ADA Guidelines Recommend Earlier Combination Therapy

American Diabetes Association guidelines recommend that combination therapy be started earlier in patients with unachieved glycemic control, within three months. 

Early combination therapy should be used in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, per ADA guidelines for pharmacologic diabetes management. Metformin is still considered the initial agent used for type 2 diabetes according to the ADA guidelines. It is deemed effective and safe in patients without contraindications, such as later stages of chronic kidney disease or a history of lactic acidosis. The extended-release form of metformin may be acceptable in patients who have gastrointestinal side effects. Using metformin long term has been linked to B12 deficiency and an increase in neuropathy. Testing B12 levels periodically would be considered sufficient. Patients who cannot tolerate metformin or have contraindications to use it should use an alternative therapy.  

The ADA committee selected and reviewed published studies, developed the recommendations, and solicited feedback from the broader clinical community. The guidelines focus on the pharmacologic treatment of adults with type 2 diabetes. Oral, insulin, and non-insulin injectable therapies and combination therapies are also included. The 2020 Standards of Care mentions that if injectable medication therapy is needed to lower a patient’s HbA1C levels, a glucagon-like peptide-1 receptor  (GLP-1 RA) should be thought of before insulin use. GLP-1 RAs have benefits that include weight loss.  

One principal recommendation includes lifestyle changes as first-line treatment. Sodium-glucose cotransporter 2 inhibitors (SGLT2), basal insulin, a thiazolidinedione, sulfonylureas (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4) are considered second-line therapy agents. These agents are considered inexpensive to the patient. One of the agents should be used in conjunction with metformin. Metformin and DPP-4 inhibitors are considered weight-neutral medications. GLP-1 RAs or SGLT2 inhibitors should be considered in patients that need help with weight loss. For patients that have chronic kidney disease or heart failure, SGLT2 inhibitors are recommended. If an SGLT2 inhibitor cannot be administered, the patient should be placed on a GLP-1.  The therapy prescribed should be individualized based on the patient’s characteristics, choices, and drug effects. Patient characteristics include risk of ASCVD (Atherosclerotic Cardiovascular Disease) or diagnosis, heart failure, and other comorbid conditions’ adverse impact on the medication. Insulin therapy should be reviewed with patients to accelerate treatment. Insulin should be initiated early on if weight loss is needed and hyperglycemia symptoms are present. Insulin should also be considered when HbA1C levels are greater than 10%, and blood glucose levels are greater than or equal to over 300mgm/L(16.7 mmol/L).  

A patient-centered approach should be used in choosing pharmacologic agents. The first step in determining which medication should be combined with metformin is to see if the patient has ASCVD or is at high risk for ASCVD. These patients would be 55 or older with carotid, coronary, or lower-extremity artery stenosis greater than 50%, or left ventricular hypertrophy, established chronic kidney disease, or heart failure. For patients who have symptoms that arise from hyperglycemia, insulin therapy is recommended. Patients with symptoms of hypoglycemia, ketosis, or weight loss present should also use insulin, and patients with a blood glucose level of 300mgm/L. (16.7 mmol/L) or higher. Insulin therapy will help reduce lipotoxicity and glucotoxicity. 

There were several trials mentioned in the clinical guidelines that were used to help formulate the treatment guidelines. The trials that focused on DPP-4 inhibitors did meet the primary result of noninferiority. There were no cardiovascular benefits shown in comparison to the placebo. In the EMPA-REG OUTCOME trial, SGLT2 inhibitors showed a decrease in hospitalization for heart failure. Insulin is routinely required for patients that have type 2 diabetes. Patient education should incorporate blood glucose monitoring, diet, and hypoglycemia management. In the LEADER trial, liraglutide was shown to reduce neuropathy and the risk of heart attack, stroke, and death from cardiovascular events in patients with type 2 diabetes.   

Practice Pearls: 

• Getting to goal safely and timely should be the primary consideration. 
• A patient-specific approach and cost of treatment should be considered when deciding which multiple medication therapies should be administered. 
• SGLT2 inhibitors are recommended for patients with chronic kidney disease or heart failure, and GLP-1 should be considered for its weight loss benefits. 

Kacie Doyle-Delgado, DNP, APRN, James J. Chamberlain, MD, Jay H. Shubrook, D.O., et al., “Pharmacologic Approaches to Glycemic Treatment of Type 2 Diabetes: Synopsis of the 2020 American Diabetes Association’s Standards of Medical Care in Diabetes Clinical Guideline.“ Annals of Internal Medicine, Sept. 1, 2020. 

Shadrielle Robbins, PharmD Candidate, South College School of Pharmacy 

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