Drug Therapy for Type 2 Diabetes:Questions and Caveats

Dr Gregory Rutecki’s interactive teaching case, “A Middle-Aged Man With Polyuria: The Initial Visit” (CONSULTANT, March 2001, page 357), provided a welcome opportunity for me to review the care I provide to my patients with type 2 diabetes, who comprise a very large percentage of my practice. I am particularly interested in identifying, preventing, and treating diabetic kidney disease. I have also found metformin(Drug information on metformin) to be a good oral hypoglycemic agent, provided certain precautions are observed when it is used. Dr Rutecki points out in his case presentation that the only major contraindication to metformin use is renal disease. The patient in his case presentation has microalbuminuria near the threshold range for overt nephropathy. My understanding of the effects of metformin in this setting is that it will not induce nephropathy in an adequately hydrated patient—although it increases the risk of lactic acidosis if significant nephropathy of any type is already present. I want to continue prescribing metformin for my patients with microalbuminuria in the range of 30 to 300 mg/d. Does Dr Rutecki support this therapeutic approach?
— John Mosby, MD
   Corpus Christi, Tex Metformin is not contraindicated in patients who have proteinuria and normal filtration rates. Metformin is contraindicated if the serum creatinine level is greater than 1.5 mg/dL in men or 1.4 mg/dL in women, or if the creatinine clearance is less than 70 mL/min. These recommendations are outlined in a recent review.¹ In the UK Prospective Diabetes Study, proteinuria was not a contraindication to metformin use.² However, it is important to monitor renal function and discontinue metformin when the glomerular filtration rate declines.
— Gregory Rutecki, MD
   Associate Professor of Medicine
   Northwestern University Medical School
   Chicago In the second installment of his interactive teaching case, “A Middle-Aged Man With Type 2 Diabetes, Part 2: Progress and Problems in First Year After Diagnosis” (CONSULTANT, April 1, 2001, page 533), Dr Rutecki discusses treatment options for the same patient who, a year after type 2 diabetes was diagnosed, had an acute myocardial infarction. Gemfibrozil(Drug information on gemfibrozil) was added to the patient’s regimen to raise his low high-density lipoprotein (HDL) cholesterol level, and all his previous medications, including a statin, were continued. I wish to point out that the combination of gemfibrozil and a statin would markedly increase the risk of rhabdomyolysis in this patient. The recent withdrawal of cerivastatin followed 80 patient deaths; half of these were believed to be related to a statin-fibrate combination. In fact, this risk was well established years before the recent drug withdrawal. A nonpharmacologic alternative would be to use grape-seed oil as a fat substitute. Grape-seed oil has been shown to raise low HDL levels.
— David T. Nash, MD
   Syracuse, NY The use of the word “markedly” to describe how the risk of rhabdomyolysis increases when gemfibrozil and a statin are used together requires scrutiny. A markedly increased risk of rhabdomyolysis may be associated with cerivastatin, but this drug is a “straw man.” The negative press it has received in this regard should be tempered when other statins are considered. A review of statin-induced rhabdomyolysis was recently published in the Annals of Pharmacotherapy;³ carefully researched recommendations for combination therapy appeared in the previous issue of that journal.⁴ The risk of rhabdomyolysis with statin monotherapy is 0.1% to 0.2%. With combination therapy it ranges up to 5%. This is indeed an increased risk, but it would not qualify as a “markedly” increased risk. In light of your appropriate caveat—as well as the American Diabetes Association’s listing of combination therapy with a statin and an agent such as gemfibrozil as a second-line option—I would proceed cautiously, following the recommendations of Omar and colleagues³ and of Shek and Ferrill.⁴ However, I would still use this combination in patients who require both reduction of their low-density lipoprotein cholesterol level and an increase in their HDL level.
— Gregory Rutecki, MD
   Associate Professor of Medicine
   Northwestern University Medical School
   Chicago