What are the recommended medications for treating type 2 diabetes?

Best Diabetes Drugs for Type 2 Diabetes

Start with metformin as first-line therapy, then add either an SGLT-2 inhibitor or GLP-1 agonist based on comorbidities—specifically prioritize SGLT-2 inhibitors for heart failure or chronic kidney disease, and GLP-1 agonists for stroke risk or weight loss goals. 1

First-Line Therapy

Metformin is the preferred initial pharmacologic agent for type 2 diabetes when lifestyle modifications (diet, exercise, weight loss) fail to adequately control hyperglycemia. 1 This recommendation is based on:

• Strong evidence for efficacy and safety with a long-standing track record 1
• Low cost compared to newer agents 1
• Weight-neutral or modest weight loss effect 1, 2
• Minimal hypoglycemia risk when used as monotherapy 1, 2
• Potential cardiovascular benefits, including 36% reduction in all-cause mortality and 39% reduction in myocardial infarction in the UKPDS trial 3

Important caveats with metformin:

• Monitor vitamin B12 levels periodically, especially in patients with anemia or peripheral neuropathy, as long-term use may cause biochemical B12 deficiency 1
• Continue metformin indefinitely as long as tolerated and not contraindicated, even when adding other agents 1, 2
• Gastrointestinal side effects are common but usually dose-dependent and manageable 4, 3

Second-Line Therapy: The Critical Decision Point

When metformin plus lifestyle modifications fail to achieve HbA1c targets after approximately 3 months, add either an SGLT-2 inhibitor or GLP-1 agonist. 1 This is a strong recommendation with high-certainty evidence. 1

SGLT-2 Inhibitors: Prioritize When

Use SGLT-2 inhibitors to reduce:

• All-cause mortality 1
• Major adverse cardiovascular events (MACE) 1
• Progression of chronic kidney disease 1
• Hospitalization due to congestive heart failure 1

Specifically prioritize SGLT-2 inhibitors in patients with:

• Type 2 diabetes AND heart failure 1
• Type 2 diabetes AND chronic kidney disease 1
• Atherosclerotic cardiovascular disease at high risk of heart failure 1

The evidence shows 18-25% risk reduction for heart failure and 24-39% risk reduction for kidney disease progression over 2-5 years. 5

GLP-1 Agonists: Prioritize When

Use GLP-1 agonists to reduce:

• All-cause mortality 1
• Major adverse cardiovascular events (MACE) 1
• Stroke risk 1

Specifically prioritize GLP-1 agonists in patients with:

• Type 2 diabetes AND increased stroke risk 1
• Type 2 diabetes where weight loss is an important treatment goal 1
• Established atherosclerotic cardiovascular disease 1, 2

GLP-1 agonists demonstrate 12-26% risk reduction for atherosclerotic cardiovascular disease over 2-5 years, with weight loss exceeding 5% in most patients and potentially exceeding 10% with high-potency agents. 5

What NOT to Use

Avoid DPP-4 inhibitors as add-on therapy to metformin for reducing morbidity and all-cause mortality—this is a strong recommendation with high-certainty evidence. 1 While DPP-4 inhibitors are weight-neutral with low hypoglycemia risk, they do not provide the mortality and cardiovascular benefits of SGLT-2 inhibitors or GLP-1 agonists. 1, 2

Alternative Second-Line Agents (When SGLT-2i/GLP-1RA Not Feasible)

If SGLT-2 inhibitors or GLP-1 agonists are contraindicated, not tolerated, or cost-prohibitive, consider:

• Sulfonylureas: Lower HbA1c by 1.0-1.5% but carry high hypoglycemia risk and cause moderate weight gain 1, 2
• Thiazolidinediones: Lower HbA1c by 1.0-1.5% but cause weight gain, edema, heart failure risk, and bone fractures 1, 2
• Insulin: Most effective for glycemic control (lowers HbA1c by 1.0-2.0%) but has highest hypoglycemia risk and causes weight gain 1, 2

Note: Sulfonylureas and long-acting insulins are inferior to SGLT-2 inhibitors and GLP-1 agonists for reducing mortality and morbidity but may still have limited value for glycemic control alone. 1

Glycemic Targets

• Aim for HbA1c between 7% and 8% in most adults with type 2 diabetes 1
• Deintensify therapy if HbA1c falls below 6.5% to reduce hypoglycemia risk 1
• Consider dual therapy from the start if newly diagnosed with HbA1c ≥1.5% above target 1, 2

When to Initiate Insulin Early

Start insulin immediately (regardless of other therapy) when:

• HbA1c >10% or blood glucose ≥300 mg/dL, especially if symptomatic with weight loss or hyperglycemic symptoms 1, 2
• Evidence of ongoing catabolism is present 1

Critical Safety Considerations

When adding SGLT-2 inhibitors or GLP-1 agonists achieves adequate glycemic control:

• Reduce or discontinue sulfonylureas or long-acting insulins due to increased severe hypoglycemia risk 1
• Self-monitoring of blood glucose may be unnecessary in patients on metformin combined with SGLT-2 inhibitor or GLP-1 agonist 1

Cost considerations:

• No generic SGLT-2 inhibitors or GLP-1 agonists are currently available 1
• Discuss medication costs when selecting between these drug classes 1
• Prescribe generic medications when available rather than brand-name options 1

The Evidence Hierarchy

The 2024 American College of Physicians guideline 1 represents the most recent and highest-quality evidence, superseding older recommendations. While the 2014 ADA guidelines 1 and 2019 ADA guidelines 1 provided a broader menu of options without strong preference between newer agents, the 2024 ACP guideline makes definitive recommendations based on mortality and morbidity outcomes—not just glycemic control. This represents a fundamental shift: the goal is no longer just lowering HbA1c, but preventing death, heart attacks, strokes, kidney failure, and heart failure hospitalizations. 1