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Diabetes Meds 101

Neil Skolnik, MD, Heidi James, MD, and Mizuho Morrison, DO

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There are no shortage of medications to choose from in the management of Type 2 diabetes! We review the pharmacologic classes with attention to their unique features and drawbacks.



  • The A1c goals of treating diabetes are not the same for every patient. Younger patients can probably tolerate a lower goal closer to normal while older patients cannot tolerate the risks of hypoglycemia that come with such tight control.

  • Glance below or come back and reference the chart below for the diabetes medications.

  • Metformin is going to be your first-line agent.

  • Insulin comes into the picture after you’ve exhausted 3-4 agents without glycemic control.

  • When choosing medications, the effective medications are the ones your patient will take. Consider cost, side effects and dosing.


  • What are your treatment goals with diabetes?

    • Achieve an A1c less than 7 for most. For younger people it may be even lower and for older people SHOULD BE higher to avoid hypoglycemia.

    • Find a set of medications that patients will actually take, which means finding those that have a cost, side effect and dosing profile that works for them.

    • If not at your goal with a medication in 3-6 months, troubleshoot and consider adding another agent.

  • A framework for approaching treatment:

    • A1c >6.4 – 6.9: serious trial of lifestyle modification and weight loss before moving to metformin

    • Keep adding medications every 3-6 months considering cost and side effects, uptitrate to maximum dose before adding additional agents


Efficacy: safe and effective (first-line)

Hypoglycemia Risk: min

Effect on Weight: mild

Cost: low


  • 1/3 experience GI side effects

  • Start at 500mg in the evening for a couple of weeks and uptitrate to 1000mg BID to avoid GI side effects

  • May be used up to GFR 30 but would use at lower doses

  • Consider checking B12 levels because it can lower

  • CV benefit from the UKPDS study


Efficacy: reduce A1c 1-2%

Hypoglycemia Risk: mod to high

Effect on Weight: cause weight gain (increase insulin secretion)

Cost: low


  • Start low because they can cause hypoglycemia


Efficacy: reduce A1c by ~1%

Hypoglycemia Risk: low

Effect on Weight: cause weight gain through fluid retention so not to be used in caution with CHF patients

Cost: low


  • Rosiglitazone was shown to increase risk of MI but increasing evidence shows pioglitazone has positive cardiovascular effects

  • May also cause osteoporosis

SGLT-2 inhibitor

Efficacy: reduce A1c by ~1%

Hypoglycemia Risk: low

Effect on Weight: cause weight LOSS

Cost: high


  • Inhibits the enzyme in the nephron that reabsorbs glucose so that it is excreted in the urine

  • EMPA-REG trial showed 30% reduction in CV endpoints with empagliflozin

  • Side effects: 5-10% risk of yeast infections, dehydration and increase fracture risk

  • FDA warning: Rarely and in select populations (DM1, DM2 with severe illnesss/surgery) may cause euglycemic ketoacidosis (gap metabolic acidosis with hyperglycemia).

DPP-4 inhibtior

Efficacy: reduce A1c 0.7%

Hypoglycemia Risk: low

Effect on Weight: neutral

Cost: high


  • Works on the incretin system by inhibiting DPP-4, a hormone that breaks down GLP-1, the enzyme responsible for causing insulin release.


Efficacy: as effective as prandial insulin

Hypoglycemia Risk: low

Effect on Weight: cause weight LOSS

Cost: high


  • One-third of patients have GI side effects

  • LEADER study in 2016 showed decreased rate of MI and CV-related death

  • Injectable as twice daily, once daily and even once weekly


Efficacy: most effective

Hypoglycemia Risk: high

Effect on Weight: high risk of weight gain

Cost: varies based on insurance coverage


  • Reserved for patients who cannot get to goal with multiple agents or who have had longstanding DM with few insulin-producing islet cells

  • Multiple basal and prandial options

Bruce W. -

Diabetes Meds 101 was a great overview of current available medications. I work in a preventive medicine clinic and treat diabetic patients each day who are taking some combination of these medications. My supervising physician is a hospitalist and recently, we were discussing the potential downside of SGLT2 inhibitors.

He informed me that he sees cases of severe dehydration and ketoacidosis on an almost weekly basis in which these medications play a role. He related that it is typically a case of a patient who is initially has any illness in which the patient experiences reduced free water intake and/or reduced caloric intake, usually paired with GI losses of vomiting and/or diarrhea.

He passed along his own practical, clinical recommendation to me. Basically, it would be a good idea to inform patients to discontinue SGLT2 inhibitors f they become ill with aforementioned symtoms and only resume taking them once they are feeling better. I believe that using this clinical pearl in practice will help reduce ER visits and hospital admissions in the patients that I treat.

Bruce Wing, PA-C

Heidi J., MD -

Great pearl - thanks for sharing!

Bruce W. -

Should read "if" after "inhibitors" in paragraph three. Thanks!

Jill L. -

glp1 - weight gain or weight loss?

Jill L. -

the summary has weight gain but the pdf says weight loss. ADA also says weight loss

Heidi J., MD -

Thanks for picking that discrepancy up, Jill. Weight loss is indeed correct for the GLP-1s. We'll fix that error.

James Copley -

Hi Team

I've had two patients on empagliflozin come in complaining of a possible UTI. When the urinalysis was done we found ketonuria. Neither had any symptoms of euglycemic DKA. The first time I saw this, I spoke to an endocrinologist to see if this was a concern. They recommended that my patients stop their SGLT2i immediately and not restart it. They also recommended the patient return the following day for another urinalysis and if ketones were still present they recommended the patient be assessed in the emergency department.

Do we know how often patients get simple ketonuria with SGLT2is? Should we be stopping the medication if we see ketones on a urinalysis?

Thanks for the info! This was a great summary!

James Copley MDCM CCFP

Heidi J., MD -

Now that's a good question, James. I've passed it along to Dr. Skolnik and will keep you apprised re his reply.

Heidi J., MD -

Ok, James, we're still stumped. I've asked the team to weigh in. They'll be adding to this thread.

Adrien Selim -

Good question James.

The American College of Endocrinology have published a position statement on the association of SGLT2 inhibitors and DKA. They don’t explicitly say what to do if a patient has ketonuria but they do say that “routine measurement of urine ketones is not recommended for patients on SGLT2 inhibitors because the results can be misleading, instead the measurement of blood ketones is preferred for diagnosis of DKA in symptomatic patients.” (Handelsman et al)

Also, “Tofogliflozin has been demonstrated to cause a dose-dependent hyperketonaemia and ketonuria in a combined phase 2 and 3 trial in patients with type 2 diabetes, though none of the patients required emergency admission.” (Rajeev)

Bottomline, I think context matters. If a patient is vomiting, has abdominal pain, is unwell, etc then, yes, ketonuria would be worrisome and the patient should be referred to the ED and investigated/treated for DKA. On the other hand, if someone comes in to the office feeling perfectly well but happens to have ketones on their urine I’m not sure stopping their SGLT2 inhibitor is really warranted. Maybe just some close follow up and clear instructions to go to the ED ASAP if they develop symptoms of DKA.

Interested to hear what others think about this…

1. Handelsman, Yehuda, et al. "American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis." (2016).

2. Rajeev, Surya Panicker, and John PH Wilding. "SGLT2 inhibition and ketoacidosis–should we be concerned?." British Journal of Diabetes 15.4 (2015): 155-158.

James Copley -

Thanks, Adrien!

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Diabetes and Whispered Pectorilo….what??? Full episode audio for MD edition 194:27 min - 91 MB - M4AHippo Primary Care RAP August 2017 Written Summary 271 KB - PDF