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

Body weight effects

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



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.
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 Placebo Comparisons
Primary outcome (%/year) 2.7 3.15 HR 0.86 95%CI [0.75 – 0.97]
Overall mortality (%/year) 1.73 1.95 HR 0.87, 95%CI [0.74 - 1.01]
Death from cardiovascular causes (%/year) 1.16 1.28 HR 0.87, 95%CI [0.72 - 1.06]
Nonfatal heart attack (%/year) 0.97 1.16 HR 0.85, 95%CI [0.69 - 1.05]
Nonfatal stroke (%/year) 0.71 0.84 HR 0.90, 95%CI [0.71 - 1.15]
Hospitalization for heart failure (%/year) 0.55 0.87 HR 0.67, 95%CI [0.52 - 0.87]
Amputations (%/year) 0.63 0.34 p<0.001
Male genital infections (%/year) 3.49 1.08 p<0.001
Female mycotic infections (%/year) 6.88 1.75 p<0.001
Diabetic ketoacidosis (%/year) 0.06 0.03 p=0.14
All fractures (%/year) 1.54 1.19 p=0.02
Hyperkalemia (%/year) 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 Placebo Comparisons
Primary outcome (%/year) 4.32 6.12 p=0.00001
Overall mortality (%/year) 2.9 3.5 HR 0.83, 95%CI [0.68 - 1.02]
Doubling of serum creatinine (%/year) 2.07 3.38 p<0.001
Dialysis or kidney transplant (%/year) 1.33 1.77 HR 0.74, 95%CI [0.55 - 1.00]
Amputations (%/year) 1.23 1.12 HR 1.11 95%CI [0.79 - 1.56]
Diabetic ketoacidosis (%/year) 0.22 0.02 HR 10.80 95%CI [1.39 - 83.65]
Fracture (%/year) 1.18 1.21 HR 0.98 95%CI [0.70 - 1.37]
Hyperkalemia (%/year) 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
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 rare, but it did occur more frequently in canagliflozin-treated patients



Overview
  • The DECLARE-TIMI 58 trial detailed below looked at the effects of dapagliflozin on both CVD and renal outcomes
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 (CV death or hospitalization for heart failure) 4.9% 5.8% HR 0.83, 95%CI [0.73 to 0.95], p=0.005
Primary outcome (MACE) 8.8% 9.4% HR 0.93, 95%CI [0.84 - 1.03], p=0.17
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]
Composite of ≥40% decrease in GFR to < 60 ml/min, ESRD, or death from renal cause 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.
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



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.
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
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





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
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
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






Hypersensitivity reactions

Yeast infections
Overview
  • 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

  • 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%

Urinary tract infections (UTI)
Overview
  • SGLT2 inhibitors appear to cause a small, but significant increase in the risk for UTIs
  • The incidence of UTIs for each drug in placebo-controlled trials is detailed in the table below

  • 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%

Diuresis effects (fluid loss)
Overview
  • SGLT2 inhibitors increase the amount of glucose in the urine which in turn increases the volume of urine through a process called osmotic diuresis
  • Increases in urine volume lead to systemic fluid loss which can lead to symptoms of dehydration
  • In trials, the incidence of these side effects was generally low (< 5%). Older patients, patients with kidney disease, and patients taking loop diuretics may be at greater risk.
  • The table below details the incidences of increased urination and symptoms associated with hypovolemia that were seen in placebo-controlled trials with SGLT2 inhibitors

  • 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%

Low blood sugar (hypoglycemia)

Decreased kidney function

Bone effects
Canagliflozin
  • In rats, canagliflozin was associated with carbohydrate malabsorption and calcium hyperabsorption which led to abnormal bone formation
  • These effects are related to inhibition of SGLT1 by canagliflozin
  • In humans, canagliflozin is considered a weak inhibitor of SGLT1 (see mechanism above)
  • 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, no increased risk of fractures was seen with dapagliflozin when compared to placebo
Empagliflozin
  • The empagliflozin PI does not mention bone effects [7]
  • In the EMPA-REG OUTCOME study, the risk of fracture was similar between empagliflozin and placebo (3.8% vs 3.9% respectively)
Ertugliflozin
  • The ertugliflozin PI does not mention bone effects [12]
Summary
  • In studies, the effects of SGLT2 inhibitors on bone health have been mixed
  • Canagliflozin has the most negative data and probably should be avoided in patients who are at increased risk for fractures (e.g. osteoporosis, osteopenia)

Diabetic ketoacidosis (DKA)
Overview
  • Diabetic Ketoacidosis (DKA) is a metabolic syndrome typically seen in type 1 diabetics. It occurs when the body resorts to metabolizing fatty acids as an energy source as opposed to carbohydrates. Fatty acid metabolism causes acidic byproducts to build up that can lead to acidosis. DKA can be life-threatening if untreated.
  • In May 2015, the FDA issued a drug safety warning stating that there had been 20 cases of diabetic ketoacidosis (DKA) reported in the FDA Adverse Event Reporting System between March 2013 to June 6, 2014 in patients taking SGLT2 inhibitors.
  • In Dec 2015, the FDA issued an update stating that 73 cases of DKA had been identified in the Adverse Event Reporting System from March 2013 to May 2015 in patients taking SGLT2 inhibitors.
Important information about the cases:
  • A temporal association with SGLT2 inhibitor initiation was noted in all cases
  • The median time to onset of symptoms following initiation of SGLT2 therapy was 2 weeks (range 1 to 175 days)
  • DKA case presentations were atypical in that glucose levels were only mildly elevated at less than 200 mg/dL in some reports
  • Potential DKA-triggering factors - acute illness; trauma; reduced caloric or fluid intake; reduced insulin dose
  • Potential contributing patient factors - hypovolemia; acute renal impairment; hypoxemia; reduced oral intake; history of alcohol use
  • Half of cases had no identifiable triggering factor
Efficacy trials
  • In the efficacy trials detailed above, the overall risk of DKA in all trials was low (< 1%/year). DKA occurred significantly more in SGLT2-treated patients in the CREDENCE study and the DECLARE-TIMI 58 study
STUDY
Diabetic Ketoacidosis with Canagliflozin in Patients With Type 1 Diabetes, Diabetes Care (2016) [PubMed abstract]
  • 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.
STUDY
Risk of Diabetic Ketoacidosis in New Users of SGLT2 Inhibitors, BMJ (2018) [PubMed abstract]
  • 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
Summary
  • By some unknown mechanism, SGLT2 inhibitors appear to increase the risk of DKA in type two diabetics. The overall risk is very low.
  • Providers should be aware of the possibility of DKA in patients taking SGLT2 inhibitors, particularly those with the triggering factors mentioned above

Bladder cancer (dapagliflozin)

Lower extremity amputations
Canagliflozin (Invokana®)
  • In 2017, the FDA issued a drug safety communication stating that they had determined that canagliflozin increases the risk of leg and foot amputations
  • Based on their findings, the FDA decided to put a Boxed Warning on canagliflozin about the potential risk of amputations
  • The warning was based on information from two trials, CANVAS and CANVAS-R. 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 placebo group, 0.2% of patients in the ertugliflozin 5 mg group, 0.5% of patients in the ertugliflozin 15 mg group [12]
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 package insert and the EMPA-REG OUTCOME study do not mention amputations
STUDY
Risk of Amputations in New Users of SGLT2 Inhibitors, BMJ (2018) [PubMed abstract]
  • 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
  • There is some evidence that SGLT2 inhibitors increase the risk of amputations. The overall risk is very low.

Necrotizing fasciitis (Fournier's gangrene)



Lab effects
All SGLT2 inhibitors
  • Urine glucose
    • SGLT2 inhibitors increase urine glucose levels through their mechanism of action
    • Urine glucose tests should not be used to monitor diabetes activity in patients taking SGLT2 inhibitors
  • Uric acid
  • 1,5-anhydroglucitol (1,5AG)
    • 1,5 anhydroglucitol is a monosaccharide that is excreted into the urine. 1,5AG can be used as a measure of postprandial blood sugars.
    • SGLT2 inhibitors make 1,5AG measurements unreliable, and alternative methods of measuring glycemic control should be used. [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]






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®)
  • GFR ≥ 45 ml/min: no dose adjustment necessary
  • GFR < 45 ml/min: DO NOT USE [6]
Empagliflozin (Jardiance®)
  • GFR ≥ 45 ml/min: no dose adjustment necessary
  • GFR < 45 ml/min: - DO NOT USE [7]
Ertugliflozin (Steglatro™)
  • GFR 30 to < 60 ml/min: do not initiate therapy. If GFR is persistently in this range, discontinue use.
  • GFR < 30 ml/min: DO NOT USE [12]

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

High potassium (canagliflozin)

Dehydration

Bladder cancer


SGLT2 inhibitor drug interactions

All SGLT2 inhibitors

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)
  • UGT enzyme inducers
    • UGT is an enzyme involved in drug metabolism
    • UGT is the primary means by which canagliflozin is metabolized
    • Drugs that induce UGT may decrease blood levels of canagliflozin
    • The manufacturer recommends using the 300 mg dose when canagliflozin is taken with a UGT inducer
  • Digoxin - Canagliflozin has the potential to raise digoxin levels. Monitor levels appropriately.