Safety and Weight Gain with Drugs for Type 2 Diabetes
How safe is a drug for type 2 diabetes that causes weight gain? This question pops up as we read a big new study of outcomes with second line drugs for type 2 diabetes. That’s because two types of drugs that cause weight gain – basal insulin and sulfonylureas – had a clear link to bad outcomes for heart health.
A Careful Observational Study
Matthew O’Brien, Susan Karam, and Amisha Wallia published their study last week in JAMA Network Open. It was an observational cohort study of 132,737 adults with type 2 diabetes. The prespecified primary outcome was the time to first major adverse cardiovascular event (MACE) after starting a second-line diabetes med.
Because O’Brien et al had such a large cohort of patients, they captured robust data on a diverse set of drugs. In addition to basal insulin and sulfonylureas, they had outcomes for DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and thiazolidinediones (TZDs). A companion editorial praises the careful design and transparency of this study.
Bottom line, the researchers found that bad heart outcomes (MACEs) started cropping up significantly sooner in patients who receive basal insulin or sulfonylureas. These two classes of drugs clearly cause weight gain. The other class associated with weight gain – TZDs – did not have a higher risk of MACEs than the reference group, DPP-4 inhibitors. However, TZDs carry a warning that they can cause heart failure or make it worse.
GLP-1 inhibitors had a lower incidence of MACE compared to the DPP-4 inhibitors in some of the analyses. But this was not a consistent finding across all analyses. So the bottom line conclusion was that the newer drugs – GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors – may offer better cardiovascular outcomes. Thus, O’Brien et al suggest they should be used more routinely than sulfonylureas or basal insulin.
And incidentally, these newer drugs can also help a patient lose a bit of weight along the way.
Two Distinctly Different Views of Treating Type 2 Diabetes
This study shines a bright light on two competing approaches for treating type 2 diabetes. At one extreme, clinicians view weight gain as an unfortunate side effect for some very useful drugs. Clinicians prescribe them to bring A1C under control. They’ve done their part. Patients can do their part with diet and exercise to prevent weight gain. Right?
Well, not exactly. In what’s becoming a more dominant view, it makes no sense to manage diabetes by using overusing drugs that make obesity worse. These two diseases go hand in hand. Excess weight leads to more insulin resistance. As a result, smart clinicians (in our view) are very reluctant to prescribe drugs for type 2 diabetes that will pack on the pounds.
This new study adds to our convictions on this point.
Click here for the study and here for the companion editorial. For further perspective, click here and here.
Safety Helmets, photograph © Jon Culver / flickr
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December 27, 2018
December 27, 2018 at 11:20 am, Christine said:
I think the fact that both basal insulin and sulfonylureas can cause hypoglycemia while the others are less likely to should also be considered. The study even says specifically in the conclusion that “Hypoglycemia may be most important for short-term cardiovascular outcomes.”
It would also be important to look at how these medications are used. Anyone who works in diabetes knows that patients are frequently over-basalized, increasing their risk of hypoglycemic events – which additionally causes them to “feed” their insulin, resulting in the weight gain you’re so focused on.
I’m all for PCPs prescribing the newer diabetes medications for patients, but I think your assessment of this study is a bit off-base.
December 27, 2018 at 4:31 pm, Ted said:
Christine, thanks for the added perspective. This is a complex subject and a good study, albeit observational. You have some good points to make.
Yes indeed, glycemic control is important – and it gets lots of attention. The authors did a good job of covering that point. But in the past – and even today – too many clinicians have ignored the overlapping problem of obesity. Sometimes they make it worse. This issue is getting more attention and I hope that continues. That is the subject I wanted to focus upon in my post and I’m sorry you thought I was off base.
Perhaps you think this concerns me too much, but I have personal experience watching clinicians add to a patient’s weight and health problems. Some of those patients were very dear to me. So I’m very glad to see progress.
January 06, 2019 at 7:10 pm, Paul Ernsberger said:
These patients are not all the same. Patients getting insulin have more severe disease. Patients getting sulfonylureas are often poor because these pills cost pennies a day while the agents you advocate are many times more expensive.
You didn’t mention thiazolidinediones such as Actos, which have good mortality outcomes as shown in the graph but cause a great deal of weight gain (some may be fluid retention).
January 06, 2019 at 7:21 pm, Ted said:
Thanks, Paul. If you read this post more closely, you’ll see that I did discuss the thiazolidinediones (TZDs), which carry a black box warning because they can cause heart failure or make it worse.
January 07, 2019 at 4:33 pm, Jen said:
I 100% agree with this – the list of both physical & mental benefits brought on by weight loss in those who are overweight/obese is just endless, EVEN MORE SO in those who have type 2 diabetes and the effects on insulin sensitivity & beta cell function. Therefore any such agent which is unhelpful in this process, such as SU’s and insulin is not optimal IMO. As you have stated (& also as demonstrated in Wilding 2014), in my opinion too we should be optimizing therapy by choosing agents which will aid the process of weight loss, such as those DPP4-i’s, SGLT-2i’s and GLP1-agonists.. along side behavioural support in an ideal world.
I do however understand the point mentioned above & how insulin is only at a latter stage of therapy, and so there is not really an alternative option at this point. I also live in the UK where choice of drug therapy is not determined by health insurance/payments. However the costs of these agents to the NHS are reflected by the high quantity of SU’s I see prescribed in the pharmacy relative to those alternative 2nd line drugs mentioned.