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My T2DM Patient is Not at Goal with Metformin . . . What’s Next?


A 52-year-old woman with T2DM is on metformin, works with a dietitian, and exercises regularly, but her hemoglobin A1c has increased. What would you advise? 



During your busy day in clinic, you allow yourself to look away for a few moments from your computer monitor, and notice a smile forming on your patient’s face. Even in the face of the myriad challenges that threaten to send you over the threshold of burnout, you’ve felt that you’ve helped your patients.

As usual, this week is a blur-of prior authorizations; the seemingly limitless clicks you have to make to clear those clinical reminders on EHR; and running behind 30 minutes or more, as you see your 20 patients. Many of these visits stretch way beyond the 15 to 20 minutes each is allotted. But, once again, you’ve made it. You preview that last chart. Your last patient of the week, Ms M, is a 52-year-old woman with type 2 diabetes (T2DM) diagnosed 3 years ago. She’s had her struggles, and had been in denial after being diagnosed. But she’s been earnest, and has been thriving since selecting 1 aspect of her lifestyle to change-her exercise. She’s on metformin 1000 mg BID, has worked with the dietitian and lost 4 pounds, and is walking, biking, or swimming a total of 150-200 minutes a week, often significantly more.

So, you ready yourself to congratulate her, convey how proud you are of her, review her SMBGs, renew her meds, and return to that EHR, maybe get home in time for dinner with the family, right?

But (and haven’t you noticed, there’s always seems to be a wrinkle, especially in a blog post like this?) you see her hemoglobin A1c has gradually inched upward. She had been between 6.2 and 7.0% since being inspired to turn around. Now it’s 8.8%. She wonders, aloud, if she’s the source.

What would you advise?
I can sum up in 3 words: it’s complicated.

As I’m sure you’d agree, I’d discuss with her that other factors besides adherence to exercise and dietary changes, as well as to consistently taking medications, impact glycemic control - diabetes is a chronic, progressive disease. We would delve into selecting a medication, such as insulin, a GLP-1 RA, along with further optimizing lifestyle changes.

Refer to the American Diabetes Association1 (ADA) and American Association of Clinical Endocrinologists’ 2(AACE) clinical guidelines-there are many treatment options when patients fail metformin alone. What your patient and you decide upon via a shared decision-making approach, will result from multiple factors, including: the extent of HbA1c increase, formulary coverage, cost, patient preference, potential AEs. For instance, avoiding weight gain and hypoglycemia may steer you way from a sulfonylurea or a thiazolidinedione, and towards a GLP-1 receptor agonist, a DPP-IV inhibitor, or an SGLT2-inhibitor. Insulin is an option, though there is a stigma and many misconceptions attached to this agent. We do have more options than ever before, yet, the greater number of choices can leave both physician and patient feeling overwhelmed.

No clinical studies had been done to investigate the question of whether there’s an optimal second-line agent for those with T2DM, after metformin alone is no longer effective-until May 2013. That’s when The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) began. GRADE is examining which of 4 FDA-approved medications for T2DM-glimepiride (sulfonylurea), sitagliptin (DPP-4 inhibitor), liraglutide (GLP-1 agonist), and basal insulin glargine-when added to metformin is most effective and has the fewest adverse effects.4

Funded by the National Institute of Health's National Institute of Diabetes and Digestive and Kidney Diseases, GRADE was closed to enrollment last summer. There are 5,047 individuals participating at 45 sites across the US, and they will be followed over the next 4 to 7 years.

We have so much yet to learn. What clinical pearls and insights have served you well in your approach to patients with T2DM? Ms M deserves no less than our continued best efforts as her partner, helping her to continue to live well with diabetes.

My recommendations for Ms M are as follows:

Ms M wants to lose more weight, and is hesitant about a daily injection of a long-acting insulin. She realizes that adding another oral medication may not be sufficient. She agrees to try a once-weekly GLP-1 receptor agonist, such as Bydureon (exenatide extended-release), and continue refining her lifestyle changes.

Dr. Chao is a sub-investigator in the GRADE Study at the University of California, San Diego/VA San Diego site.


1. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment. Standards of Medical Care in Diabetes – 2018. Diabetes Care. 2018;41(Suppl 1):S75-S85.

2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2018 Executive Summary. Endocrine Practice. 2018;24(1):91-120.

3. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan - 2015. Endocrine Practice. 2015;21(Suppl1):1-87.

4. Nathan DM, Buse JB, Kahn SE, et al. GRADE Study Research Group. Rationale and design of the Glycemia Reduction Approaches in Diabetes: a comparative effective study (GRADE). Diabetes Care. 2013;36:2254-2261.

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