The ADA 2020 synopsis outlines recommendations related to pharmacologic management to glycaemic treatment of type 2 diabetes. Recommendations cover oral and noninsulin injectable therapies, insulin treatment, and combination injectable therapies. The recommendations are based on the results of recent large trials with cardiovascular and renal outcomes.

As per the guidelines, early combination therapy can be considered in some patients at treatment initiation to extend the time to treatment failure. Combination therapy for type 2 diabetes should be considered for patients in whom atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD) predominate.

Pharmacologic Therapy for Type 2 Diabetes: Recommendations

Metformin as the initial therapy

Recommendation - Metformin is the preferred initial pharmacologic agent for the treatment of type 2 diabetes.

Lifestyle interventions are the cornerstone for initial treatment of type 2 diabetes includes. Apart from lifestyle changes, metformin is recommended as the initial pharmacotherapy in patients with no contraindications (such as stage 4 or 5 CKD, advanced heart failure, or a history of lactic acidosis).

Combination therapy to extend the time to treatment failure

Recommendation - Early combination therapy can be considered in some patients at treatment initiation to extend the time to treatment failure.

Due to the progressive nature of type 2 diabetes, combination therapy is often required. As per current guidelines, if the HbA1c target is not achieved after approximately 3 month, a stepwise approach is recommended, which involves the sequential addition of other therapies to metformin.

As per the ADA 2020 synopsis, initial combination therapy is advised in patients with HbA1c levels 1.5% to 2% above target, as most medications rarely decrease HbA1c concentrations by more than 1%. The approach of initial combination therapy may be superior to a stepwise approach for achieving glycaemic goals more rapidly and may also help in long term maintenance of glycaemic control.

Recommendation - A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include cardiovascular comorbid conditions, hypoglycaemia risk, impact on weight, cost, risk for side effects, and patient preferences.

Recommendation - Among patients with type 2 diabetes who have established ASCVD or indicators of high risk, established kidney disease, or heart failure, a sodium–glucose cotransporter-2 (SGLT2) inhibitor or glucagon-like peptide-1 receptor agonist (GLP-1 RA) with demonstrated cardiovascular disease benefit is recommended.

Recommendation - The medication regimen and medication-taking behavior should be reevaluated at regular intervals (every 3 to 6 months) and adjusted as needed to incorporate specific factors that affect choice of treatment.

Second-line options include SGLT2 inhibitors, GLP-1 RAs, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinedione, sulfonylureas, and basal insulin. The drug of choice to add to metformin should be based on patient characteristics, preferences, and drug-specific effects. The following are some drug specific recommendations in patients with established ASCVD, indicators of high ASCVD risk, CKD, or heart failure.

1. Add SGLT2 inhibitor or GLP-1 RA with demonstrated CVD benefit - If the patient has ASCVD or a high ASCVD risk, heart failure, or established CKD. The addition of these medications should be considered independent from HbA1c level in this patient population.
2. Add SGLT2 inhibitor - If a patient has heart failure or CKD. If an SGLT2 inhibitor cannot be used, a GLP-1 RA should be administered.
3. Thiazolidinediones should not be used in patients with symptomatic heart failure. Metformin can be considered in patients who have stable heart failure with adequate kidney function.

The following are some drug specific recommendations in patients without established ASCVD, indicators of high ASCVD risk, CKD, or heart failure. In this case, the drug is selected based on avoidance of side effects such as hypoglycaemia and weight gain; cost; and patient preferences.

1. Add Sulfonylurea or thiazolidinedione - If cost is the main patient factor.
2. Add GLP-1 RAs, SGLT2 inhibitors, DPP-4 inhibitors, or a thiazolidinedione - If the main concern is avoiding hypoglycaemia.
3. Add GLP-1 RAs or SGLT2 inhibitors - If there is a compelling need to minimize weight gain or promote weight loss.

Recommendation - In patients with type 2 diabetes who need greater glucose lowering than can be obtained with oral agents, GLP-1 RAs are preferred to insulin when possible.

If injectable agents are required to reduce HbA1c levels, then a GLP-1 RA is advised in most patients before the use of insulin.

Insulin therapy

Recommendation - The early introduction of insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycaemia are present, or when hemoglobin A1c (HbA1c) or blood glucose levels are very high (HbA1c >10% [86 mmol/mol], blood glucose ≥16.7 mmol/L [300 mg/dL]).

Insulin therapy is recommended in patients with advanced hyperglycaemia in order to reduce glucotoxicity and lipotoxicity. Once glucotoxicity resolves, simplifying the treatment regimen or transitioning to oral agents may be considered.

The addition of basal insulin to metformin and other oral agents is the most convenient initial insulin therapy. Basal insulin limits hyperglycaemia overnight and postprandially and restricts hepatic glucose production. Long-acting insulin analogues or human neutral protamine Hagedorn (NPH) insulins are used to manage fasting glucose levels. In addition to basal insulin, many patients may require preprandial insulin to achieve glucose targets. Preprandial insulin dosing may be intensified on the basis of patient needs.

Concentrated insulins such as U-500 regular insulin, U-200 degludec and U-300 glargine can also be used in patients with type 2 diabetes. U-200 degludec and U-300 glargine is useful in patients with higher basal insulin requirements.

Combination injectable therapy can be considered in patients whose basal insulin has been titrated appropriately to target fasting blood glucose values but whose HbA1c levels remain above target, or for those whose basal insulin dose is greater than 0.5 IU/kg per day. Basal insulin combined with GLP-1 RA therapy helps to improve blood glucose levels and is accompanied with less hypoglycaemia and weight gain relative to basal–bolus insulin routines.