- ACRONYMS AND DEFINITIONS
- ACR - American College of Rheumatology
- ADA - American Diabetes Association
- CAD - Coronary artery disease
- CHF - Congestive heart failure
- CV - Cardiovascular
- CVD - Cardiovascular disease
- DKA - Diabetic ketoacidosis
- DKD - Diabetic kidney disease
- EF - Ejection fraction
- FBS - Fasting blood sugar
- GFR - Glomerular filtration rate
- HFpEF - Heart failure with preserved ejection fraction
- HFrEF - Heart failure with reduced ejection fraction
- HgA1C - Hemoglobin A1C
- NYHA - New York Heart Association heart failure classification
- PAD - Peripheral artery disease
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- SGLT2 - Sodium-glucose co-transporter 2
- T2DM - Type 2 diabetes
- UTI - Urinary tract infection
- DRUGS IN CLASS
- SGLT2 Inhibitors
- Canagliflozin (Invokana®)
- Dapagliflozin (Farxiga®)
- Empagliflozin (Jardiance®)
- Ertugliflozin (Steglatro™)
- Combination products with metformin
- Invokamet® (canagliflozin + metformin)
- Invokamet® XR (canagliflozin + extended-release metformin)
- Segluromet® (ertugliflozin + metformin)
- Synjardy® (empagliflozin + metformin)
- Synjardy® XR (empagliflozin + extended-release metformin)
- Xigduo™ XR (dapagliflozin + extended-release metformin)
- Combination products with DPP-4 inhibitors
- Glyxambi® (empagliflozin + linagliptin)
- Qtern® (dapagliflozin + saxagliptin)
- Steglujan® (ertugliflozin + sitagliptin)
- Combination product with a DPP-4 inhibitor and metformin
- Trijardy® XR (empagliflozin + linagliptin + metformin ER)
- MECHANISM OF ACTION
- Kidneys
- Sodium-glucose co-transporter (SGLT) has 2 types, SGLT1 and SGLT2. In the kidneys, glucose passes freely from the bloodstream into the lumen of the nephron. In the first part of the proximal tubule, 90% of filtered glucose is reabsorbed by SGLT2 through secondary active transport with sodium. The remaining 10% is reabsorbed by SGLT1 in the latter part of the proximal tubule. SGLT2 inhibitors block the action of SGLT2 in the proximal tubule, and glucose is lost in the urine. SGLT2 inhibitors may also inhibit SGLT1 to a small degree, but their primary action is through SGLT2 inhibition. [16,18]
- Pancreas
- Recent research has shown that SGLT2 is also present in the pancreas. Alpha cells in the pancreas secrete glucagon. Glucagon is a hormone that counteracts the effects of insulin by stimulating hepatic glucose production. Alpha cells have SGLT2 in their membrane which allows glucose to enter the cell. Higher glucose concentrations in the cell suppress glucagon secretion. SGLT2 inhibitors block glucose from entering alpha cells and intracellular glucose concentrations decline. This causes the cells to secrete glucagon. Rising glucagon activity counteracts some of the glucose-lowering effects of SGLT2 inhibitors. The significance of these opposing actions is not completely understood. [8]
- FDA-APPROVED INDICATIONS
- Canagliflozin (Invokana®)
- Type 2 diabetes
- As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- To reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with T2DM and established CVD (see CANVAS studies below)
- Diabetic kidney disease - to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria > 300 mg/day (see CREDENCE study (renal) and CANVAS studies (heart failure) below)
- Dapagliflozin (Farxiga®)
- Type 2 diabetes
- As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established CVD or multiple CV risk factors (see DECLARE-TIMI 58 study)
- Heart failure (HFrEF and HFpEF)
- To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure
- To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors (see DAPA-HF trial and DELIVER trial below)
- Chronic kidney disease - to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression. (see DAPA-CKD trial)
- Empagliflozin (Jardiance®)
- Type 2 diabetes
- As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus
- To reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease (see EMPA-REG study below)
- Heart failure (HFrEF and HFpEF) - to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (HFrEF and HFpEF) (see EMPEROR-Reduced trial [HFrEF] and EMPEROR-Preserved trial [HFpEF] below)
- Ertugliflozin (Steglatro™)
- Type 2 diabetes - as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
- TYPE 2 DIABETES
Effects of SGLT2 inhibitors on blood sugars in trials lasting 24 - 26 weeks✝ | ||||
---|---|---|---|---|
Drug | A1C (monotherapy) |
FBS (monotherapy) |
A1C (added to metformin) |
FBS (added to metformin) |
Canagliflozin 100 mg daily | -0.77% | -27 | -0.79% | -27 |
Canagliflozin 300 mg daily | -1.03% | -35 | -0.94% | -38 |
Dapagliflozin 5 mg daily | -0.8% | -24 | -0.7% | -22 |
Dapagliflozin 10 mg daily | -0.9% | -29 | -0.8% | -24 |
Empagliflozin 10 mg daily | -0.7% | -19 | -0.7% | -20 |
Empagliflozin 25 mg daily | -0.8% | -25 | -0.8% | -22 |
Ertugliflozin 5 mg daily | -0.7% | -31 | -0.7% | -30 |
Ertugliflozin 15 mg daily | -0.8% | -36 | -0.9% | -41 |
- Body weight effects
- In 24 - 26 week trials, patients on SGLT2 inhibitors lost an average of 6 - 9 pounds
- Some of the weight loss is likely due to the diuretic effect of SGLT2 inhibitors (see diuresis below) [3,6,7]
- Cholesterol effects
- Canagliflozin (Invokana™)
- In 4 pooled, placebo-controlled trials, patients on canagliflozin had increases in LDL cholesterol of 4.5% (100 mg dose) and 8% (300 mg dose). Baseline LDL levels in the trials ranged from 104 - 110 mg/dl.
- HDL levels increased by 1.5% (100 mg dose) and 3.6% (300 mg dose) [3]
- Dapagliflozin (Farxiga™)
- In 13 pooled, placebo-controlled trials, patients on dapagliflozin had an increase in LDL cholesterol of 3% (10 mg dose) [6]
- Empagliflozin (Jardiance®)
- In trials, patients treated with empagliflozin had an increase in LDL cholesterol of 4.6% (10 mg dose) and 6.5% (25 mg dose). The baseline LDL level in the trials was 90 mg/dl. [7]
- Ertugliflozin (Steglatro™)
- In trials, patients treated with ertugliflozin had an increase in LDL cholesterol of 2.6% (5 mg dose) and 5.4% (15 mg dose). The baseline LDL level in the trials was 97 mg/dl. [12]
- Blood pressure effects
- SGLT2 inhibitors tend to have a small blood pressure-lowering effect
- This is likely due to their diuretic effect (see diuresis below)
- In trials, SGLT2 inhibitors lower systolic blood pressure by 2 - 6 mmHg on average and diastolic blood pressure by 1 - 2 mmHg on average [1,4,7,12]
- TYPE 2 DIABETES | Clinical outcomes - Canagliflozin
- Overview
- Two randomized controlled trials, CANVAS and CANVAS-R, compared canagliflozin to placebo for CVD outcomes. The results from those trials were combined and presented as one study. Another trial, CREDENCE, compared canagliflozin to placebo for renal outcomes. Both studies are detailed below.
- The CANVAS studies enrolled 10,142 type 2 diabetics with documented CVD or ≥ 2 risk factors for CVD
Main inclusion criteria
- Type 2 diabetes
- A1C of 7 - 10.5%
- Established cardiovascular disease or ≥ 50 years with ≥ 2 risk factors
Main exclusion criteria
- GFR < 30 ml/min
- History of ≥ 1 severe hypoglycemic episode within 6 months
- CVD event within 3 months
Baseline characteristics
- Average age 63 years
- Average BMI - 32
- Average A1C - 8.2%
- Average GFR - 76 ml/min
- Average duration of DM - 13.5 years
- History of CVD - 72%
Randomized treatment groups
- Group 1 (5795 patients): Canagliflozin 100 - 300 mg once daily
- Group 2 (4347 patients): Placebo once daily
- Use of other DM meds and risk factor management were guided by local guidelines
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
Results
Duration: Average of 3.6 years | |||
Outcome | Canagliflozin (% / year) |
Placebo (% / year) |
Comparisons |
---|---|---|---|
Primary outcome | 2.7% | 3.15% | HR 0.86 95%CI [0.75 – 0.97] |
Overall mortality | 1.73% | 1.95% | HR 0.87, 95%CI [0.74 - 1.01] |
Death from cardiovascular causes | 1.16% | 1.28% | HR 0.87, 95%CI [0.72 - 1.06] |
Nonfatal heart attack | 0.97% | 1.16% | HR 0.85, 95%CI [0.69 - 1.05] |
Nonfatal stroke | 0.71% | 0.84% | HR 0.90, 95%CI [0.71 - 1.15] |
Hospitalization for heart failure | 0.55% | 0.87% | HR 0.67, 95%CI [0.52 - 0.87] |
Amputations | 0.63% | 0.34% | p<0.001 |
Male genital infections | 3.49% | 1.08% | p<0.001 |
Female mycotic infections | 6.88% | 1.75% | p<0.001 |
Diabetic ketoacidosis | 0.06% | 0.03% | p=0.14 |
All fractures | 1.54% | 1.19% | p=0.02 |
Hyperkalemia | 0.69% | 0.44% | p=0.10 |
|
Findings: In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.
- The CREDENCE study enrolled 4401 type 2 diabetics with macroalbuminuria and chronic kidney disease
Main inclusion criteria
- Type 2 diabetes
- A1C of 6.5 - 12%
- GFR 30 - 90 ml/min
- Macroalbuminuria (≥ 300 mcg albumin/mg creatinine)
- Stable dose of ACE inhibitor or ARB
Main exclusion criteria
- Nondiabetic kidney disease
- Received immunosuppression for kidney disease
- < 30 years old
Baseline characteristics
- Average age 63 years
- Average A1C - 8.3%
- Average GFR - 56 ml/min
- Average duration of DM - 15.8 years
- Median albumin/creatinine ratio - 927
Randomized treatment groups
- Group 1 (2202 patients): Canagliflozin 100 mg once daily
- Group 2 (2199 patients): Placebo once daily
- Use of other DM meds and risk factor management were guided by local guidelines
Primary outcome: composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m²), a doubling of the serum creatinine level, or death from renal or cardiovascular causes
Results
Duration: The trial was stopped after a median follow-up of 2.62 years due to clear superiority of canagliflozin | |||
Outcome | Canagliflozin (events/100 patient-yr) |
Placebo (events/100 patient-yr) |
Comparisons |
---|---|---|---|
Primary outcome | 4.32 | 6.12 | p=0.00001 |
Overall mortality | 2.9 | 3.5 | HR 0.83, 95%CI [0.68 - 1.02] |
Doubling of serum creatinine | 2.07 | 3.38 | p<0.001 |
Dialysis or kidney transplant | 1.33 | 1.77 | HR 0.74, 95%CI [0.55 - 1.00] |
Amputations | 1.23 | 1.12 | HR 1.11 95%CI [0.79 - 1.56] |
Diabetic ketoacidosis | 0.22 | 0.02 | HR 10.80 95%CI [1.39 - 83.65] |
Fracture | 1.18 | 1.21 | HR 0.98 95%CI [0.70 - 1.37] |
Hyperkalemia | 2.97 | 3.69 | HR 0.80 95%CI [0.65 - 1.0] |
|
Findings: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years
- Summary
- The CANVAS studies found that canagliflozin lowered the risk of cardiovascular outcomes when compared to placebo. Canagliflozin-treated patients had better blood sugar control throughout the trial (A1C diff 0.58%), and this likely accounted for some of the effect. In the subgroup of patients with hemoglobin A1C values < 8% at baseline, canagliflozin had no significant effect on the primary outcome.
- In the CREDENCE study, canagliflozin improved renal outcomes among diabetics with kidney disease. The overall difference in A1C values between groups was small (0.25%) which supports the possibility of an SGLT2-specific renoprotective effect.
- In the CANVAS studies, patients treated with canagliflozin had an increased risk of lower extremity amputations, and this prompted the FDA to place a black box warning on the drug. In the CREDENCE study, the risk of amputations was not significantly different between groups.
- DKA was a rare event, but it did occur more frequently in canagliflozin-treated patients
- TYPE 2 DIABETES | Clinical outcomes - Dapagliflozin
- Overview
- The DECLARE-TIMI 58 trial detailed below looked at the effects of dapagliflozin on both CVD and renal outcomes
- The DECLARE-TIMI 58 Study enrolled 17,160 diabetics who had or were at risk for cardiovascular disease
Main inclusion criteria
- Type 2 diabetes
- HgA1C of 6.5 - 12%
- CrCl ≥ 60 ml/min
- Established CVD or multiple risk factors for CVD
Main exclusion criteria
- Current or recent (within 24 months) use of pioglitazone
- Current or recent (within 12 months) use of rosiglitazone
- Uncontrolled hypertension (> 180/110)
Baseline characteristics
- Average age 64 years
- Average HgA1C - 8.3%
- Median duration of diabetes - 10 years
- Established CVD - 41%
- Insulin therapy - 41%
Randomized treatment groups
- Group 1 (8582 patients): Dapagliflozin 10 mg once daily
- Group 2 (8578 patients): Placebo once daily
- All other diabetes meds were left at the discretion of the treating provider
- Non-study SGLT2 inhibitors, pioglitazone, and rosiglitazone were not allowed
Primary outcomes:
- 1. Major adverse cardiovascular events (MACE) defined as cardiovascular death, myocardial infarction, or ischemic stroke
- 2. Composite of cardiovascular death or hospitalization for heart failure
Results
Duration: Median of 4.2 years | |||
Outcome | Dapagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome (MACE) | 8.8% | 9.4% | HR 0.93, 95%CI [0.84 - 1.03], p=0.17 |
Primary outcome (CV death or CHF) | 4.9% | 5.8% | HR 0.83, 95%CI [0.73 - 0.95], p=0.005 |
Overall mortality | 6.2% | 6.6% | HR 0.93, 95%CI [0.82 - 1.04] |
Hospitalization for heart failure | 2.5% | 3.3% | HR 0.73, 95%CI [0.61 - 0.88] |
Death from cardiovascular cause | 2.9% | 2.9% | HR 0.98, 95%CI [0.82 - 1.17] |
≥ 40% decrease in GFR to < 60 ml/min, ESRD, or renal death | 1.5% | 2.8% | HR 0.53, 95%CI [0.43 - 0.66] |
Diabetic ketoacidosis | 0.3% | 0.1% | HR 2.18, 95%CI [1.10 - 4.30], p=0.02 |
Amputation | 1.4% | 1.3% | HR 1.09, 95%CI [0.84 - 1.40], p=0.53 |
Genital infection | 0.9% | 0.1% | HR 8.36, 95%CI [4.19 - 16.68], p<0.001 |
Fractures | 5.3% | 5.1% | HR 1.04, 95%CI [0.94 - 1.18], p=0.59 |
Bladder cancer | 0.3% | 0.5% | HR 0.57, 95%CI [0.35 - 0.93], p=0.02 |
|
Findings: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in
a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of
hospitalization for heart failure.
- Summary
- Dapagliflozin lowered the risk of hospitalization for heart failure when compared to placebo. The diuretic effect of SGLT2 inhibitors is the likely mechanism behind this benefit.
- The dapagliflozin group had lower A1C values throughout the trial, and this undoubtedly accounted for some of the benefit seen
- The benefit seen in renal outcomes is probably multifactorial and includes better blood sugar control, lower blood pressure, and possible SGLT2 inhibitor-specific effects on glomerular pressures
- The incidence of diabetic ketoacidosis was significantly higher in the dapagliflozin group, although the overall risk was small (0.3%)
- The risk of amputations was not significantly higher with dapagliflozin, nor was the risk of bladder cancer
- The effects of dapagliflozin on heart failure in patients both with and without diabetes was evaluated in the DAPA-HF trial detailed below
- TYPE 2 DIABETES | Clinical outcomes - Empagliflozin
- Overview
- The effects of empagliflozin on cardiovascular outcomes were evaluated in the EMPA-REG OUTCOME trial. A secondary analysis of that trial looked at renal outcomes. Results from both studies are detailed below.
- The EMPA-REG OUTCOME study enrolled 7020 diabetics with established cardiovascular disease
Main inclusion criteria
- Type 2 diabetes
- Established cardiovascular disease
- HgA1C of 7 - 9% if no meds for previous 12 weeks, HgA1C 7 - 10% if receiving meds
Main exclusion criteria
- CrCl < 30 ml/min
- BMI > 45
Baseline characteristics
- Average age 63 years
- Average BMI - 30.6
- Average A1C - 8%
- Average GFR - 74 ml/min
- Microalbuminuria - 29%
- Macroalbuminuria - 11%
- Metformin therapy - 74%
- Insulin therapy - 48%
- Sulfonylurea therapy - 43%
Randomized treatment groups
- Group 1 (2345 patients): Empagliflozin 10 mg once daily
- Group 2 (2342 patients): Empagliflozin 25 mg once daily
- Group 3 (2333 patients): Placebo once daily
- For the first 12 weeks after randomization, all other meds were left unchanged. After week 12, investigators were encouraged to adjust other glucose-lowering therapy at their discretion to achieve glycemic control according to local guidelines.
Primary outcome: composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction),
or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group
Results
Duration: Median of 3.1 years | |||
Outcome | Empagliflozin groups | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 10.5% | 12.1% | HR 0.86, 95%CI [0.74 - 0.99], p=0.04 |
Overall mortality | 5.7% | 8.3% | HR 0.68, 95%CI [0.57 - 0.82], p<0.001 |
Death from CV causes | 3.7% | 5.9% | HR 0.62, 95%CI [0.49 - 0.77], p<0.001 |
Nonfatal heart attack | 4.5% | 5.2% | HR 0.87, 95%CI [0.70 - 1.09], p=0.22 |
Nonfatal stroke | 3.2% | 2.6% | HR 1.24, 95%CI [0.92 - 1.67], p=0.16 |
Hospitalization for heart failure | 2.7% | 4.1% | HR 0.65, 95%CI [0.50 - 0.85], p=0.002 |
Genital infections | 6.4% | 1.8% | p<0.05 |
UTI | 18% | 18% | p>0.05 |
Fractures | 3.8% | 3.9% | p>0.05 |
Diabetic ketoacidosis | 0.1% (4 cases) | <0.1% (1 case) | p>0.05 |
|
Findings: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate
of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.
- A secondary analysis of the EMPA-REG OUTCOME study (see above) looked at renal outcomes
Duration: Median of 3.1 years | |||
Outcome | Empagliflozin groups | Placebo | Comparisons |
---|---|---|---|
Progression to macroalbuminuria | 11.2% | 16.2% | HR 0.62, 95%CI [0.54 - 0.72], p<0.001 |
Doubling of serum creatinine with GFR ≤ 45 ml/min | 1.5% | 2.6% | HR 0.56, 95%CI [0.39 - 0.79], p<0.001 |
Initiation of renal replacement therapy | 0.3% | 0.6% | HR 0.45, 95%CI [0.21 - 0.97], p=0.04 |
Incidence of albuminuria in patients without baseline albuminuria | 51.5% | 51.2% | HR 0.95, 95%CI [0.87 - 1.04], p=0.25 |
Findings: In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care
- Summary
- The EMPA-REG OUTCOME study found that empagliflozin improved cardiovascular and renal outcomes when compared to placebo
- Hemoglobin A1C levels were significantly lower in the empagliflozin groups throughout the entire trial, and this likely accounted for some of the difference in outcomes. A1C levels did not change much in the placebo group even though providers were encouraged to treat to goals.
- The benefit seen in renal outcomes is probably multifactorial and includes better blood sugar control, lower blood pressure, and possible SGLT2 inhibitor-specific effects on glomerular pressures
- One interesting finding is that the empagliflozin groups had significantly fewer hospitalizations for heart failure. Empagliflozin-treated patients also had more weight loss and lower average systolic blood pressure. This is likely due to the diuretic effect seen with SGLT2 inhibitors. Patients with heart failure and diabetes may be good candidates for SGLT2 therapy.
- Based on the EMPA-REG OUTCOME study, the FDA approved a new indication for empagliflozin to reduce the risk of cardiovascular death in adult patients with type 2 diabetes and cardiovascular disease
- TYPE 2 DIABETES | Clinical outcomes - Ertugliflozin
- Overview
- The effects of ertugliflozin on cardiovascular outcomes were evaluated in the VERTIS CV trial detailed below
- The VERTIS CV trial enrolled 8246 patients with type 2 diabetes and CVD
Main inclusion criteria
- Age ≥ 40 years
- Type 2 diabetes with A1C 7 - 10.5%
- History of CAD, PAD, stroke, or carotid stenosis
Main exclusion criteria
- History of DKA
- GFR < 30 ml/min
- NYHA Class IV heart failure
Baseline characteristics
- Average age 64 years
- Average A1C - 8.2%
- Average BP - 133/76
- History of CAD - 76%
- History of PAD - 19%
- History of stroke - 21%
- Heart failure - 24%
Randomized treatment groups
- Group 1 (5499 patients): Ertugliflozin 5 mg (N=2752) or Ertugliflozin 15 mg (N=2747) once daily
- Group 2 (2747 patients): Placebo
- Doses of background antihyperglycemic medication were held constant for the initial 18 weeks of the trial except in the patients who met the criteria for glycemic rescue and those with clinically significant hypoglycemia
- For the results comparisons, the two ertugliflozin groups (5 mg and 15 mg) were pooled and compared to placebo
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction,
or nonfatal stroke
Results
Duration: Average of 3.5 years | |||
Outcome | Ertugliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 11.9% | 11.9% | HR 0.97 (0.85 – 1.11) |
Death from CV cause | 6.2% | 6.7% | HR 0.92 (0.77 – 1.11) |
Nonfatal MI | 5.6% | 5.4% | HR 1.04 (0.86 – 1. 27) |
Nonfatal stroke | 2.9% | 2.8% | HR 1 (0.76 – 1.32) |
Overall mortality | 8.6% | 9.2% | HR 0.93 (0.80 – 1.08) |
Hospitalization for CHF | 2.5% | 3.6% | HR 0.70 (0.54 – 0.90) |
Composite renal outcome✝ | 3.2% | 3.9% | HR 0.81 (0.63 – 1.04) |
|
Findings: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events.
- Summary
- Ertugliflozin was comparable to placebo for most CVD outcomes in the VERTIS CV trial. Canagliflozin and empagliflozin were superior to placebo in their respective CVD trials. Based on the results of this trial, it's unlikely ertugliflozin will get an indication for CVD risk reduction.
- TYPE 2 DIABETES | Professional recommendations
- ADA recommendations
- TYPE ONE DIABETES
- Overview
- Most oral diabetes medications are not useful in type one diabetics because their mechanism relies on insulin production; one exception is alpha-glucosidase inhibitors which block the absorption of glucose from the intestine
- SGLT2 inhibitors cause glucose loss in the urine, and their mechanism is independent of insulin. Because of this, there has been interest in using them to treat type one diabetes.
- The DEPICT-1 study detailed below compared dapagliflozin to placebo in type one diabetics
- The DEPICT-1 trial enrolled 833 patients with uncontrolled type one diabetes
Main inclusion criteria
- Age 18 - 75 years
- Type one diabetes
- HgA1C of 7.7 - 11%
- Insulin therapy for ≥ 12 months
Main exclusion criteria
- History of type two diabetes
- DKA or hyperglycemia/hypoglycemia requiring hospitalization within 1 month
- Frequent severe hypoglycemia
- Symptomatic diabetes
- CrCl < 60 ml/min
Baseline characteristics
- Average age 42 years
- Average HgA1C - 8.53%
- Average duration of diabetes - 20 years
Randomized treatment groups
- Group 1 (259 patients) - Dapagliflozin 5 mg once daily
- Group 2 (259 patients) - Dapagliflozin 10 mg once daily
- Group 3 (260 patients) - Placebo once daily
- After the first dose of study drug, the total daily insulin dose was recommended to be reduced symmetrically in basal and bolus insulin by up to 20% to minimise the risk of hypoglycemia
Primary outcome: Change from baseline in HgA1C after 24 weeks of treatment
Results
Duration: 24 weeks | ||||
Outcome | Dapagliflozin 5 mg | Dapagliflozin 10 mg | Placebo | Comparisons |
---|---|---|---|---|
Change in A1C from baseline | -0.45% | −0.47% | -0.03% | 1 or 2 vs 3 p<0·0001 |
Genital infection | 12% | 11% | 3% | N/A |
Urinary tract infection | 7% | 4% | 5% | N/A |
Diabetic ketoacidosis (adjudicated) | 1% | 2% | 1% | N/A |
Severe hypoglycemia | 8% | 6% | 7% | N/A |
Findings: Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes
- Summary
- In the DEPICT-1 trial, dapagliflozin had a modest effect on blood sugar control in type one diabetics
- The risk of DKA in this trial was not significantly greater than placebo. Other studies have shown a possible link between DKA and SGLT2 inhibitors in both type one and type two diabetics (see diabetic ketoacidosis below).
- Larger studies are needed in order to better define the benefits/risks of SGLT2 inhibitors in type one diabetes
- HEART FAILURE WITH REDUCED EJECTION
- Overview
- In diabetes studies, it was noted that SGLT2 inhibitors improved heart failure outcomes (see DECLARE-TIMI 58 study). Given these findings, trials were then performed to evaluate the effects of SGLT2 inhibitors on heart failure with reduced ejection fraction in patients both with and without diabetes. The DAPA-HF trial evaluated the effects of dapagliflozin, and the EMPEROR-Reduced trial looked at empagliflozin. Both studies are detailed below.
- The DAPA-HF trial enrolled 4744 patients with NYHA class II, III, or IV heart failure and an ejection fraction < 40%
Main inclusion criteria
- EF < 40%
- NYHA II, III, or IV heart failure
- NT-proBNP ≥ 600 pg/ml or ≥ 400 pg/ml with CHF hospitalization within 12 months
Main exclusion criteria
- Type 1 diabetes
- Recent SGLT2 inhibitor
- SBP < 95 mmHg
- GFR < 30 ml/min
Baseline characteristics
- Average age 66 years
- Average EF - 31%
- Type 2 diabetes - 42%
- Median NT-proBNP - 1435 pg/ml
- Taking Entresto - 11%
- Heart failure type: Ischemic - 56% | Nonischemic - 36%
- NYHA class: II - 67% | III - 32% | IV - 1%
Randomized treatment groups
- Group 1 (2373 patients): Dapagliflozin 10 mg once daily
- Group 2 (2371 patients): Placebo once daily
- Patients were required to receive standard heart failure device therapy (an implantable cardioverter–defibrillator, cardiac resynchronization therapy, or both)
- Patients were treated with standard CHF therapy: ACE, ARB, or Entresto + beta blocker. Aldosterone antagonists were encouraged.
Primary outcome: Composite of worsening heart failure or death from cardiovascular
causes. An episode of worsening heart failure was either an unplanned hospitalization or an urgent visit resulting in intravenous therapy for heart failure.
Results
Duration: Median of 18.2 months | |||
Outcome | Dapagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 16.3% | 21.2% | p<0.001 |
Hospitalization for heart failure | 9.7% | 13.4% | HR 0.70 95%CI [0.59 - 0.83] |
Urgent heart failure visit | 0.4% | 1.0% | HR 0.43 95%CI [0.20 - 0.90] |
Cardiovascular death | 9.6% | 11.5% | HR 0.82 95%CI [0.69 - 0.98] |
Overall mortality | 11.6% | 13.9% | HR 0.83 95%CI [0.71 - 0.97] |
Amputation | 0.5% | 0.5% | N/A |
DKA | 0.1% | 0% | N/A |
Fournier's gangrene | 0% | <0.1% | N/A |
Fractures | 2.1% | 2.1% | p=1.0 |
|
Findings: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who
received dapagliflozin than among those who received placebo, regardless of the
presence or absence of diabetes.
- The EMPEROR-Reduced trial enrolled 3730 patients with NYHA class II, III, or IV heart failure and an EF < 40%
Main inclusion criteria
- NYHA class II, III, or IV heart failure
- EF < 40%
- If EF > 30%: hospitalization for heart failure within 12 months or NT-proBNP ≥ 1000 pg/ml (EF 31 - 35%) or ≥ 2500 pg/ml (EF 36 - 40%)
- If EF ≤ 30%: NT-proBNP ≥ 600 pg/ml
- In patients with A fib, NT-proBNP thresholds were doubled
Main exclusion criteria
- CVD event within 90 days
- Cardiomyopathy
- Severe heart valve disease
- GFR < 20 ml/min
Baseline characteristics
- Average age 67 years
- Average EF - 27%
- Average NT-proBNP - 1900 pg/ml
- Diabetes - 50%
- A fib - 36%
- Heart failure cause: Ischemic - 52% | Nonischemic - 48%
- NYHA class: II - 75% | III - 24% | IV - 0.5%
Randomized treatment groups
- Group 1 (1863 patients): Empagliflozin 10 mg once daily
- Group 2 (1867 patients): Placebo
- All the patients were receiving appropriate treatments for heart failure, including diuretics, inhibitors of the renin–angiotensin system and neprilysin, beta blockers, mineralocorticoid receptor antagonists, and, when indicated, cardiac devices
Primary outcome: Composite of adjudicated cardiovascular death or hospitalization for heart failure, analyzed as the time to the first event
Results
Duration: Median of 16 months | |||
Outcome | Empagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 19.4% | 24.7% | p<0.001 |
Hospitalization for HF | 13.2% | 18.3% | HR 0.69 (0.59 to 0.81) |
CV death | 10% | 10.8% | HR 0.92 (0.75 to 1.12) |
Overall mortality | 13.4% | 14.2% | HR 0.92 (0.77 to 1.10) |
Composite renal outcome✝ | 1.6% | 3.1% | HR 0.50 (0.32 to 0.77) |
Change in SBP (52 weeks) | -2.4 mmHg | -1.7 mmHg | diff –0.7 (–1.8 to 0.4) |
Change in body weight (52 weeks) | -0.73 kg | +0.08 kg | diff –0.82 (–1.18 to –0.45) |
|
Findings: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.
- Professional recommendations
- ADA recommendations
- The ADA guidelines state that SGLT2 inhibitors are preferred second-line therapy after metformin in diabetics with heart failure. See ADA treatment recommendations.
- AHA recommendations
- Summary
- In the two trials above, dapagliflozin and empagliflozin improved outcomes in patients with HFrEF. SGLT2 inhibitors promote diuresis, which helps to reduce fluid overload and lower blood pressure. This effect was demonstrated in a small trial (N=60) of patients with decompensated heart failure, where empagliflozin increased urine output by 25%. [PMID 35766022]. It's unclear if SGLT2 inhibitors have any beneficial effects beyond their diuretic properties.
- HEART FAILURE WITH PRESERVED EJECTION FRACTION
- Overview
- Heart failure with preserved ejection fraction (HFpEF) is a subtype of heart failure where patients have congestive symptoms, but the ejection fraction remains > 40%. Effective treatments for HFpEF have been elusive, and therapies that have proven beneficial in HFrEF have not been shown to help HFpEF.
- Two large trials that examined the effects of empagliflozin and dapagliflozin in HFpEF are detailed below
- The EMPEROR-Preserved trial enrolled 5988 patients with NYHA class II - IV heart failure and an EF > 40%
Main inclusion criteria
- NYHA class II - IV heart failure
- EF > 40%
- NT-proBNP level > 300 pg/ml (> 900 pg/ml if has A fib)
- BMI < 45
Main exclusion criteria
- MI, CABG, CVA within 90 days
- Cardiac resynchronization therapy
- SBP ≥ 180 mmHg
- A fib with rate > 100 bpm
Baseline characteristics
- Average age 72 years
- Average BMI - 30
- Average EF - 54%
- Median NT-proBNP - 995 pg/ml
- Diabetes - 49%
- A fib - 51%
- Ischemic heart failure - 35%
- NYHA class: II - 81% | III - 18% | IV - <1%
Randomized treatment groups
- Group 1 (2997 patients): Empagliflozin 10 mg once daily
- Group 2 (2991 patients): Placebo
Primary outcome: Composite of adjudicated cardiovascular death or hospitalization for heart failure, analyzed as the time to the first event
Results
Duration: Median of 2.2 years | |||
Outcome | Empagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 13.8% | 17.1% | HR 0.79, 95%CI [0.69 - 0.90], p<0.001 |
Heart failure hospitalization | 8.6% | 11.8% | HR 0.71, 95%CI [0.60 - 0.83] |
Cardiovascular death | 7.3% | 8.2% | HR 0.91, 95%CI [0.76 - 1.09] |
Overall mortality | 14.1% | 14.3% | HR 1.0, 95%CI [0.87 - 1.15] |
Hypotension | 10.4% | 8.6% | N/A |
UTI | 9.9% | 8.1% | N/A |
Genital infections | 2.2% | 0.7% | N/A |
Bone fractures | 4.5% | 4.2% | N/A |
Lower limb amputations | 0.5% | 0.8% | N/A |
Ketoacidosis | 0.1% | 0.2% | N/A |
|
Findings: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes.
- The DELIVER trial enrolled 5988 patients with NYHA class II - IV heart failure and an EF > 40%
Main inclusion criteria
- Age ≥ 40 years
- NYHA class II - IV heart failure
- EF > 40%
- NT-proBNP level ≥ 300 pg/ml (≥ 600 pg/ml if has A fib)
Main exclusion criteria
- Type 1 diabetes
- GFR < 25 ml/min
- MI, CABG, CVA within 12 weeks
- SBP ≥ 180 mmHg
- BMI > 50
Baseline characteristics
- Average age 72 years
- Average EF - 54%
- Diabetes - 45%
- Receiving loop diuretic - 77%
- NYHA class: II - 75% | III - 24% | IV - <1%
Randomized treatment groups
- Group 1 (3131 patients): Dapagliflozin 10 mg once daily
- Group 2 (3132 patients): Placebo
Primary outcome: Composite of worsening heart failure, which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure, or cardiovascular death
Results
Duration: Median of 2.3 years | |||
Outcome | Dapagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 16.4% | 19.5% | HR 0.82, 95%CI [0.73 - 0.92], p<0.001 |
Heart failure hospitalization | 10.5% | 13.3% | HR 0.77, 95%CI [0.67 - 0.89] |
Urgent heart failure visit | 1.9% | 2.5% | HR 0.76, 95%CI [0.55 - 1.07] |
Cardiovascular death | 7.4% | 8.3% | HR 0.88, 95%CI [0.74 - 1.05] |
Overall mortality | 15.9% | 16.8% | HR 0.94, 95%CI [0.83 - 1.07] |
Any amputation | 0.6% | 0.8% | N/A |
DKA | 0.1% | 0% | N/A |
|
Findings: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved
ejection fraction.
- Professional recommendations
- Summary
- In their respective HFpEF trials, dapagliflozin and empagliflozin reduced the absolute risk of heart failure hospitalization by about 3% over two years while having no significant effect on mortality or cardiovascular death.
- SGLT2 inhibitors cause marked diuresis, likely accounting for much of their benefit. The effect of empagliflozin on fluid overload was demonstrated in a small trial (N=60) of patients with decompensated heart failure, where it increased urine output by 25%. [PMID 35766022] Given these effects, the question arises as to whether optimal diuretic therapy is just as effective.
- The FDA granted empagliflozin a Breakthrough Therapy Designation in HFpEF shortly after the EMPEROR-Preserved trial was published. Several years later, dapagliflozin became the second drug to receive an HFpEF indication.
- CHRONIC KIDNEY DISEASE
- Overview
- After SGLT2 inhibitors were found to improve renal outcomes in diabetics, their effects in other types of kidney disease were evaluated. The DAPA-CKD trial looked at dapagliflozin, and the EMPA-KIDNEY study evaluated empagliflozin. Both studies are detailed below.
- The DAPA-CKD trial enrolled 4304 patients with chronic kidney disease and albuminuria
Main inclusion criteria
- Age ≥ 18 years
- GFR of 25 - 75 ml/min
- Urinary Alb/Cr ratio of 200 - 5000 mg/g
- ACE/ARB therapy unless contraindicated
Main exclusion criteria
- Type 1 diabetes
- Polycystic kidney disease
- Lupus nephritis
- ANCA-associated vasculitis
- Immunotherapy for kidney disease within 6 months
Baseline characteristics
- Average age 62 years
- Average GFR - 43 ml/min
- Median Alb/Cr ratio - 945
- Average BP - 137/78
- Diabetes - 67%
Randomized treatment groups
- Group 1 (2152 patients): Dapagliflozin 10 mg once daily
- Group 2 (2152 patients): Placebo
Primary outcome: First occurrence of any of the following: a decline of at least 50% in the estimated GFR (confirmed by a second serum creatinine measurement after ≥ 28 days), the onset of end-stage kidney disease (defined as maintenance dialysis for ≥ 28 days, kidney transplantation, or an estimated GFR of < 15 ml/min confirmed by a second measurement
after ≥ 28 days), or death from renal or cardiovascular causes
Results
Duration: Median 2.4 years | |||
Outcome | Dapagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 9.2% | 14.5% | p<0.001 |
GFR decline ≥ 50% | 5.2% | 9.3% | HR 0.53 (0.42 – 0.67) |
End-stage kidney disease | 5.1% | 7.5% | HR 0.64 (0.50 – 0.82) |
Overall mortality | 4.7% | 6.8% | p=0.004 |
Amputations | 1.6% | 1.8% | p=0.73 |
DKA | 0% | <0.1% | p=0.50 |
Fracture | 4% | 3.2% | p=0.22 |
|
Findings: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo
- The EMPA-KIDNEY trial enrolled 6609 patients with chronic kidney disease
Main inclusion criteria
- GFR 20 - 44 ml/min OR 45 - 89 ml/min with Alb:Cr ratio ≥ 200
- Taking RAAS inhibitor unless not indicated
Main exclusion criteria
- DM2 + CVD + GFR > 60 ml/min
- Polycystic kidney disease
- History of kidney transplant
- SBP > 180 or < 90
Baseline characteristics
- Average age 64 years
- Male sex - 67%
- Diabetes - 46%
- Average GFR - 37 ml/min
- Average Alb:Cr ratio - 222
- Taking RAAS inhibitor - 85%
- CKD etiology: DKD - 31% | Glomerular - 25% | HTN/Vascular - 22%
Randomized treatment groups
- Group 1 (3304 patients): Empagliflozin 10 mg once daily
- Group 2 (3305 patients): Placebo
Primary outcome: First occurrence of progression of kidney disease or
death from cardiovascular causes. Progression of kidney disease was defined as end-stage kidney disease (ESKD; the initiation of maintenance dialysis or receipt of a kidney transplant), a sustained decrease in the eGFR < 10 ml/min, a sustained decrease
from baseline in the eGFR of at least 40%, or death from renal causes.
Results
Duration: Median of 2 years | |||
Outcome | Empagliflozin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 13.1% | 16.9% | p<0.001 |
Progression of kidney disease | 11.6% | 15.2% | HR 0.71, 95%CI(0.62–0.81) |
Death from CV causes | 1.8% | 2.1% | HR 0.84, 95%CI(0.60–1.19) |
Overall mortality | 4.5% | 5.1% | p=0.21 |
Ketoacidosis | 6 cases | 1 case | N/A |
Lower-limb amputation | 0.8% | 0.6% | HR 1.43, 95%CI(0.80–2.57) |
|
Findings: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo.
- Summary
- Dapagliflozin and empagliflozin improved renal outcomes in patients with chronic kidney disease, regardless of their diabetes status. The mechanism by which SGLT2 inhibitors improve renal function is not completely understood but may be related to decreased intraglomerular pressure from SGLT2 inhibitor-induced osmotic diuresis.
- In 2021, dapagliflozin received an indication for chronic kidney disease. It's likely that empagliflozin will also.
- GOUT
- Overview
- Gout is an inflammatory joint disease caused by elevated uric acid levels
- SGLT2 inhibitors promote uric acid excretion in the kidneys and therefore may be beneficial in the treatment and prevention of gout [15]
- The mechanism of the effect is believed to occur through the increased exchange of glucose for uric acid through the renal SLC2A9 (GLUT9) transporter. The transporter removes glucose from the tubular lumen in exchange for uric acid. Higher luminal glucose concentrations secondary to SGLT2 inhibitors may increase the activity of the transporter. [9,10,11]
- In a study that pooled results from four randomized controlled trials, the average uric acid level in 34 patients treated with canagliflozin 100 mg a day for 26 weeks decreased from 8.5 mg/dl to 6.52 mg/dl. In placebo-treated patients (n=32), the average uric acid level decreased from 8.8 mg/dl to 7.964 mg/dl. In the same study, 34 patients treated with canagliflozin 300 mg a day had their average uric acid levels decrease from 8.6 mg/dl to 6.85 mg/dl. [PMID 25600248]
- Professional recommendations
- The American College of Rheumatology 2012 hyperuricemia guidelines state that if target uric acid levels are not achieved with a xanthine oxidase inhibitor, a uricosuric drug should be added. Probenecid is the first choice, but other uricosuric drugs (fenofibrate, losartan) may be considered in appropriate patients.
- See hyperuricemia treatment recommendations for more
- Summary
- SGLT2 inhibitors appear to have a modest effect on uric acid levels and may be beneficial in patients with gout
- The latest ACR guidelines were completed before SGLT2 inhibitors were available
- SIDE EFFECTS
- Hypersensitivity reactions
- Hypersensitivity reactions including angioedema, anaphylaxis, and serious skin reactions have been reported in a small number of patients taking SGLT2 inhibitors
- Reactions typically occurred within hours to days of starting the SGLT2 inhibitor
- SGLT2 inhibitors should be discontinued permanently in patients who experience a reaction [3,6]
- Yeast infections
- SGLT2 inhibitors cause an increase in yeast infections for both women and men
- Yeast infections in women are vaginal, and yeast infections in men occur on the head of the penis (balanitis)
- Yeast infections in men are more common if the man is uncircumcised
- The table below gives the risk of yeast infection in men and women that was observed for each drug in placebo-controlled trials
Incidence of yeast infection in men and women on SGLT2 inhibitors | ||
---|---|---|
Drug | Incidence with drug | Incidence with placebo |
Canagliflozin (women) | 10 - 12% | 3% |
Canagliflozin (men) | 3.5 - 4.5% | 0.6% |
Dapagliflozin 5 mg (women) | 8.4% | 1.5% |
Dapagliflozin 10 mg (women) | 6.9% | 1.5% |
Dapagliflozin 5 mg (men) | 2.8% | 0.3% |
Dapagliflozin 10 mg (men) | 2.7% | 0.3% |
Empagliflozin 10 mg (women) | 5.4% | 1.5% |
Empagliflozin 25 mg (women) | 6.4% | 1.5% |
Empagliflozin 10 mg (men) | 3.1% | 0.4% |
Empagliflozin 25 mg (men) | 1.6% | 0.4% |
Ertugliflozin 5 mg (women) | 9.1% | 3.0% |
Ertugliflozin 15 mg (women) | 12.2% | 3.0% |
Ertugliflozin 5 mg (men) | 3.7% | 0.4% |
Ertugliflozin 15 mg (men) | 4.2% | 0.4% |
- Urinary tract infections (UTI)
- SGLT2 inhibitors cause a slight increase in the risk of UTIs. Serious infections, including pyelonephritis and urosepsis, have also been reported. The table below shows the incidence of UTIs for each drug in placebo-controlled trials.
Incidence of UTIs with SGLT2 inhibitors | ||
---|---|---|
Drug | Incidence with drug | Incidence with placebo |
Canagliflozin | 8.2% | 6.7% |
Dapagliflozin 5 mg | 5.7% | 3.7% |
Dapagliflozin 10 mg | 4.3% | 3.7% |
Empagliflozin 10 mg | 7.6% | 7.6% |
Empagliflozin 25 mg | 9.3% | 7.6% |
Ertugliflozin 5 mg | 4.0% | 3.9% |
Ertugliflozin 15 mg | 4.1% | 3.9% |
- Volume depletion (diuresis effect)
- SGLT2 inhibitors increase the amount of glucose in the urine, and this pulls more water into the urine through osmosis. Increased urinary volume can lead to dehydration, hypotension, and serum creatinine increases. In trials, the incidence of side effects related to diuresis was generally low (< 5%). Older patients, patients with kidney disease (GFR < 60 ml/min), and patients taking diuretics may be at greater risk. Volume status should be assessed before initiating SGLT2 inhibitors, and patients should be monitored for volume depletion during therapy.
- The table below gives the incidences of diuresis-related side effects that were seen in placebo-controlled trials with SGLT2 inhibitors
Diuresis symptoms with SGLT2 inhibitors | ||
---|---|---|
Drug | Incidence with drug | Incidence with placebo |
Increased urination | ||
Canagliflozin | 4.5 - 5.5% | 0.8% |
Dapagliflozin 5 mg | 2.9% | 1.7% |
Dapagliflozin 10 mg | 3.8% | 1.7% |
Empagliflozin 10 mg | 3.4% | 1.0% |
Empagliflozin 25 mg | 3.2% | 1.0% |
Ertugliflozin 5 mg | 2.7% | 1.0% |
Ertugliflozin 15 mg | 2.4% | 1.0% |
Symptoms associated with volume depletion✝ | ||
Canagliflozin | 3 - 5% | 2.4% |
Dapagliflozin 5 mg | 0.6% | 0.4% |
Dapagliflozin 10 mg | 0.8% | 0.4% |
Empagliflozin 10 mg | 0.5% | 0.3% |
Empagliflozin 25 mg | 0.3% | 0.3% |
Ertugliflozin 5 mg | 4.4% | 0% |
Ertugliflozin 15 mg | 1.9% | 0% |
- Low blood sugar (hypoglycemia)
- By themselves, SGLT2 inhibitors do not appear to cause significant hypoglycemia
- When added to medications that carry a risk for hypoglycemia (e.g. insulin, sulfonylureas), SGLT2 inhibitors can increase the risk for hypoglycemic episodes [2, 6]
- Bone effects
- In some studies, the risk of fractures has been greater in patients treated with SGLT2 inhibitors when compared to placebo. The possible mechanism behind adverse bone effects with SGLT2 inhibitors is not completely understood, but may be related to SGLT2 inhibitor stimulation of fibroblast growth factor 23 (FGF23). FGF23 decreases vitamin D levels which reduces calcium absorption in the intestine and causes PTH levels to rise. [17]
- Evidence of bone effects for each drug is discussed below
- Canagliflozin
- In clinical trials lasting 1 year, bone density tests showed a significant decrease in bone mineral density at the lumbar spine and hip in patients taking canagliflozin when compared to placebo. In the CANVAS studies, the risk of fractures was significantly greater in canagliflozin-treated patients (by 0.35%/year) while in the CREDENCE study, the risk was not increased with the 100 mg dose.
- In 2015, the FDA issued a drug safety warning stating that more data from trials has confirmed that canagliflozin decreases bone mineral density and increases the risk of fractures. Fractures can occur as early as 12 weeks after starting the drug.
- Dapagliflozin
- In one small trial, patients with moderate kidney disease (GFR 30 - 60 ml/min) who took dapagliflozin had more bone fractures than patients on placebo. Patients on dapagliflozin (165 patients) - 13 fractures; Placebo group (87 patients) - 0 fractures. [6]
- In the DECLARE-TIMI trial and DAPA-CKD trial, no increased risk of fractures was seen in the dapagliflozin groups.
- Empagliflozin
- The empagliflozin PI does not mention bone effects [7]
- In the EMPA-REG OUTCOME, EMPEROR-Reduced, and EMPEROR-Preserved trials, the risk of fracture was not significantly different between empagliflozin and placebo
- Ertugliflozin
- The ertugliflozin PI does not mention bone effects. In the VERTIS CV trial, the incidence of fractures in the ertugliflozin groups was similar to placebo.
- Summary
- In studies, the effects of SGLT2 inhibitors on bone health have been mixed
- Patients at high risk for bone fractures may want to avoid canagliflozin
- Diabetic ketoacidosis (DKA)
- Diabetic Ketoacidosis (DKA), a metabolic syndrome typically seen in type 1 diabetics, occurs when the body utilizes fatty acids as an energy source instead of carbohydrates. Fatty acid metabolism produces acidic byproducts that can lead to high anion gap metabolic acidosis. If untreated, DKA can be life-threatening.
- SGLT2 inhibitors have been associated with rare but serious cases of DKA in both type 1 and type 2 diabetics. In many patients, DKA occurred at glucose levels < 250 mg/dl, causing a delay in diagnosis. SGLT2 inhibitor-induced DKA may last longer than expected, with some patients experiencing ketoacidosis and glucosuria for up to 2 weeks after drug discontinuation. Patients presenting with nausea, vomiting, abdominal pain, malaise, and/or shortness of breath should be evaluated for DKA.
- In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. The risks and benefits of SGLT2 inhibitors should be considered when prescribing to patients with these conditions.
- When possible, stop SGLT2 inhibitor therapy 3 - 4 days before surgery. In other situations where prolonged fasting may occur, consider holding SGLT2 inhibitors.
- In the type 2 diabetes efficacy trials detailed above, the overall risk of DKA was low (< 1%/year). In two of the trials, DKA occurred significantly more in SGLT2-treated patients than in placebo-treated patients. See CREDENCE study (canagliflozin) and the DECLARE-TIMI 58 study (dapagliflozin) for more.
- Design: Cohort study (N=417,514 | Length = 370,454 person-years) among diabetics who received new prescriptions for SGLT2 inhibitors or DPP-4 inhibitors
- Treatment: SGLT2 inhibitor vs DPP-4 inhibitor
- Primary outcome: Incidence of DKA
- Results:
- Primary outcome: SGLT2 inhibitors - 2.03 events/1000 patient-years, DPP-4 inhibitors - 0.75 events/1000 patient-years (HR 2.85, 95%CI [1.99 - 4.08])
- Molecule-specific HRs were 1.86 (95%CI [1.11 to 3.10]) for dapagliflozin, 2.52 (95%CI [1.23 to 5.14]) for empagliflozin, and 3.58 (95%CI [2.13 to 6.03]) for canagliflozin
- Findings: SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect.
- STUDY
- A randomized controlled trial published in Diabetes Care compared the risk of ketone-related adverse events including DKA in type 1 diabetics (N=351) randomized to canagliflozin 100 mg, canagliflozin 300 mg, and placebo for 18 weeks
- The incidence of ketone-related adverse events was 5.1% and 9.4%, for canagliflozin 100 mg and 300 mg, respectively. There were no events in the placebo group.
- The incidence of DKA was 4.3%, and 6.0% for canagliflozin 100 mg and 300 mg, respectively. There were no events in the placebo group.
- Design: Propensity score matched registry cohort study (N=34,426 | Length = 272 days) among diabetics who received new prescriptions for SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) or GLP-1 analogs
- Treatment: SGLT2 inhibitor vs GLP-1 analog
- Primary outcome: Lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis
- Results:
- Diabetic ketoacidosis: SGLT2 inhibitors - 1.3 events/1000 patient years, GLP-1 analogs - 0.6 events/1000 patient years (HR 2.14, 95%CI [1.01 - 4.52])
- Findings: In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP-1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern
STUDY
STUDY
- Professional recommendations
- In 2019, the FDA required that SGLT2 inhibitors carry a warning about the possibility of DKA in patients who were scheduled to undergo surgery or exposed to other situations that may involve a prolonged fast (e.g. acute illness). The warning stated that providers should consider holding the SGLT2 inhibitor during the fasting event.
- For surgery, the manufacturers of canagliflozin, dapagliflozin, and empagliflozin recommend holding the drugs for at least 3 days prior to surgery, and for ertugliflozin, the manufacturer recommends 4 days.
- Lower extremity amputations
- Canagliflozin (Invokana®)
- In two trials (CANVAS and CANVAS-R), the risk of lower extremity amputations was significantly greater with canagliflozin when compared to placebo. Amputations of the toe and middle foot were the most common. In the CREDENCE study which only used a dose of 100 mg, the risk of amputations was not significantly increased with canagliflozin.
- Annual risk of foot or leg amputation in the CANVAS trial
- 0.59% of patients treated with canagliflozin
- 0.28% of patients treated with placebo
- Annual risk of foot or leg amputation in the CANVAS-R trial
- 0.75% of patients treated with canagliflozin
- 0.42% of patients treated with placebo
- Ertugliflozin (Steglatro™)
- Across seven phase 3 clinical trials, non-traumatic lower limb amputations (primarily of the toe) were reported in 0.1% of patients in the comparator group, 0.2% of patients in the ertugliflozin 5 mg group, and 0.5% of patients in the ertugliflozin 15 mg group. [12] In the VERTIS CV trial, the incidence of amputations was 2% for ertugliflozin 5 mg, 2.1% for ertugliflozin 15 mg, and 1.6% for placebo.
- Dapagliflozin (Farxiga®)
- In the DECLARE TIMI Study detailed above, there was no significant difference in the incidence of amputations between dapagliflozin and placebo.
- Empagliflozin (Jardiance®)
- The empagliflozin PI does not mention lower extremity amputations. In the EMPEROR-Reduced and EMPEROR-Preserved trials, the risk of lower extremity amputations was not increased in empagliflozin-treated patients.
- STUDY
- Design: Propensity score matched registry cohort study (N=34,426, length = 272 days) among diabetics who received new prescriptions for SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) or GLP-1 analogs
- Treatment: SGLT2 inhibitor vs GLP-1 analog
- Primary outcome: Lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis,
- Results:
- Lower limb amputations: SGLT2 inhibitors - 2.7 events/1000 patient years, GLP-1 analogs - 1.1 events/1000 patient years (HR 2.32, 95%CI [1.37 - 3.91])
- Findings: In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP-1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern
- Summary
- The FDA had placed a boxed warning on canagliflozin about amputation risk, but they later removed it after they reviewed more data and decided the risk was lower than previously thought
- In summary, there is some evidence that SGLT2 inhibitors increase the risk of amputations. The overall risk is very low.
- Necrotizing fasciitis (Fournier's gangrene)
- In 2018, the FDA issued a drug safety warning about the possible association of SGLT2 inhibitors with a rare infection called necrotizing fasciitis of the perineum (also known as Fournier’s gangrene)
- Symptoms of necrotizing fasciitis include tenderness, redness, and/or swelling of the genitals or the area from the genitals back to the rectum and fever
- The FDA identified 55 unique cases of Fournier's gangrene in patients receiving SGLT2 inhibitors between March 1, 2013 and January 31, 2019. By comparison, the FDA identified 19 cases of Fournier's gangrene in patients taking other diabetes drugs from 1984 to January 31, 2019.
- Affected patients ranged in age from 33 - 87 years old, and time to onset after initiation of SGLT2 inhibitor therapy ranged from 5 days to 49 months. Sixteen of the affected patients were women which is unusual since the condition typically affects men. [14]
- LAB EFFECTS
- All SGLT2 inhibitors
- Urine glucose
- SGLT2 inhibitors work by increasing urinary glucose excretion; therefore, urinary glucose tests should not be used to monitor diabetes activity
- Uric acid
- See gout above
- 1,5-anhydroglucitol (1,5AG)
- 1,5-anhydroglucitol is a monosaccharide excreted in the urine, and plasma levels can be used to assess glucose control. SGLT2 inhibitors make 1,5AG measurements unreliable. [3]
- Canagliflozin
- Liver functions (ALT, AST, GGT, bilirubin)
- Canagliflozin causes a decrease in ALT, AST, alk phos, and GGT levels
- Canagliflozin causes an increase in total bilirubin levels (about 6.4%) [2]
- Potassium
- Canagliflozin may cause a small increase in potassium levels
- This effect appears to be more pronounced with the 300 mg dose [2,3]
- Phosphate
- Canagliflozin causes a dose-dependent increase in serum phosphate levels of 3.6 - 5.1%
- In patients with reduced kidney function (GFR 30 - 50 ml/min), serum phosphate increases were higher, 4.6% - 9.4% [2]
- Magnesium
- Canagliflozin causes a dose-dependent increase in serum magnesium levels of 8.1 - 9.3%
- The clinical significance of these effects is unclear [2]
- Hemoglobin
- Canagliflozin may cause an increase in hemoglobin levels
- This is likely due to the diuretic effect which causes hemoconcentration [2]
- Calcium, Vitamin D, PTH
- Canagliflozin does not appear to affect serum calcium levels, urinary calcium levels, Vitamin D levels, or parathyroid hormone (PTH) levels [2]
- Dapagliflozin
- Serum creatinine
- Dapagliflozin causes a slight increase in the serum creatinine level
- In patients with normal kidney function, the effect appears to resolve with time. After one week, an increase of 0.029 (5 mg dose) and 0.041 mg/dl (10 mg dose) was seen in studies.
- In patients with moderate kidney disease, larger increases were seen - 0.13 - 0.18 mg/dl after 1 week
- Hematocrit
- Dapagliflozin causes an increase in the hematocrit
- In studies, the hematocrit increased by an average of 2.3% by week 24 in patients on the 10 mg dose [6]
- Phosphorus
- Dapagliflozin causes an increase in phosphorus levels
- In studies, phosphorus levels increased by an average of 0.13 mg/dl by week 24 in patients on dapagliflozin [6]
- Empagliflozin
- Serum creatinine
- Empagliflozin may cause a slight increase in the serum creatinine level
- In patients with moderate kidney disease (CrCl 30 - 60 ml/min), serum creatinine rose an average of 0.09 mg/dl at 52 weeks when compared to placebo [7]
- Hematocrit
- Empagliflozin may cause an increase in the hematocrit
- In studies, the median hematocrit increased by an average of 2.8% [7]
- Ertugliflozin
- Serum creatinine
- Ertugliflozin may cause a slight increase in the serum creatinine level
- In patients with moderate kidney disease (CrCl 30 - 60 ml/min), serum creatinine rose an average of 0.08 mg/dl at 26 weeks when compared to placebo [12]
- Hemoglobin
- Ertugliflozin may cause an increase in hemoglobin
- In studies, average hemoglobin rose 3.5% in patients treated with ertugliflozin 15 mg for 26 weeks [12]
- Phosphate
- Ertugliflozin may cause an increase in serum phosphate levels
- In studies, serum phosphate levels rose up to 10% in patients treated with ertugliflozin for 26 weeks [12]
- CONTRAINDICATIONS
- Canagliflozin (Invokana®)
- History of hypersensitivity
- Severe renal impairment (GFR less than 45 mL/min), end stage renal disease or patients on dialysis
- Dapagliflozin (Farxiga®)
- History of hypersensitivity
- Patients on dialysis
- Empagliflozin (Jardiance®)
- History of hypersensitivity
- Patients on dialysis
- Ertugliflozin (Steglatro™)
- History of hypersensitivity reaction
- Patients on dialysis
- PRECAUTIONS
- Kidney disease
- Canagliflozin (Invokana®)
- GFR 45 - 59 ml/min: Dose should not exceed 100 mg a day
- GFR < 45 ml/min: DO NOT USE [3]
- Dapagliflozin (Farxiga®)
- Empagliflozin (Jardiance®)
- Type 2 diabetes
- GFR ≥ 30 ml/min: no dose adjustment necessary
- GFR < 30 ml/min: not recommended. Likely to be ineffective for glucose control.
- Heart failure with reduced EF
- GFR ≥ 20 ml/min: no dose adjustment necessary
- GFR < 20 ml/min: has not been studied. Not recommended.
- Ertugliflozin (Steglatro™)
- GFR ≥ 45 ml/min: no dose adjustment necessary
- GFR < 45 ml/min: not recommended. Do not use in patients on dialysis.
- Liver disease
- Canagliflozin (Invokana®)
- Mild-to-moderate liver disease (Child-Pugh class A and B): No dosage adjustment is necessary
- Severe liver disease (Child-Pugh class C): Has not been studied. Do not use. [3]
- Dapagliflozin (Farxiga®)
- No dose adjustment is necessary in mild, moderate, or severe liver disease
- Has not been studied extensively in patients with severe liver disease [6]
- Empagliflozin (Jardiance®)
- No dose adjustment necessary [7]
- Ertugliflozin (Steglatro™)
- Mild-to-moderate liver disease (Child-Pugh class A and B): No dosage adjustment is necessary
- Severe liver disease (Child-Pugh class C): Has not been studied. Not recommended. [12]
- Osteoporosis
- Canagliflozin causes a decrease in bone mineral density and may increase the risk for fractures. Other SGLT2 inhibitors may carry the same risk, but there is less data available to substantiate their risk.
- Canagliflozin should be avoided in patients with osteoporosis and in those who are at increased risk for fractures (See bone effects for more)
- Caution should be exercised before prescribing other SGLT2 inhibitors to these patients
- High potassium (canagliflozin)
- Canagliflozin may cause an increase in potassium levels. This effect appears to be more pronounced with the 300 mg dose.
- In the CANVAS studies and the CREDENCE study, the incidence of hyperkalemia was not significantly different than placebo
- Use caution when using canagliflozin (particularly 300 mg dose) in patients who are at high risk for hyperkalemia (ex. decreased kidney function) and in those who are on other medications that raise potassium levels (see drug Interactions below) [2,3]
- Dehydration
- SGLT2 inhibitors cause an osmotic diuresis and fluid loss
- Use with caution in patients who are dehydrated or in those who are taking other medications (ex. diuretics) which cause fluid loss [3]
- Surgery/fasting
- The risk of DKA (see diabetic ketoacidosis) may be increased in patients who are fasting for various reasons (e.g. surgery, acute illness)
- In 2019, the FDA required that SGLT2 inhibitors carry a warning about the possibility of DKA in patients who were scheduled to undergo surgery or exposed to other situations that may involve a prolonged fast (e.g. acute illness)
- For surgery, the manufacturers of canagliflozin, dapagliflozin, and empagliflozin recommend holding the drugs for at least 3 days prior to surgery, and for ertugliflozin, the manufacturer recommends 4 days
- SGLT2 inhibitors may be restarted once oral intake is back to baseline and other risk factors for ketoacidosis have resolved
- Bladder cancer
- Dapagliflozin may increase the risk for bladder cancer (see bladder cancer above)
- Patients with a history of bladder cancer should not take dapagliflozin [6]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All SGLT2 inhibitors
- Diuretics - SGLT2 inhibitors may potentiate the diuresis that occurs with diuretics. This may result in increased urination and volume depletion. Monitor patients for signs of dehydration when prescribing together. Diuretics include thiazide diuretics, loop diuretics, and aldosterone antagonists.
- Insulin and insulin secretagogues - the risk of hypoglycemia is increased when SGLT2 inhibitors are prescribed with insulin and insulin secretagogues (e.g. sulfonylureas, meglitinides). Monitor blood sugars closely when combining, particularly during initiation and dose changes.
- Lithium - SGLT2 inhibitors may reduce serum lithium concentrations. Monitor lithium levels closely during SGLT2 inhibitor initiation and dosage changes.
- Canagliflozin (Invokana™)
- Drugs that raise potassium levels
- Canagliflozin has the potential to raise potassium levels. This effect appears to be more pronounced with the 300 mg dose.
- It may interact with other drugs that raise potassium causing hyperkalemia (high blood potassium levels)
- Drugs that may raise potassium levels include:
- Aldosterone antagonists (spironolactone, eplerenone)
- Aliskiren (Tekturna®)
- ARBs (losartan, valsartan, etc.)
- Cyclosporine (Neoral®)
- ENaC inhibitors (triamterene, amiloride)
- Penicillin G potassium injection (1 million units contains 1.68mEq of potassium)
- Potassium supplements (K-Dur®, etc.)
- Tacrolimus
- Trimethoprim (part of Bactrim® and Septra®)
- UGT enzyme inducers
- Canagliflozin is primarily metabolized through O-glucuronidation by UGT1A9 and UGT2B4. UGT inducers may decrease canagliflozin exposure and reduce its effectiveness. When prescribing UGT inducers (e.g. rifampin, phenytoin, phenobarbital, ritonavir) with canagliflozin, the following is recommended:
- CrCl ≥ 60 ml/min: for patients taking 100 mg/day, increase to 200 mg/day. For patients taking 200 mg/day, increase to 300 mg/day.
- CrCl < 60 ml/min: for patients taking 100 mg/day, increase to 200 mg/day
- Digoxin - Canagliflozin has the potential to raise digoxin levels. Monitor levels appropriately.
- Metabolism and clearance
- Canagliflozin (Invokana®)
- UGT1A9 - substrate
- UGT2B4 - substrate
- CYP3A4 - minor substrate
- Dapagliflozin (Farxiga®)
- UGT1A9 - major substrate
- OAT3 - substrate
- P-glycoprotein - weak substrate
- Cytochrome P450 metabolism - undefined, minor pathway
- Empagliflozin (Jardiance®)
- UGT2B7, UGT1A3, UGT1A8, and UGT1A9 - substrate
- OAT3 - substrate
- OATP1B1 and OATP1B3 - substrate
- P-glycoprotein - substrate
- BCRP - substrate
- Ertugliflozin (Steglatro™)
- UGT2B7 and UGT1A9 - substrate
- UGT1A1 and UGT1A4 - weak inhibitor
- P-glycoprotein - substrate
- BCRP - substrate
- LONG TERM SAFETY
- SGLT2 inhibitors are a relatively new class of drugs. Canagliflozin, approved in March 2013, was the first SGLT2 inhibitor marketed in the U.S.
- The long-term safety of SGLT2 inhibitors is unknown, but they have been studied in a number of large trials and appear to be mostly safe and effective.
- DOSING
- BIBLIOGRAPHY
- 1 - PMID 23279307
- 2 - FDA advisory committee materials for canagliflozin
- 3 - Canagliflozin PI
- 4 - PMID 20566676 - Dapagliflozin mono trial
- 5 - PMID 20609968
- 6 - Dapagliflozin PI
- 7 - Empagliflozin PI
- 8 - PMID 26332554 - SGLT2 in the pancreas
- 9 - PMID 25600248 - Canagliflozin and uric acid
- 10 - PMID 25126408 - Dapagliflozin and uric acid
- 11 - PMID 25377916 - Empagliflozin and uric acid
- 12 - Ertugliflozin PI
- 13 - ADA Standards of Medical Care in Diabetes (2019)
- 14 - PMID 31060053 Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases, Ann Intern Med (2019)
- 15 - PMID 31931526 Assessing the Risk for Gout With Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes: A Population-Based Cohort Study, Ann Intern Med (2020)
- 16 - PMID 31081587 - What Does SGLT1 Inhibition Add: Prospects for Dual Inhibition, Diabetes Obes Metab (2019)
- 17 - PMID 29875481 - Adverse effects of SGLT2 inhibitors on bone, Nat Rev Nephrol (2018)
- 18 - Guyton, Arthur C. Guyton And Hall Textbook Of Medical Physiology. Philadelphia, PA : Saunders/Elsevier, 13 ed. (2016)