What Can You Do When Metformin is Not An Option

Gregory W. Rutecki, MD 

The treatment of type 2 diabetes mellitus is usually comprised of metformin plus additional agents. In fact, both the US and European guidelines consider metformin the “gold standard.”1 Yet, the reality is that one size does not fit all. 

For example, some patients have serious GI side effects from the drug. Glomerular filtration rates (GFRs) of 30 cc to 44 cc per minute should lead to caution in prescribing metformin and the drug should be avoided in patients with GFRs less than 30 cc per minute.

All of this leads to an important primary care question. What regimens should be prescribed when you cannot use metformin in your patients? Here is a breakdown of regimens without insulin. 

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

These agents are listed as the first option after metformin for single, double, or triple therapy in patients with hemoglobin A1c (HbA1c) levels >6.5%.1 There is data regarding their use without metformin. One study added liraglutide to a sulfonylurea (SU) and the effect was greater than adding rosiglitazone to the SU.1 Furthermore, a meta-analysis found that combining a GLP-1 with basal insulin improved both weight and HbA1c better than any other combination of drugs.1 

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

DPP-4 combination therapy with a SU or thiazolidinedione is a good option. Thiazolidinediones should not be used in individuals with heart failure. When adding a DPP-4 to an SU, you may need to decrease the dose of the SU to protect against hypoglycemia.1 DPP-4 agents can be used in persons with chronic kidney disease (CKD), but may necessitate a dose reduction.1 They are a class of oral drugs and do not require injections as GLP-1 agents do. They are not as potent in lowering HbA1c as GLP-1 formulations.

Sodium-Glucose CoTransporter-2 (SGLT-2) Inhibitors or Sodium-Glucose Linked Cotransporter Proteins

Recent recommendations have landed SGLT-2s in the top 4 choices when dual therapy is needed for type 2 diabetes.1 They offer other a number of advantages. They are oral agents. They may lower systolic blood pressure, lead to weight loss, and have proven benefits in regimens that do not contain metformin.1 Using an SGLT-2 agent with a DPP-4 drug avoids issues with hypoglycemia and weight gain. Unfortunately, SGLT-2 agents, like metformin, cannot be used with severe CKD.1

In this day and age, all is not lost when metformin cannot be prescribed for patients with type 2 diabetes. We are at the interface of a pharmaceutical revolution with agents that affect disparate mechanisms responsible for hyperglycemia. Some of the newer drugs have powerful effects in lowering HbA1C without significant risks for hypoglycemia. Much more data will be available about other benefits, especially for GLP-1, DPP-4, and SGLT-2, shortly. The important thing to remember is that we have choices.

Gregory W. Rutecki, MD, is a physician at the National Consult Service at the Cleveland Clinic. He is also a member of the editorial board of Consultant. Dr Rutecki reports that he has no relevant financial relationships to disclose.


1. Goldman-Levine JD. Combination therapy when metformin is not an option for type 2 diabetes. Ann Pharmacother. 2015;49(6):