic acidosis.

The traditional test for kidney impairment is a blood test called creatinine. When kidneys start to fail, serum creatinine rises. Another way to measure kidney function is eGFR, which takes into account creatinine plus other factors.

By the way, you can’t tell about your kidney function simply from the way you feel; by the time you have signs or symptoms of renal failure until the process is fairly advanced.

The FDA now recommends not using  metformin if your eGFR (estimated glomerular function rate) is under 30 ml/min/1.73 m squared), and use only with extreme caution if eGFR drops below 45 while using metformin. Don’t start metformin if eGFR is between 30 and 45. Your doctor can calculate your eGFR and should do so annually if you take metformin.

Steve Parker, M.D.

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Metformin Impairs Brain Function In Some Users



Conquer Diabetes and Prediabetes

Metformin is the most-recommended drug for type 2 diabetes

…according to an article at MedPageToday. I consider this finding preliminary, but definitely something to keep an eye on. We need confirmatory data before taking action. Long-term metformin users should get vitamin B12 levels checked periodically in view of the well-established association of low levels in users. Low B12 impairs cognition and is easily preventable or treated.

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How To Recognize and Treat Hypoglycemia (Low Blood Sugar)

Insulin and sulfonylurea drugs are common causes of hypoglycemia

Insulin and sulfonylurea drugs are common causes of hypoglycemia

Hypoglycemia is the biggest immediate risk for a diabetic on drugs starting a carbohydrate-restricted diet such as the Low-Carb Mediterranean Diet. Traditional calorie-restricted diets also have the potential to cause hypoglycemia.


Your personal physician and other healthcare team members should teach you how to recognize and manage hypoglycemia.  Hypoglycemial means an abnormally low blood sugar (under 60–70 mg/dl or 3.33–3.89 mmol/l) associated with symptoms such as weakness, malaise, anxiety, irritability, shaking, sweating, hunger, fast heart rate, blurry vision, difficulty concentrating, or dizziness. Symptoms often start suddenly and without obvious explanation. If not recognized and treated, hypoglycemia can lead to incoordination, altered mental status (fuzzy thinking, disorientation, confusion, odd behavior, lethargy), loss of consciousness, seizures, and even death (rare).

You can imagine the consequences if you develop fuzzy thinking or lose consciousness while driving a car, operating dangerous machinery, or scuba diving.


Immediate early stage treatment involves ingestion of glucose as the preferred treatment—15 to 20 grams. You can get glucose tablets or paste at your local pharmacy without a prescription. Other carbohydrates will also work: six fl oz (180 ml) sweetened fruit juice, 12 fl oz (360 ml) milk, four tsp (20 ml) table sugar mixed in water, four fl oz (120 ml) soda pop, candy, etc. Fifteen to 30 grams of glucose or other carbohydrate should do the trick. Hypoglycemic symptoms respond within 20 minutes.

If level of consciousness is diminished such that the person cannot safely swallow, he will need a glucagon injection. Non-medical people can be trained to give the injection under the skin or into a muscle. Ask your doctor if you are at risk for severe hypoglycemia. If so, ask him for a prescription so you can get an emergency glucagon kit from a pharmacy.

Some people with diabetes, particularly after having the condition for many years, lose the ability to detect hypoglycemia just by the way they feel. This “hypoglycemia unawareness” is obviously more dangerous than being able to detect and treat hypoglycemia early on. Blood sugar levels may continue to fall and reach a life-threatening degree. Hypoglycemia unawareness can be caused by impairment of the nervous system (autonomic neuropathy) or by beta blocker drugs prescribed for high blood pressure or heart disease. People with hypoglycemia unawareness need to check blood sugars more frequently, particularly if driving a car or operating dangerous machinery.

Do not assume your sugar is low every time you feel a little hungry, weak, or anxious. Use your home glucose monitor for confirmation when able.

If you do experience hypoglycemia, discuss management options with your doctor: downward medication adjustment, shifting meal quantities or times, adjustment of exercise routine, eating more carbohydrates, etc. If you’re trying to lose weight or control high blood sugars, reducing certain diabetic drugs makes more sense than eating more carbs. Eating at regular intervals three or four times daily may help prevent hypoglycemia. Spreading carbohydrate consumption evenly throughout the day may help. Someone most active during daylight hours as opposed to nighttime will generally do better eating carbs at breakfast and lunch rather than concentrating them at bedtime.


Diabetics considering or following a low-carb or very-low-carb ketogenic diet must work closely with their personal physician and dietitian, especially to avoid hypoglycemia caused by certain classes of diabetic drugs. Two common diabetes drug classes that cause hypoglycemia are the insulins and sulfonylureas. More are listed below. Those who don’t know the class of their diabetic medication should ask their physician or pharmacist.

Clinical experience with thousands of patients has led to generally accepted guidelines that help avoid hypoglycemia in diabetics on medications.

Diabetics and prediabetics not being treated with pills or insulin rarely need to worry about hypoglycemia.

Similarly, diabetics treated only with diet, metformin, colesevalam, and/or an alpha-glucosidase inhibitor (acarbose, miglitol) should not have much, if any, trouble with hypoglycemia. The DPP4-inhibitors (sitagliptan and saxagliptin) do not seem to cause low glucose levels, whether used alone or combined with metformin or a thiazoladinedione.

Thiazolidinediones by themselves cause hypoglycemia in only 1 to 3% of users, but might cause a higher percentage in people on a reduced calorie diet. Bromocriptine may slightly increase the risk of hypoglycemia.


Type 2 diabetics are at risk for hypoglycemia if they use the following drug classes. Also listed are a few of the individual drugs in some classes:

■  insulin

■  sulfonylureas: glipizide, glyburide, glimiperide, chlorpropamide, acetohexamide, tolbutamide

■  meglitinides: repaglinide, nateglinide

■  pramlintide plus insulin

■  exenatide plus sulfonylurea

■  possibly thiazolidinediones: pioglitazone, rosiglitazone

■  possibly bromocriptine

Open wide!

Open wide!

Remember, drugs have both generic and brand names. The names vary from country to country, as well as by manufacturer. If you have any doubt about whether your diabetic drug has the potential to cause hypoglycemia, ask your physician or pharmacist.


Common management strategies for diabetics on the preceding drugs and starting a very-low-carb diet include:

■  reduce the insulin dose by half

■  change short-acting insulin to long-acting (such as glargine)

■  stop the sulfonylurea, or reduce dose by half

■  reduce the thiazolidinedione by half

■  stop the meglitinide, or reduce the dose by half

■  monitor blood sugars frequently, such as four times daily, at least until a stable pattern is established

■  spread what few carbohydrates are eaten evenly throughout the day

Management also includes frequent monitoring of glucose levels with a home glucose monitor, often four to six times daily. Common measurement times are before meals and at bedtime. It may be helpful to occasionally wake at 3 AM and check a sugar level. To see the effect of a particular food or meal on glucose level, check it one or two hours after eating. Keep a record. When eating patterns are stable, and blood sugar levels are reasonable and stable, monitoring can be done less often. When food consumption or exercise habits change significantly, check sugar levels more often.

If you’re thinking that many type 2 diabetics on low-carb and very-low-carb ketogenic diets use fewer diabetic medications, you’re right. That’s probably a good thing since the long-term side effects of many of the drugs we use are unknown. Remember Rezulin (troglitazone)? Introduced in 1997, it was pulled off the U.S. market in 2001 because of fatal liver toxicity. More recently, rosiglitazone usage has been highly restricted due to concern for heart toxicity.

Steve Parker, M.D.

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Latest Research: 1) Sleep Patterns and Diabetes, 2) Drop Metformin When You Start Insulin?

1) Lack of sleep coupled with disrupted day-night cycles predisposes to diabetes and prediabetes.  Night-shift workers take note.

2) Compared to those using metformin alone, type 2 diabetics who also took insulin needed less insulin and had better blood sugar levels.  Real-world benefits are not entirely clear.

Steve Parker, M.D. 


Filed under Drugs for Diabetes

Metformin May Prevent Cancer and Heart Trouble

David Spero at Diabetes Self-Management has an interesting article about how metformin may prevent cancer and heart disease, and slow the aging process.  Metformin is the usual first drug of choice for type 2 diabetes.

Steve Parker, M.D.

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The Holy Grail of Diabetes Treatment: Preserving Beta Cell Function

 A Nobel Prize in Medicine belongs to whoever (whomever?) figures out how to reliably and affordably protect and preserve beta cell function starting early in the course of type 2 diabetes.  Or type 1 diabetes, for that matter.

Dietary carbohydrates lead to secretion of insulin into the bloodstream by the pancreas’s beta cells.  The insulin limits and reverses the rise in blood sugar that results from digestion of carbohydrates.  If blood sugar rises too high, it damages our bodies. 

Type 2 diabetes is a disorder of carbohydrate metabolism.  Insulin from the beta cells isn’t doing its job adequately because tissues that should be taking up bloodstream sugar are resistant to insulin’s effect of driving sugar into the cells.  The beta cells pump out increasing amounts of insulin, trying to overcome the resistance of the tissues.  Eventually the beta cells become exhausted or “burned out,” reflected in diminished beta cell mass.  This situation has usually been present for years before type 2 diabetes is formally diagnosed.  This scenario is a leading theory of the development of type 2 diabetes.

Type 2 diabetes is considered by most physicians to be a progressive illness, requiring more and more drugs to control as the years pass.  That’s because the beta cells are dying off or otherwise becoming totally nonfunctional.  Once they’re gone, it’s hard (impossible?) to get them back.  If diabetes could be diagnosed early on, we’d find healthier beta cells to work with.  Perhaps we could strengthen or protect them.  This is what beta cell preservation is all about.  Keep them working as nature intended, avoiding the expense and risks of drug therapy.

So I was excited to find an article entitled “Effects of exenatide on measures of beta cell function after three years in metformin-treated patients with type 2 diabetes.”  Exenatide is sold in the U.S. as Byetta.  It’s a GLP-1 analogue.  

European researchers studied 36 type 2 diabetics for three years.  All were taking metformin.  Sixteen of them also took exenatide, whereas 20 also took insulin glargine (e.g., Lantus in the U.S.). 

What Did They Find?

Both groups achieved similar levels of blood sugar control after three years.  Exanatide users lost 5.7  kg (12.5 lb) while glargine users gained 2.1 kg (4.6 lb). 

After three years of drug use, the subjects were told to stop exenatide and glargine while continuing metformin. After four weeks off-drug:

  • insulin sensitivity improved significantly in the exenatide group while glargine had no effect
  • first-phase insulin secretion improved by a small amount in the exenatide group

However, 12 weeks after stopping the study drugs, hemoglobin A1c and fasting blood sugars returned to pretreatment levels in both groups.  (Hemoglobin A1c is a blood test of overall diabetes control over the preceeding three months.)   

Final Thoughts

You have to wonder if the improved insulin sensitivity in the exenatide group simply reflects their weight loss as compared to the weight gain in the insulin glargine group.  Improved insulin sensitivity is good, any way you can get it. 

ResearchBlogging.orgWhen measured 12 weeks after stopping the study drugs, hemoglobin A1c and fasting blood sugar levels were no better than baseline levels three years earlier.  Very disappointing.  If exanatide or glargine preserved beta cell function, you’d want to see better post-treatment numbers.  The search for beta cell preservation continues.

Steve Parker, M.D.

Reference: Bunck, M., Corner, A., Eliasson, B., Heine, R., Shaginian, R., Taskinen, M., Smith, U., Yki-Jarvinen, H., & Diamant, M. (2011). Effects of Exenatide on Measures of Beta-Cell Function After 3 Years in Metformin-Treated Patients With Type 2 Diabetes Diabetes Care, 34 (9), 2041-2047 DOI: 10.2337/dc11-0291

PS: In case it matters to you, this study was funded at least partially by Amylin Pharmaceuticals and Eli Lilly and Company.

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Yet Another Diabetes Drug: Linagliptin

On May 2, 2011, the U.S. Food and Drug Administration approved the use of linagliptin for adults with type 2 diabetes.  It’s in the class called DPP-4 inhibitors.  You’ll see it sold in the U.S. as Tradjenta

How do they come up with names like Tradjenta?  The manufacturer wants it unique, so there are no claims of copyright infringement.  You also want to avoid sounding like another drug on the market, to avoid mixing up the drugs.  A committee is usually involved to consider all the angles, especially marketing.

How Does Linagliptin Work?

It’s complicated.  It inhibits an enzyme, dipeptidyl peptidase-4, ultimately leading to insulin release from the pancreas into the bloodstream, and lowered glucagon levels. 

Any Side Effects?

Linagliptin may slightly increase the risk of pancreatitis.  It seems to be pretty well tolerated overall, with the most common adverse effects being a runny or stuffy nose, or sore throat.  When given with an insulin secretagogue drug, like sulfonylureas, linagliptin can increase the odds of hypoglycemia.  Due to an interaction, it’s best not to use linagliptin with rifampin.

What’s the Dose?

Only one: 5 mg by mouth daily.  No need to adjust the dosage for underlying kidney or liver disease or age.


It’s for adults with type 2 diabetes.  It may be used as the sole diabetic drug along with diet and exercise.  It can also be used in combination with metformin, a sulfonylurea, or pioglitazone.  It’s not been studied in people taking insulin, in pregnancy, or in nursing mothers, so it’s best to avoid those settings for now.

Steve Parker, M.D.

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Metformin Raises Risk of Vitamin B-12 Deficiency

ResearchBlogging.orgA recent study out of the Netherlands shows that type 2 diabetics taking insulin and metformin are at risk of clinically significant vitamin B12 deficiency.

B12 deficiency may cause anemia, nerve damage (neuropathy), and dementia, among other problems.

Metformin is the cornerstone of drug therapy for type 2 diabetes.  One reason is that it’s associated with improved cardiovascular disease outcomes—a claim few diabetic drugs can make.  Prior studies established that metformin interferes with B12 absorption.  The study at hand indicates that such malabsorption can reach a clinically significant degree, and that the falling blood levels are progressive over time.

No B12 here

How Was the Study Done?

Three diabetes clinic in the Netherlands provided 390 patients with type 2 diabetes between the ages of 30 and 80.  They were all treated with 1) insulin and metformin 850 mg three times daily, or 2) insulin and placebo three times daily.  B12 levels were drawn periodically over the course of the 4-year study.  Seventy-two percent of participants completed the study (the drop-outs included 30 on metformin and 16 on placebo).

What Did the Investigators Find After Four Years?

  • Compared with the placebo group, B12 levels in the metformin group dropped an average of 19%.
  • Compared to the placebo group, the metformin cohort had a 7% risk of developing B12 deficiency (blood level under 150 pmol/l) and 11% risk of dropping into the “low B12” category (level 150-220 pmol/l).

Clinical Implications

It’s unclear whether these findings apply to diabetics not taking insulin or to other ethnicities and nationalities.  I suspect they do.

The risk of developing B12 deficiency with metformin is not huge, but it seems to be real.  Once B12 deficiency does it’s damage, it may not be totally reversible.  So it’s important to know about this issue if you take or prescribe metformin.  At this point I wouldn’t depend on my doctor to be aware of this adverse drug effect, nor to remember to check B12 levels periodically.

The researchers recommend that B12 levels be checked “regularly” in patients taking metformin, without defining a time frame.  I suggest every year or two—closer to yearly if the patient has other risk factors for B12 deficiency, such as malnutrition, advanced age, removal of part of the stomach, some weight-loss surgeries, vegan diet, celiac disease, and Crohn’s disease.

Steve Parker, M.D.

de Jager, J., Kooy, A., Lehert, P., Wulffele, M., van der Kolk, J., Bets, D., Verburg, J., Donker, A., & Stehouwer, C. (2010). Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial BMJ, 340 (may19 4) DOI: 10.1136/bmj.c2181


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Drug Review: Metformin

metformin for type 2 diabetesMetformin is a major drug for treatment of type 2 diabetes.  In fact, it’s usually the first choice when a drug is needed. 

This review is quite limited—consult your physician or pharmacist for full details.  Remember that drug names vary by country and manufacturer.  Glucophage is a common brand name for metformin in the U.S. 


Biquanide (it’s the only one in this class).

How does it work?

In short, metformin decreases glucose output by the liver.  The liver produces glucose (sugar) either by breaking down glycogen stored there or by manufacturing glucose from smaller molecules and atoms.  The liver then kicks the glucose into the bloodstream for use by other tissues.  Insulin inhibits this function of the liver, thereby keeping blood sugar levels from getting too high.  Metformin improves the effectiveness of insulin in suppressing sugar production.  In other words, it works  primarily by decreasing the liver’s production of glucose.

Physicians talk about metformin as an “insulin sensitizer,” primarily in the liver but also to a lesser extent in peripheral tissues such as fat tissue and muscle.  It doesn’t work without insulin in the body.

Metformin typically lowers fasting blood sugar by about 20% and hemoglobin A1c by 1.5% (absolute decrease, not relative).

When used as the sole diabetic medication, metformin is associated with decreased risk of death and heart attack, compared to therapy with sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides.

Not uncommonly, metformin leads to a bit of weight loss and improved cholesterol levels.  Insulin and sulfonylurea therapy, on the other hand, typically lead to weight gain of 8–10 pounds (4 kg) on average.


Metformin works by itself, but can also be used in combination with most of the other diabetic medications.  It’s usually taken 2–3 times daily.


Starting dose is typically 500 mg taken with the evening meal.  The dose can be increased every week or two.  If more than 500 mg/day is needed the second dose—500 mg—is usually given with breakfast.  Usual effective maximum dose is around 2,000 mg daily.

Side effects

Metallic taste, diarrhea, belly pain, loss of appetite.  Possible impaired absorption of vitamin B12, leading to anemia.  When used alone, it has very little risk of hypoglycemia.  Rare: lactic acidosis.

Don’t use metformin if you have . . .

Impaired kidney function (keep reading), congestive heart failure of a degree that requires drug therapy (this is debatable), active liver disease, chronic alcohol abuse.

Regarding impaired kidney function: don’t use metformin if your eGFR (estimated glomerular function rate) is under 30 ml/min/1.73 m squared), and use only with extreme caution if eGFR drops below 45 while using metformin. Don’t start metformin if eGFR is between 30 and 45. Your doctor can calculate your eGFR and should do so annually if you take metformin.

Steve Parker, M.D.

Updated April 10, 2016


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Which Drug Is Best for Treatment of Type 2 Diabetes?

Physicians now have an amazing array of drug therapies  for control of type 2 diabetes.  Until now, there has been no consensus as to which drugs to use, and when.

The American Association of Clinical Endocrinologists and the American College of Endocrinology have just issued a joint statement with specific drug recommendations.  Their algorithm is quite detailed.  Here are a few highlights you might not know about:

  • Regular human insulin is not recommended
  • NPH insulin is not recommended
  • The following should be used earlier and more frequently:  GLP-1 agonists (exenatide) and DPP-4 inhibitors (sitagliptin and saxagliptin)
  • sulfonylureas are a lower priority
  • metformin is still a key drug

In the U.S., exenatide is sold as Byetta; sitagliptin is Januvia; saxagliptin is Onglyza; metformin is Glucophage (among others). 

If you have type 2 diabetes and are arguing with your physician about optimal drug therapy, this treatment algorithm may be a helpful tie-breaker. 

Steve Parker, M.D.

Reference:  Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: An algorithm for glycemic controlEndocrine Practice, 15 (2009): 540-559.


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