When Metformin Isn’t Enough: Effectiveness of Type 2 Drugs Compared
New study results, presented at the American Diabetes Association (ADA) 81st Scientific Sessions, show that liraglutide (Victoza) and basal insulin may be the best options for people with type 2 diabetes when metformin isn’t enough to achieve good glucose control.
The study, known as GRADE (Glycemia Reduction Approaches in Diabetes), was conducted between 2013 and 2021. At the time of their enrollment, participants were in their mid-50s, had received a type 2 diabetes diagnosis within the past five years, had an A1C level (a measure of long-term blood glucose control) between 6.8% and 8.5%, and were taking metformin, the first-line type 2 diabetes drug. Men accounted for about 65% of participants. About 66% of participants were non-Hispanic white, while 20% were Black, 19% were Hispanic or Latino, 4% were Asian, and 3% were American Indians or Alaska Natives.
As described in an article on the study at MedPage Today, participants in the study were randomly assigned to take one of four treatments in addition to metformin: glimepiride (Amaryl), sitagliptin (Januvia), liraglutide (Victoza), or insulin glargine (Lantus, Basaglar, Toujeo), a long-acting basal insulin. Each of these treatments comes from a completely different class of drugs, so the study wasn’t comparing similar drugs with one another. Glimepiride is a sulfonylurea, which works by making the pancreas produce more insulin. Sitagliptin is a DPP-4 inhibitor, which works by inhibiting the release of the hormone glucagon. Liraglutide is a GLP-1 receptor agonist, which works by increasing the release of insulin from the pancreas and reducing the release of glucagon.
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Notably, the study didn’t include any SGLT2 inhibitors, a group of drugs that was still somewhat new at the time when GRADE was being designed. SGLT2 inhibitors have grown enormously in popularity since then, due to not just their glucose-lowering benefits, but also their positive impact on kidney health, a major area of concern for people with type 2 diabetes. This omission means that the results of the study may be of limited use, in the opinion of some diabetes experts, as noted in a Medscape article on the study.
Liraglutide, basal insulin tied to best glucose control
The main outcome that GRADE looked at was an A1C level of 7.0% or higher at some point, meaning that the most successful treatments had a lower number of participants who reached this endpoint. Insulin glargine came out on top at 67%, while liraglutide wasn’t far behind at 68%. Glimepiride had 72% of people reach this endpoint, and sitagliptin had 77%. These numbers indicate that both glimepiride and sitagliptin were significantly less effective than either insulin glargine or liraglutide for overall glucose control. During just the first year of treatment, people who took liraglutide had the best glucose control, with an average A1C level of 6.7%. But by the end of four years, some of the improvement seen with liraglutide had faded, and it ended up virtually tied with insulin glargine for overall A1C over the study period.
Liraglutide and insulin glargine saw participants maintain A1C within the target range for the longest average period of time — about 2.4 years for both. For glimepiride, this number was 2.2 years, and for sitagliptin it was 1.9 years.
The study’s second outcome of interest was an A1C level of 7.5% or higher at some point — again, an outcome where greater success meant avoiding this as much as possible. For this outcome, insulin glargine came out on top, with only 39% of participants having an A1C of 7.5% or higher. Liraglutide came in second at 46%, followed by glimepiride at 50%, and sitagliptin at 55%.
One additional benefit from taking liraglutide was an average weight loss of about 4 kilograms (8.8 pounds) during the first year of treatment. Participants who took sitagliptin also lost some weight over the four years of treatment, while those who took insulin glargine neither gained nor lost weight, on average. The lack of weight gain seen with basal insulin was considered an unexpectedly positive outcome, as was the fact that only about 1.5% of participants who took insulin experienced severe hypoglycemia (low blood glucose).
As always, talk to your doctor about the best treatment options if you already take metformin for type 2 diabetes, but your A1C level shows that you may need to take further steps to improve your blood glucose control.
Want to learn more about blood glucose management? See our “Blood Sugar Chart,” then read “Blood Sugar Monitoring: When to Check and Why” and “Strike the Spike II: How to Manage High Blood Glucose After Meals.”
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