SGLT-2 inhibitors

Definition and Classification
SGLT-2 inhibitors are a class of oral antihyperglycemic agents that act by inhibiting the sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, leading to reduced reabsorption of filtered glucose and sodium, and thereby promoting urinary glucose excretion. Originally developed to treat type 2 diabetes mellitus (T2DM), SGLT-2 inhibitors have demonstrated benefits beyond glycemic control, particularly in cardiovascular protection, renal function preservation, and heart failure management.

These agents are also known as "gliflozins" due to the common suffix in their generic names.

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Mechanism of Action

SGLT2 is responsible for reabsorbing approximately 90% of filtered glucose in the proximal convoluted tubule of the nephron. Inhibiting this transporter:

• Prevents glucose reabsorption

• Increases urinary glucose excretion

• Lowers plasma glucose levels

• Promotes natriuresis and osmotic diuresis

• Reduces blood pressure and body weight

This insulin-independent mechanism makes SGLT2 inhibitors useful at all stages of insulin resistance.

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Approved Generic and Brand Names

Generic Name	Brand Name(s)
Canagliflozin	Invokana
Dapagliflozin	Farxiga (Forxiga in EU)
Empagliflozin	Jardiance
Ertugliflozin	Steglatro
Sotagliflozin	Inpefa
Ipragliflozin (Japan)	Suglat
Luseogliflozin (Japan)	Lusefi
Tofogliflozin (Japan)	Apleway, Deberza

Some combinations:

• Empagliflozin + Linagliptin (Glyxambi)

• Dapagliflozin + Saxagliptin (Qtern)

• Canagliflozin + Metformin (Invokamet)

• Empagliflozin + Metformin (Synjardy)

• Dapagliflozin + Metformin (Xigduo)

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Indications

Primary Indication	Approved Use
Type 2 Diabetes Mellitus	All agents
Heart Failure (HFrEF and HFpEF)	Dapagliflozin, Empagliflozin (with or without diabetes)
Chronic Kidney Disease (CKD)	Dapagliflozin (approved), others off-label
Type 1 Diabetes Mellitus	Limited and region-specific (Dapagliflozin in EU with insulin)

Dosing Overview

Drug	Starting Dose	Max Dose
Canagliflozin	100 mg once daily	300 mg once daily
Dapagliflozin	5 mg once daily	10 mg once daily
Empagliflozin	10 mg once daily	25 mg once daily
Ertugliflozin	5 mg once daily	15 mg once daily
Sotagliflozin	200 mg once daily	400 mg once daily

Doses may be adjusted based on renal function and clinical indication (e.g., lower doses in heart failure or CKD).

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Clinical Benefits Beyond Glycemic Control

1. Cardiovascular Benefits

   • Empagliflozin: ↓ cardiovascular death in EMPA-REG OUTCOME trial

   • Dapagliflozin: ↓ heart failure hospitalizations (DECLARE-TIMI 58)

   • Benefit in both diabetic and non-diabetic patients with heart failure

2. Renal Protection

   • Dapagliflozin (DAPA-CKD trial): slowed CKD progression and ↓ renal death

   • Reduced proteinuria and improved eGFR trajectory

   • Canagliflozin (CREDENCE trial): renal and cardiovascular benefit in diabetic kidney disease

3. Heart Failure (HF)

   • DAPA-HF and EMPEROR-Reduced: ↓ hospitalization for HF

   • Used in HFrEF and HFpEF with or without diabetes

4. Weight Reduction

   • Average 2–3 kg weight loss via urinary glucose excretion

5. Blood Pressure Reduction

   • ~3–5 mmHg systolic BP reduction via mild diuresis

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Adverse Effects

Adverse Effect	Description
Genital Mycotic Infections	Candida vulvovaginitis, balanitis (common)
Urinary Tract Infections	May be mild to moderate
Polyuria/Dehydration	Due to osmotic diuresis
Hypotension	Especially in elderly or volume-depleted
Diabetic Ketoacidosis (DKA)	Rare but serious; can be euglycemic
Fournier's Gangrene	Rare necrotizing fasciitis of the perineum
Fractures and Amputations	Reported in Canagliflozin (CANVAS trial)
Increased LDL	Mild rise seen with some agents

Contraindications

Condition	Reason
Type 1 Diabetes (US)	Risk of DKA
eGFR < 30 mL/min/1.73 m² (varies by drug)	Reduced efficacy and safety
History of recurrent mycotic infections	Increased risk
Hypotension-prone patients	Risk of volume depletion
Severe liver disease	Use with caution (particularly with dapagliflozin)

Drug Interactions

Interacting Drug	Mechanism/Effect
Diuretics	Additive diuretic effect → risk of dehydration
Insulin/Sulfonylureas	↑ risk of hypoglycemia
Rifampin	↓ SGLT-2 inhibitor levels via CYP induction
ACE inhibitors/ARBs	Potential additive effect on renal function
Lithium	Monitor levels closely (diuretic effect)

Monitoring Parameters

Parameter	Frequency/Reason
HbA1c	Every 3–6 months (glycemic control)
Renal Function (eGFR)	Baseline and periodically
Electrolytes	Especially sodium and potassium
Signs of infection	Genitourinary symptoms
Volume status	Especially in elderly or diuretic users
Ketones (in DKA risk)	In symptomatic or acutely ill patients

Advantages and Disadvantages Summary

Advantages	Disadvantages
Effective glucose lowering (HbA1c ↓ 0.5–1%)	Genital and urinary infections
CV and renal protection	Risk of DKA (especially euglycemic)
Weight loss	Cost (relatively expensive)
BP reduction	Volume depletion and orthostatic hypotension
Insulin-independent action	Contraindicated in T1DM and severe CKD

SGLT2 Inhibitors vs. Other Antidiabetics

Parameter	SGLT2 Inhibitors	DPP-4 Inhibitors	GLP-1 RAs
Route	Oral	Oral	Injectable (mostly)
Hypoglycemia Risk	Low (unless with insulin)	Low	Low
Weight	↓ 2–3 kg	Neutral	↓ significant
CV Benefit	Strong (empagliflozin, dapagliflozin)	Modest (saxagliptin may ↑ HF risk)	Strong (liraglutide, semaglutide)
Renal Benefit	Yes	Neutral	Yes

Prescribing Considerations

• For T2DM patients with cardiovascular disease, heart failure, or CKD, empagliflozin or dapagliflozin is preferred.

• Consider dapagliflozin 10 mg daily in CKD even without diabetes (DAPA-CKD).

• Stop prior to major surgery or prolonged fasting to reduce DKA risk.

• Counsel patients on hydration, genital hygiene, and early signs of DKA (nausea, vomiting, fatigue, abdominal pain).

• Use in combination therapy with metformin, DPP-4 inhibitors, or GLP-1 receptor agonists is common and effective.

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Clinical Trials Supporting Use

Trial Name	Agent	Key Findings
EMPA-REG OUTCOME	Empagliflozin	↓ CV mortality, ↓ HF hospitalization
CANVAS	Canagliflozin	↓ CV events; ↑ risk of amputations/fractures
DECLARE-TIMI 58	Dapagliflozin	↓ HF hospitalization; neutral on CV death
DAPA-HF	Dapagliflozin	↓ HF hospitalization in HFrEF
DAPA-CKD	Dapagliflozin	↓ renal failure, ↓ CV death
EMPEROR-Reduced	Empagliflozin	↓ HF hospitalization and CV death