Can dapagliflozin be added to a patient with type 2 diabetes and established atherosclerotic cardiovascular disease who is already taking metformin?

Dapagliflozin Should Be Added to Metformin in Patients with Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease

Yes, dapagliflozin should be added to metformin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD), as this combination reduces cardiovascular death or hospitalization for heart failure and provides renal protection. 1

Guideline-Based Recommendation

Multiple major cardiovascular societies explicitly recommend adding SGLT2 inhibitors like dapagliflozin to patients with type 2 diabetes and established ASCVD:

• The American Diabetes Association (2020) recommends SGLT2 inhibitors or GLP-1 receptor agonists as add-on therapies in patients with type 2 diabetes who have established ASCVD, with SGLT2 inhibitors preferred in patients at risk for heart failure. 1

• The American College of Cardiology Expert Consensus (2018) advises considering addition of SGLT2 inhibitors or GLP-1 receptor agonists in type 2 diabetes with established ASCVD, with SGLT2 inhibitors prioritized when reducing heart failure hospitalization is a goal. 1

• The European Society of Cardiology (2019) states that first-line treatment of type 2 diabetes in heart failure should include metformin and SGLT2 inhibitors. 1

• The American Association of Clinical Endocrinologists (2020) recommends that patients with type 2 diabetes at high risk for or with established ASCVD should be prescribed SGLT2 inhibitors or GLP-1 receptor agonists independent of glycemic levels. 1

Evidence from DECLARE-TIMI 58 Trial

The DECLARE-TIMI 58 trial provides the strongest evidence for dapagliflozin specifically:

• Dapagliflozin 10 mg daily reduced cardiovascular death or hospitalization for heart failure by 17% (HR 0.83; 95% CI 0.73-0.95; P=0.005) compared to placebo. 1, 2

• Hospitalization for heart failure was reduced by 27% (HR 0.73; 95% CI 0.61-0.88). 1, 2

• Renal outcomes improved significantly, with a 24% reduction in the renal composite endpoint (HR 0.76; 95% CI 0.67-0.87), defined as ≥40% decrease in estimated glomerular filtration rate, new end-stage renal disease, or death from renal or cardiovascular causes. 1, 2

• The trial enrolled 17,160 patients with type 2 diabetes who had or were at risk for ASCVD, with 41% having established ASCVD at baseline and median follow-up of 4.2 years. 1, 2

• Most patients were already on metformin at baseline, demonstrating the benefit of adding dapagliflozin to existing metformin therapy. 1

Practical Implementation Algorithm

Step 1: Verify Patient Eligibility

Check renal function before initiating dapagliflozin:

• Do not start if eGFR <30 mL/min/1.73 m² (though dapagliflozin can be continued if eGFR falls below this threshold after initiation). 3
• Dapagliflozin has been studied and shown benefit even in patients with eGFR as low as 30-44 mL/min/1.73 m². 3

Exclude pregnancy or breastfeeding:

• Dapagliflozin is contraindicated in pregnancy and breastfeeding. 1

Step 2: Initiate Dapagliflozin

Start dapagliflozin 10 mg once daily:

• This is the dose used in DECLARE-TIMI 58 and proven to reduce cardiovascular and renal outcomes. 1, 4, 2
• No dose titration is required. 1
• Continue metformin at current dose (typically 1000-2000 mg daily). 3

Step 3: Adjust Other Antihyperglycemic Therapies

Reduce insulin or sulfonylurea doses if present:

• This prevents hypoglycemia when adding dapagliflozin, as it provides additional glucose-lowering effect. 1

Step 4: Monitor Response and Safety

Monitor renal function:

• Check eGFR at least annually, increasing to every 3-6 months when eGFR falls below 60 mL/min/1.73 m². 3

Assess for volume depletion:

• Monitor for orthostatic lightheadedness, dizziness, or feeling faint when standing, especially in elderly patients, those on concurrent diuretics, or with low baseline blood pressure. 5

Watch for genital mycotic infections:

• These occur in approximately 6% of patients on SGLT2 inhibitors and typically resolve with brief antifungal treatment. 3, 5

Educate about euglycemic diabetic ketoacidosis (DKA):

• Although rare (0.3% in DECLARE-TIMI 58), patients should discontinue dapagliflozin immediately and seek urgent care if they develop dyspnea, nausea, vomiting, or abdominal pain. 6, 2
• Up to 71% of SGLT2-associated DKA cases present with glucose ≤250 mg/dL, making diagnosis challenging. 6
• Precipitating factors include very-low-carbohydrate diets, prolonged fasting, dehydration, excessive alcohol intake, acute illness, surgery, or reduced oral intake. 6

Common Pitfalls to Avoid

Do not withhold dapagliflozin based solely on baseline blood pressure:

• DECLARE-TIMI 58 demonstrated consistent benefits across all baseline systolic blood pressure categories, including normotensive patients (<120 mm Hg), with no increase in volume depletion events. 7

Do not assume dapagliflozin is only for glycemic control:

• The cardiovascular and renal benefits of dapagliflozin are independent of its glucose-lowering effect and should be prescribed even if HbA1c is at target. 1, 8

Do not confuse MACE reduction with heart failure benefit:

• Dapagliflozin did not reduce major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, or ischemic stroke) in DECLARE-TIMI 58 (HR 0.93; 95% CI 0.84-1.03; P=0.17), but it did significantly reduce heart failure hospitalization and cardiovascular death or heart failure hospitalization. 2

Do not overlook the sick day protocol:

• Temporarily hold both metformin and dapagliflozin during acute illness, surgery, or procedures requiring contrast dye to prevent lactic acidosis and DKA. 3

Do not prescribe dapagliflozin to individuals with prior history of DKA:

• This is an absolute contraindication. 6

Cardiovascular and Renal Protection Beyond Glycemic Control

The combination of metformin and dapagliflozin provides complementary mechanisms:

• Metformin reduces hepatic glucose production and improves insulin sensitivity. 3
• Dapagliflozin promotes glucosuria, reduces preload and afterload through osmotic diuresis, and provides direct cardioprotective and renoprotective effects. 8, 9

Benefits extend to patients without heart failure at baseline:

• In DECLARE-TIMI 58, only 10% of patients had heart failure at baseline, yet the reduction in heart failure hospitalization was consistent across all subgroups. 1, 2

Renal protection is clinically meaningful:

• The 24% reduction in renal composite outcomes translates to preservation of kidney function and delayed progression to dialysis. 2