Most people with type 2 diabetes will most likely have been prescribed metformin at some point.  There are few places in medicine where everyone agrees on step 1, but metformin breaks the rules here and has been declared the first line champ. Because of metformin’s effect on A1C, low incidence of hypoglycemia, low cost and protective effects on the heart, it has earned the top spot in most clinical practice guidelines.

But many people with diabetes don’t reach their A1C goal with diet and metformin alone, or can’t tolerate metformin’s not-so-friendly effects on the stomach.  The time may come to add a second diabetes medication.  With numerous classes of drugs used to treat diabetes, how is the second drug chosen? Why does one person get a prescription for Januvia or Victoza, while someone else might be given Onglyza or Glipizide?

Prescribers of diabetes drugs have more choices than ever before.  While this seems like it would be an advantage (and it clearly is!), the decision-making process for the second, third, and any other medications needed is not always simple.  

There isn’t a clear-cut answer to the best drug to be added to metformin.  

Studies comparing the various treatment options have not shown a winner in terms of a drug being the best at decreasing A1C or having the least amount of side effects. So what’s a prescriber to do?

By looking at all of the diabetes drug classes through the same lens, the prescribing decision can be made a little bit easier.  This means that we can compare each drug on a set of features to see how they stack up side by side.  What are the qualities of the drugs that factor into the decision?

  • Cost – Is a generic version available? Insurance vs no insurance? Is the copay affordable if the drug is at the top tier?


  • Efficacy – How much does this medication lower A1C?  How much A1C lowering is actually needed?


  • Weight change – Does the medication cause weight gain, weight loss, or have no effect on weight?


  • Side effects – Are there significant side effects that would present a problem in a particular patient?


  • Other medical conditions – Is there another medical issue present that would prevent this medication from being a good choice? (Example: pioglitazone would not be used in someone with heart failure.)


  • Hypoglycemia risk – Is this drug more likely than others to cause episodes of blood sugar lows?


  • Heart protection – Does this drug either prevent or worsen heart disease?


Experienced prescribers will usually develop their own “go-to” drug in a medication class over time, and will even develop an unofficial algorithm of drugs they try in a particular order. But diabetes care is truly an art more than an exact science.  

What works best for one patient may not be appropriate at all for someone else.

More importantly, individual responses to medications can vary, especially in terms of side effect tolerance.  With so many drug classes to choose from, prescribers are able to add a medication from a different drug class if the desired results are not achieved with the first choice.

What about insulin as a second option after metformin?

While most people would never raise their hand and volunteer for a lifetime of insulin injections, there are some cases where it really is the next best step. When the A1C is >10% at diagnosis or when the A1C has not come down to the goal number after an adequate trial of oral drugs, insulin will move up the list and be considered sooner rather than later.  Insulin offers the benefit of dosing based on individual response with no ceiling dose.  Of course, the cost and risk of hypoglycemia are not to be taken lightly. But when diabetes has progressed to the point of beta-cell failure and oral medications are not effective, insulin can lower blood sugar with certainty.  

So what is the bottom line for the best drug to be added to metformin?  

The one you will actually take. That’s right. Yes, it becomes almost simple.

The medical world is making a shift toward something called “shared-decision making.”  This means that patients are encouraged to ask questions, express concerns and be an active part of their medical decisions.  

That drug that you absolutely refuse to take because of a horrible side effect? It won’t lower A1C one bit if you never pick it up from the pharmacy or if it sits untouched on your kitchen counter.  That drug that is impossible to remember to take multiple times per day? That drug that you struggle to pay for and end up skipping some months?  They aren’t helping!

You and your doctor have the same goal.  To achieve the best results with the least risk. It may take a few dose adjustments or even changing to a different medication before finding the right combination for you.

Drug development in the diabetes world will likely not slow down in the coming years.  More will become known about the safety of drugs currently on the market, especially their ability to protect from heart disease. There will continue to be a variety of medications working on different organ systems to try to bring down blood sugar and preserve beta cells. Combinations of 2 drugs in one pill will become more common.  

Open communication with your healthcare team about your response to medications will benefit everyone as prescribing decisions are made.  Make only one change at a time and pay attention to how your body feels.  Keep an open mind about fine-tuning your medication regimen until your prescriber finds the drugs that are best for you.

If you want a chart that compares all of the drugs used to treat type 2 diabetes, sign up here to get access to our resource library.

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