In the past decade, diabetes medications have done something once thought impossible: they've been proven to save lives by protecting the heart and kidneys.
SGLT2 inhibitors (sodium-glucose cotransporter-2 inhibitors) represent a paradigm shift in diabetes care. These medications lower blood sugar while simultaneously reducing cardiovascular death and slowing kidney disease progression.
The 2025 ADA guidelines recommend them as first-line treatment for many patients. Here's what you need to know.
What Are SGLT2 Inhibitors?
How the Kidneys Normally Handle Glucose
Your kidneys filter about 180 grams of glucose every day. Under normal conditions, they reabsorb virtually all of it back into the bloodstream, so almost no glucose appears in urine.
This reabsorption happens through a protein called SGLT2 (sodium-glucose cotransporter-2) in the kidney tubules.
How SGLT2 Inhibitors Work
SGLT2 inhibitors block this transporter:
| Action | Effect |
|---|---|
| Block SGLT2 in kidneys | Prevent glucose reabsorption |
| Excrete glucose in urine | Lowers blood sugar independent of insulin |
| Remove calories | Leads to weight loss |
| Remove sodium | Acts as a mild diuretic |
| Reduce pressure in kidney filters | Lowers intraglomerular pressure |
Result: Lower blood sugar, weight loss, blood pressure reduction, and organ protection.
Available SGLT2 Inhibitors
The Medications
| Medication | Dose | A1C Reduction | Weight Loss | FDA Approval Year |
|---|---|---|---|---|
| Empagliflozin (Jardiance) | 10-25 mg daily | 0.7-1.0% | 2-3 kg | 2014 |
| Dapagliflozin (Farxiga) | 5-10 mg daily | 0.5-0.7% | 2-3 kg | 2014 |
| Canagliflozin (Invokana) | 100-300 mg daily | 0.7-1.0% | 2-4 kg | 2013 |
| Ertugliflozin (Steglatro) | 5-15 mg daily | 0.6-0.8% | 2-3 kg | 2017 |
| Sotagliflozin (Zynquista) | 200-400 mg daily | 0.5-0.7% | 2-3 kg | 2023 (CKD indication) |
Combination Products
| Product | Components | Benefit |
|---|---|---|
| Synjardy | Empagliflozin + metformin | Two medications, one pill |
| Xigduo XR | Dapagliflozin + metformin XR | Two medications, one pill |
| Invokamet | Canagliflozin + metformin | Two medications, one pill |
| Segluromet | Ertugliflozin + metformin | Two medications, one pill |
| Trijardy XR | Empagliflozin + linagliptin + metformin | Three medications, one pill |
Cardiovascular Protection
The Evidence That Changed Everything
In 2015, the EMPA-REG OUTCOME trial stunned the medical community:
| Finding | Result |
|---|---|
| Cardiovascular death | 38% reduction |
| Hospitalization for heart failure | 35% reduction |
| Death from any cause | 32% reduction |
| All-cause hospitalization | Significant reduction |
This was the first time a diabetes medication proved it could save lives.
Cardiovascular Outcome Trials
| Trial | Medication | Patients | Key Result |
|---|---|---|---|
| EMPA-REG (2015) | Empagliflozin | CVD | 38% reduction in CV death |
| CANVAS (2017) | Canagliflozin | CVD risk | 14% reduction in MACE |
| DECLARE-TIMI (2019) | Dapagliflozin | Multiple risk | 17% reduction in heart failure |
| DAPA-CKD (2020) | Dapagliflozin | CKD with/without diabetes | 20% reduction in MACE |
MACE = Major Adverse Cardiovascular Events (CV death, nonfatal MI, nonfatal stroke)
Heart Failure Benefits
SGLT2 inhibitors are particularly effective for heart failure:
| Indication | Evidence |
|---|---|
| HFrEF (reduced ejection fraction) | Empagliflozin and dapagliflozin reduce death and hospitalization |
| HFpEF (preserved ejection fraction) | Dapagliflozin reduces cardiovascular death and hospitalization |
| Heart failure prevention | All SGLT2 inhibitors reduce new-onset heart failure |
Key point: SGLT2 inhibitors are now recommended for patients with heart failure regardless of diabetes status.
Kidney Protection
How Diabetes Damages Kidneys
High blood sugar damages the kidney's filtering units (nephrons) through:
- Increased pressure within the glomerulus (filter)
- Scarring and inflammation
- Progressive loss of kidney function
How SGLT2 Inhibitors Protect Kidneys
| Mechanism | Effect |
|---|---|
| Lower intraglomerular pressure | Reduces mechanical stress on filters |
| Mild diuresis | Reduces volume overload |
| Reduce inflammation | May slow fibrosis |
| Lower blood sugar | Reduces glucose toxicity |
The Evidence
| Trial | Medication | eGFR Range | Result |
|---|---|---|---|
| CREDENCE (2019) | Canagliflozin | 30-90 | 34% reduction in kidney failure |
| DAPA-CKD (2020) | Dapagliflozin | 25-75 | 39% reduction in kidney failure |
| EMP-KIDNEY (2021) | Empagliflozin | 20-90 | 28% reduction in kidney disease progression |
Key findings:
- SGLT2 inhibitors slow progression of chronic kidney disease
- Benefit seen even in advanced CKD (eGFR down to 20)
- Benefit is independent of A1C lowering
FDA Indications for Kidney Disease
| Medication | CKD Indication | eGFR Range |
|---|---|---|
| Dapagliflozin | CKD in type 2 diabetes | eGFR 25-75 |
| Canagliflozin | Diabetic kidney disease | eGFR 30-90 |
| Empagliflozin | CKD in type 2 diabetes | eGFR 20-90 |
Who Should Take SGLT2 Inhibitors?
2025 ADA Recommendations
SGLT2 inhibitors are recommended for:
| Patient Group | Recommendation |
|---|---|
| ASCVD (established cardiovascular disease) | Indicated to reduce cardiovascular death |
| Heart failure | Indicated to reduce hospitalization and death |
| CKD stage 3-4 (eGFR 20-60) | Indicated to slow kidney disease progression |
| High CV risk | Consider for primary prevention |
Ideal Candidates
You might be a good candidate for SGLT2 inhibitors if you:
- Have type 2 diabetes and established cardiovascular disease
- Have heart failure (with or without diabetes)
- Have chronic kidney disease (eGFR 20-90)
- Need weight loss along with glucose lowering
- Want to reduce diuretic dose (SGLT2 has diuretic effect)
Side Effects
Common Side Effects
| Side Effect | Frequency | Management |
|---|---|---|
| Genital fungal infections | 4-10% | Hygiene, treatment with antifungal |
| Urinary tract infections | 4-8% | Hydration, prompt treatment |
| Increased urination | 5-10% | Usually temporary; take morning |
| Thirst, dry mouth | 3-5% | Stay hydrated |
| Dizziness/lightheadedness | 2-4% | Stand slowly, stay hydrated |
Serious but Rare Side Effects
| Concern | Risk | Who Should Avoid |
|---|---|---|
| Euglycemic DKA | Very rare (mostly type 1) | Type 1 diabetes, very low carb diet, alcohol use disorder |
| Lower limb amputation | Small increased risk (canagliflozin) | Prior amputation, peripheral vascular disease |
| Fournier's gangrene | Very rare | Prompt medical attention for genital pain |
| Acute kidney injury | Rare (volume depletion) | Ensure adequate hydration |
Euglycemic DKA: What to Know
What it is: DKA with blood sugar < 250 mg/dL (hence "euglycemic")
Risk factors:
- Type 1 diabetes (SGLT2 not generally recommended)
- Very low carbohydrate diet
- Excessive alcohol use
- Acute illness, surgery, prolonged fasting
- Insulin dose reduction
Prevention:
- Stop SGLT2 3-4 days before surgery or procedures
- Temporarily stop during acute illness
- Avoid very low-carb diets while taking SGLT2 inhibitors
- Stay hydrated during illness
- Check ketones if feeling unwell
Symptoms: Nausea, vomiting, abdominal pain, fruity breath, confusion
Practical Considerations
Dosing
| Medication | Starting Dose | Target Dose | Timing |
|---|---|---|---|
| Empagliflozin | 10 mg daily | 25 mg daily (if tolerated) | Morning |
| Dapagliflozin | 5 mg daily | 10 mg daily | Morning |
| Canagliflozin | 100 mg daily | 300 mg daily | Before breakfast |
| Ertugliflozin | 5 mg daily | 15 mg daily | Morning |
Administration
- Take in the morning (to minimize nighttime urination)
- Can be taken with or without food
- Stay hydrated (drink 2-3 L fluid daily)
- Avoid holding urine for prolonged periods
Monitoring
| Test | Frequency |
|---|---|
| eGFR | Before starting, then annually |
| Lipids | May increase LDL slightly |
| Genital exam | Prompt evaluation of symptoms |
| Ketones | If feeling unwell (nausea, vomiting, abdominal pain) |
Special Populations
Older Adults
Benefits:
- Low hypoglycemia risk
- Diuretic effect (may reduce BP medication needs)
- Cardiovascular protection
Cautions:
- Fall risk from volume depletion
- Ensure adequate hydration
- Monitor eGFR more frequently
Kidney Disease
Can be used down to eGFR 20 (most SGLT2 inhibitors):
| eGFR Range | Recommendation |
|---|---|
| ≥ 60 | Full dose |
| 45-59 | Full dose; monitor |
| 30-44 | Consider continuation if already on; monitor |
| 20-29 | May continue if already on; consider specialist input |
| <20 | Generally avoided (insufficient data) |
Note: SGLT2 inhibitors become less effective at lowering A1C as eGFR declines below 45, but kidney protection benefits persist.
Heart Failure
Recommended for both HFrEF and HFpEF regardless of diabetes status:
- Empagliflozin approved for HFrEF
- Dapagliflozin approved for HFrEF and HFpEF
SGLT2 Inhibitors vs. Other Classes
Compared to GLP-1 Agonists
| Feature | SGLT2 Inhibitors | GLP-1 Agonists |
|---|---|---|
| A1C reduction | 0.5-1.0% | 1.0-2.0% |
| Weight loss | 2-3 kg | 5-15+ kg |
| Cardiovascular benefit | Strong for HF, CV death | Strong for MACE |
| Kidney benefit | Strong evidence | Some evidence |
| Administration | Oral pill | Weekly injection |
| Hypoglycemia risk | Low (unless with insulin/SU) | Low |
| Cost | Similar | Similar |
| Side effects | Genital infections, UTI | Nausea, vomiting |
Combination Therapy
SGLT2 inhibitors and GLP-1 agonists can be combined:
- Additive A1C lowering
- Additive weight loss
- Dual organ protection (heart + kidney)
- May allow reduction of other medications
Key Takeaways
- SGLT2 inhibitors lower A1C 0.5-1.0% while causing modest weight loss
- Cardiovascular death reduced by 38% (EMPA-REG)
- Heart failure hospitalizations reduced by 30-35%
- Kidney disease progression slowed by 30-40%
- Can be used down to eGFR 20 for kidney protection
- Generally well-tolerated with low hypoglycemia risk
- Hold during acute illness/surgery to prevent DKA
FAQ Section
What are SGLT2 inhibitors used for?
SGLT2 inhibitors are used to treat type 2 diabetes, but also have proven benefits for heart failure and chronic kidney disease. They lower blood sugar by causing the kidneys to excrete glucose in urine.
Do SGLT2 inhibitors cause weight loss?
Yes, SGLT2 inhibitors cause modest weight loss of 2-4 kg (4-9 lbs) on average. The weight loss occurs because excreting glucose in urine removes calories from the body.
Which SGLT2 inhibitor is best?
All SGLT2 inhibitors effectively lower blood sugar and have cardiovascular benefits. Empagliflozin (Jardiance) has the strongest evidence for cardiovascular death reduction. Dapagliflozin (Farxiga) has evidence for both heart failure (with preserved EF) and kidney disease.
Can SGLT2 inhibitors cause kidney damage?
No—SGLT2 inhibitors protect the kidneys. Studies show they slow progression of chronic kidney disease by 30-40% in patients with type 2 diabetes. They can be used safely even in patients with moderate to severe kidney disease (eGFR down to 20).
Why are SGLT2 inhibitors held before surgery?
SGLT2 inhibitors are held 3-4 days before surgery to prevent euglycemic DKA (diabetic ketoacidosis with normal blood sugar). The combination of fasting, stress, and SGLT2 inhibition can trigger DKA even with normal blood sugar levels.
Sources:
- American Diabetes Association. Standards of Care in Diabetes—2025. Diabetes Care 2025; 48(Suppl 1)
- EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI, DAPA-CKD, CREDENCE trials
- ADA SGLT2 Information