SGLT2 INHIBITORS


















  • All values are expressed as average change from baseline. FBS (fasting blood sugar) expressed as mg/dl.
  • Baseline A1C ∼ 8% in all studies
  • Reference [3,6,7,12]
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







CANVAS Studies - Canagliflozin vs Placebo for CVD Outcomes in Type 2 Diabetes - NEJM (2017) [PubMed abstract]
  • 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
  • The average A1C in the canagliflozin group was 0.58% lower than the placebo group
  • Differences in body weight (1.6 kg), systolic blood pressure (3.93 mmHg), and diastolic blood pressure (1.39 mmHg) were all significantly lower in the canagliflozin group

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.
CREDENCE Study - Canagliflozin vs Placebo for Renal Outcomes in Type 2 Diabetes - NEJM (2017) [PubMed abstract]
  • 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]
  • The average A1C in the canagliflozin group over the course of the study was 0.25% lower than the placebo group
  • Differences in body weight (0.80 kg), systolic blood pressure (3.30 mmHg), and diastolic blood pressure (0.95 mmHg) were all significantly lower in the canagliflozin group

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





DECLARE-TIMI 58 Study - Dapagliflozin vs Placebo for CVD Outcomes in Type 2 Diabetes, NEJM (2018) [PubMed abstract]
  • 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
  • The average A1C level in the dapagliflozin group was lower by 0.42% during the course of the trial. Dapagliflozin-treated patients also had more weight loss on average (4 lbs) and a greater reduction in SBP (2.7 mmHg).

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.





EMPA-REG OUTCOME Study - Empagliflozin vs Placebo for CVD Outcomes in Type 2 Diabetics , NEJM (2015) [PubMed abstract]
  • 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
  • From Week 12 on, patients in the empagliflozin groups had significantly lower weight (around 2 kg) and SBP (around 4 mmHg) than patients in the placebo group
  • Throughout the entire trial, the empagliflozin groups had lower A1C levels than the placebo group. At 12 weeks, the 10 and 25 mg empagliflozin groups were 0.54% and 0.60% lower, respectively. At week 206, they were 0.24% and 0.36% lower, respectively.

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.
EMPA-REG OUTCOME Study - Secondary Analysis of Renal Outcomes, NEJM (2016) [PubMed abstract]
  • 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








DEPICT-1 Study - Dapagliflozin vs Placebo in Type One Diabetes, Lancet Diabetes Endocrinol (2017) [PubMed abstract]
  • 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





DAPA-HF trial - Dapagliflozin vs Placebo for Heart Failure with Reduced Ejection Fraction [PubMed abstract]
  • 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
  • Dapagliflozin was just as effective in patients without type 2 diabetes (55%) as it was in those with diabetes. A secondary analysis that looked at outcomes based on baseline diabetes status and HgA1C values less than or greater than 5.7% came to similar conclusions. [PMID 32219386]
  • At 8 months, the average NT-proBNP had decreased by 196 pg/ml in the dapagliflozin group and increased by 101 pg/ml in the placebo group
  • At 8 months, the average SBP had decreased by 1.92 mmHg in the dapagliflozin group and by 0.38 in the placebo group (p=0.002)
  • At 8 months, the average weight had decreased by 0.88 kg in the dapagliflozin group and increased by 0.10 kg in the placebo group (p<0.001)

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.









  • Reference: Manufacturer's package insert
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%


  • Reference: Manufacturer's package insert
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%


  • Symptoms of volume depletion include hypotension, lightheadedness, dehydration, etc.
  • Reference: Manufacturer's package insert
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%