The cost of managing diabetes is going up all the time. And while pharmaceutical companies are doing a great job trying to develop new drugs, the overriding profit motive is sometimes prompting them to cut corners or suppress information that may prove to me inimical to their bottom line. A case in point is Avandia, which is now banned in many countries but still prescribed in the US, but with many caveats.
However, the safety of most diabetes drugs are time-tested — insulin was discovered in the early 1920s, and two of the other most commonly prescribed, metformin and sulfonylurea, have been around since the 1950s. Indeed, these drugs have five characteristics physicians look for in diabetes medications: few potential complications, safety, tolerability, ease of use and a low cost. (See my earlier post ‘Look to Older, Longer-Studied Treatments here.)
It’s not surprising, therefore, that Metformin, in combination or alone, remains the top choice for first-line treatment of type 2 diabetes because it demonstrates the best risk-benefit profile vs. other diabetes drugs, according to new data.
Most importantly, the newer drugs, which have no generic options, are significantly more expensive than older ones. One hundred metformin pills cost about $35.57, or 35 cents a pill, while 30 Januvia pills (a DPP-4 inhibitor) cost $192.52, or $6.42 a pill — nearly 18 times as much. Ask any diabetic and he’ll tell you why he shudders at the thought of taking the newer medication, especially if it’s out of pocket.
According to the new study, metformin, that has been around for more than 15 years, works just as well and has fewer side effects than a half-dozen other, mostly newer and more expensive classes of medication used to control the chronic disease, new Johns Hopkins research suggests.
In their report ‒ published online March 14 in the journal Annals of Internal Medicine ‒ the Johns Hopkins team found that metformin, an oral drug first approved by the US Food and Drug Administration (FDA) in 1995, not only controlled blood sugar, but was also less likely to cause weight gain or raise cholesterol levels.
“Metformin works for most people. It’s cheaper, there’s a generic form — it’s tried and true,” says study leader Wendy L. Bennett, M.D., M.P.H., an assistant professor in the Division of General Internal Medicine at the Johns Hopkins University School of Medicine. “Our study shows that even though there are all these newer drugs, metformin works just as well and has fewer side effects.”
The team looked at several popular classes of oral diabetes medication — metformin (sold as Glucophage, Fortamet and others), second-generation sulfonylureas (Amaryl, Glucotrol and more), thiazolidinediones (Avandia and Actos) and meglitinides (Starlix and Prandin) — and added two new classes of drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors (Januvia and Onglynza) and glucagon-like peptide-1 (GLP-1) receptor agonists (Byetta and Victoza), which are given by injection.
Results indicated that most medications used as monotherapy yielded comparable decreases in HbA1c (about one absolute percentage point on average throughout the course of a study). Metformin alone, however, lowered HbA1c more than DPP-4 inhibitors alone, and any type of combination therapy reduced HbA1c by about one absolute percentage point more than monotherapy.
Weight loss with metformin was a mean 2.5 kg more vs. TZDs and sulfonylureas. Other data also showed that combination metformin and GLP-1 agonists induced greater weight loss than other combination therapies, but the researchers said evidence supporting this finding was weak.
When compared with pioglitazone, sulfonylureas and DPP-4 inhibitors, metformin also significantly lowered LDL. Further, the drug decreased triglycerides and moderately raised HDL.
The researchers reported that sulfonylureas raised the risk for hypoglycemia four-fold vs. metformin monotherapy. Combination treatment with metformin and a sulfonylurea also had a six-fold higher risk for hypoglycemia than combination metformin and TZDs.
Analysis of other adverse events revealed that risk for congestive heart failure was higher with TZDs than with sulfonylureas. Risk for bone fractures was also higher with TZDs than with metformin alone or metformin combined with sulfonylurea. Diarrhea, however, was more commonly associated with metformin than with other medications.
“Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line treatment agent,” the researchers wrote.
The study is an update of Hopkins research published in 2007 that also showed there were advantages to metformin. New classes of medication for adult-onset diabetes have been approved by the FDA since then, and Bennett and her colleagues wanted to know if the newer drugs were any better than the older crop.
The research team also looked for the first time at the efficacy of two-drug combinations to treat the chronic disease, which has become increasingly common with more than one-third of diabetes patients needing multiple medications.
Researchers found that while two drugs worked better than one in those patients whose blood sugar remained poorly controlled on a single medication, there were also side effects associated with adding a second medication.
“Diabetes is an enormous public health problem, and patients have difficult decisions to make about what medications they should be taking,” Bennett says. “Our study provides good information comparing drugs and can be used to inform those decisions.”
Bennett and her colleagues reviewed 166 previously published medical studies that examined the effectiveness and safety of diabetes drugs, as well as their impact on long-term outcomes including death, cardiovascular disease, kidney disease and nerve disease.
No drug or combination of drugs was shown to have an advantage in improving long-term outcomes, Bennett says, primarily because there weren’t enough long-term studies, particularly of newer medications.
While most drugs reduced blood sugar similarly, metformin was consistently associated with fewer side effects. Though metformin is associated with increased risk of gastrointestinal side effects, Bennett, an internist, says she finds many of her patients can overcome them by starting with a low dose and taking it with meals, though patients with severe kidney disease may avoid it.
The sulfonylureas and meglitinides were associated with increased risk for hypoglycemia, or dangerously low blood sugar levels. The thiazolidinediones increased risk of heart failure, weight gain and fractures. In September 2010, the FDA placed restrictions on the use of Avandia because of concerns that the drug increases the risk of heart attack.
While the drugs all reduce blood sugar levels, Bennett says more research is needed into whether they actually improve outcomes for diabetics in the long run. It remains an open question as to whether patients with type 2 diabetes who have their blood sugar controlled by medication will reduce their chances of having complications associated with the disease, including eye, kidney and nerve diseases, she says.
“Some of the drugs haven’t been on the market long enough to study the long-term effects or even some of the short-term rare side effects, so we need longer studies in patients who are at highest risk for complications” she says.