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Drug Review - SGLT2 Inhibitors

Drug review - SGLT2 Inhibitors

Mode of action

Efficacy

Microvascular outcomes

Cardiovascular and mortality outcomes

Hypoglycaemia

Non-glycaemic benefits

Adverse events and precautions

Prescribing information

None of the SGLT2 inhibitors have been registered in South Africa at the time of this publication. The names under which these products will be available in South Africa, if at all, as well as the cost and prescribing limitations, is not known. One or more agents from this class of drug is likely to become available before the next guidelines update. SEMDSA has therefore decided to include the guidelines regarding its use. The prescriber is always referred to the product registration label for accurate information before prescribing any drug.

These drugs inhibit the sodium-glucose linked transporter 2 (SGLT2), and the first agent to be approved was dapagliflozin (2011 in Europe). They do not cause hypoglycaemia, are associated with weight loss and empagliflozin has been associated with reduced cardiovascular mortality in selected patients.

MODE OF ACTION1,2 

GLT2 in the proximal convoluted tubule is normally responsible for reabsorbing ~90% of the ~180 g of glucose filtered by the kidney each day. This renal glucose reabsorption is increased by 20-40% in type 2 diabetes and contributes to hyperglycaemia. Pharmacological inhibition of SGLT2 inhibits the reabsorption of 30-50% of filtered glucose, resulting in glycosuria of approximately 50-80 g/day. This glucosuric effect helps to ameliorate hyperglycaemia. The increased urinary glucose excretion also results in an ensuing osmotic diuresis (leading to blood pressure and volume reduction) as well as calorie losses of 200 to 300 kcal/day (leading to weight loss). This insulin-independent mode of action is independent of insulin secretion, insulin resistance, stage of disease, race and ethnicity, is associated with low rates of hypoglycaemia and is effective in combination with all other glucose lowering therapies.

EFFICACY 

Monotherapy
When used as monotherapy in type 2 diabetes, mean placebo adjusted c reductions of 0.6 to 1.2% have been noted.1,2,3,4,5 A meta- analysis of 45 monotherapy studies involving 11 232 subjects showed a mean placebo adjusted difference of -0.7% in HbA1C.6 Canagliflozin 300 mg appears to have the greatest efficacy.7

Add-on therapy

Add-on to metformin monotherapy8,9,10,11,12,13: 0.5 -1% mean HbA1C reduction.
Add-on to sulphonylurea monotherapy14-0.7% mean HbA1C reduction
Add-on to metformin and sulphonylurea15,16,17: -0.7 – 0.9%
Add-on to insulin18,19,20,21: ~ -0.5 to 0.8%

Efficacy in Renal Impairment
The glycaemic efficacy of SGLT2 inhibitors is attenuated in patients with diminished eGFR resulting in modest HbA1C reductions of 0.3 to 0.6%.22,23,24 This is presumably because glucose filtration is diminished, and there may be co-existent tubular dysfunction.

Patients with high baseline HbA1c
In a pre-specified pooled analysis of three phase 3 studies, treatment with open-label empagliflozin 25 mg in patients with severe hyperglycaemia (N=184, mean baseline HbA1c 11.15%) resulted in a 3.27% HbA1C reduction at week 24; no placebo was included in these studies.25

MICROVASCULAR OUTCOMES 

There have been no microvascular outcome studies with SGLT2 inhibitors.

CARDIOVASCULAR AND MORTALITY OUTCOMES 

Drug review - GLP-1 receptor agonists, discusses cardiovascular outcome trials (CVOT) mandated by the US FDA.26 In line with current regulations all three manufacturers of SGLT2 inhibitors have embarked on CVOTs.26,27,28 The EMPA-REG OUTCOME study has been completed, and evaluated cardiovascular safety of empagliflozin (versus placebo) in type 2 diabetes patients with established cardiovascular disease. There was ~-0.3% HbA1C difference between the active and placebo arms. There was a statistically significant 14% relative risk reduction for the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke in the empagliflozin treated participants after 3.1 years.27 

This was driven mainly by a 38% relative risk reduction in death from cardiovascular causes with no differences in the rates of myocardial infarction or stroke. Analysis of secondary endpoints showed a 35% reduction in hospitalisation for heart failure, and a non-significant increase in stroke and silent myocardial infarction. There was no difference in outcomes between the 10 and 25 mg doses of empagliflozin. The benefits noted occurred early during the course of the study (within three months) and was sustained thereafter, implying that the results were not driven by an effect on atherosclerosis.
The conclusion from this data is that empagliflozin treatment in type 2 diabetes patients with established cardiovascular disease reduces cardiovascular and all cause mortality.The number of patients that would need to be treated to prevent one death was calculated to be 39.

HYPOGLYCAEMIA

SGLT2 inhibitors have an insulin-independent mode of action and hypoglycaemia is comparable to placebo except when combined with sulphonylureas or insulin therapy.1,2,6

NON-GLYCAEMIC BENEFITS 

Weight loss

Glucosuria and caloric loss results in a mean weight loss of 1.6 kg to 2.5 kg for different drugs in the class.7 Weight loss is not dose dependent, is comparable to the weight loss with GLP-1 receptor agonists,29 and has been durable for two to four years. 11,30

Blood Pressure

Systematic reviews demonstrate that SGLT2 inhibitors significantly and  consistently  reduce  systolic  blood  pressure  by about 4.0 mmHg, and diastolic blood pressure by  about  mean -1.6 mmHg from baseline.31,32 This is presumably due to glucosuria and the ensuing osmotic diuresis. The incidence of orthostatic hypotension was not statistically increased in one systematic review,31 but was in another.6 It may be clinically relevant in certain situations (dehydration, elderly, concomitant loop-diuretic use).

Diabetic kidney disease (DKD)22,23,24,25,26,27,33

SGLT2 inhibitors improve glycaemia and lowers blood pressure. In addition they may attenuate glomerular hyperfiltration independent of blood glucose lowering.33Reduction in microalbuminuria has been noted consistently in all studies with SGLT2 inhibitors in DKD.

ADVERSE EVENTS AND PRECAUTIONS

Common

Mycotic genital infections
Fungal vulvovaginitis and balanoposthitis (infection of the penile glans and foreskin) are the commonest adverse effect of SGLT2 inhibitors. When compared to placebo patients receiving SGLT2 inhibitors, they are four to six times more likely to develop mycotic infections.7 Women are twice as likely to be affected.6,32 These infections apparently respond to over-the- counter antifungal creams or fluconazole 150 mg repeated 48 hours later.32 SGLT2 inhibitors should be avoided in patients with a history of recurrent yeast infections.

Urinary tract infections (UTI’s)

Reports of higher rates of UTI have not been consistent across studies. A recent meta-analysis reported a higher risk of UTI for dapagliflozin but not empagliflozin.7 The UTI’s typically respond to standard antibiotics.
Pyelonephritis and urosepsis (UTI complicated by septicaemia) is rare in clinical trials with SGLT2 inhibitors. However the FDA has drawn attention to 19 post-marketing reports of urosepsis or pyelonephritis.34 The true incidence of this complication is not known because the FDA has not released comparable figures for patients not taking SGLT2 inhibitor. It is prudent not to prescribe SGLT2 inhibitors to patients with a history of recurrent UTI.

Diuretic effects6,32

Polyuria (large urine volume) or pollakiuria (frequent small voids) is common. The pattern of eGFR change with SGLT2 inhibitors has been consistent – an initial decline in GFR (approximately 10%) within the first weeks of therapy (presumably due to diuretic effect and hypovolaemia) - followed by gradual return toward (and sometimes above) baseline over the ensuing weeks to months. This compares favourably to placebo where there is usually a gradual but persistent decline in eGFR. Any sustained reduction in eGFR is fully reversed within three weeks of SGLT2 inhibitor cessation.

Rare but serious

Euglycaemic diabetic ketoacidosis (euDKA)35

The incidence of DKA in clinical trial programs involving SGLT2 inhibitors has been estimated to be about 0.1%. There have been rare post-marketing reports from both the US FDA and the European Medicines Agency of cases of DKA associated with SGLT2 inhibitor use.35 Unlike conventional DKA that is associated with marked hyperglycaemia, the cases with SGLT2 inhibitors typically have blood glucose values below 14.0 mmol/L. This may delay detection, diagnosis and management. Insulin treated patients receiving SGLT2 inhibitors should be warned of the symptoms  of DKA and advised to test their urine for ketones whenever these symptoms occur, irrespective of the blood glucose measurement.

Dehydration, hypotension6,32

Dehydration is uncommon and may rarely result in acute renal injury.
Hypotension or postural hypotension is also infrequent but may necessitate reduction in anti-hypertensive doses.
It is may be wise to avoid concurrent SGLT2 inhibitor use with loop diuretics.

Malignancy

A numerical imbalance in the number of cases of bladder cancer (0.17% vs 0.03%) has been noted in pooled clinical studies with dapagliflozin. The European Medicines Agency considered the evidence and concluded that a causal relationship was unlikely. Nevertheless dapagliflozin should not be used in patients with a history of bladder cancer, or in combination with pioglitazone, until clarity from the longer- term safety trial with dapagliflozin is published.26

Bone fractures

Canagliflozin has been associated with a non-significant increase in the risk of bone fractures in pooled analyses. A prospective study demonstrating a significant reduction in bone mineral density at the hip and lumbar spine in elderly subjects (in part due to weight loss) has led to stronger warning about the potential fracture risk.36,37

Acute renal injury

Clinical trials with SGLT2 inhibitors have not demonstrated an increased risk of acute renal injury. However pooled data from regulatory authorities highlight the potential for acute renal injury in patients who become dehydrated or experience hypotension. This is more likely to occur in elderly patients (age >65 years), in patients taking diuretics and in those with stage 2 or 3 chronic kidney disease (eGFR 30 to 60 ml/min).25,38,39,40 Acute renal injury is usually reversible with drug cessation and volume correction.

Stroke

There has been a numerical imbalance (not statistically significant) in the number of patients suffering strokes in the EMPA REG OUTCOMES trial as well as pooled analysis of canagliflozin trials.27,40 This is incongruous with blood pressure lowering data, and its relationship to dehydration and raised haematocrit deserves further study. SGLT2 inhibitors should not be used in patients at high risk for stroke (uncontrolled blood pressure, significant carotid stenosis, previous history of transient ischaemic attack or stroke).

Lower limb/toe amputations

The CANVAS and CANVAS-R studies have reported a higher rate of lower limb amputations, especially of the toe (8/1000 vs. 4/100 for placebo). The European Medicines agency has added this an adverse event for canagliflozin, and has added a warning on the label for the other two members of the class.41

PRESCRIBING INFORMATION 

Each drug has two (2) strengths that have been registered in other countries:

Canagliflozin (Invokana®) 100 mg and 300 mg tablets

Dapagliflozin (Forxiga®) 5 mg and 10 mg tablets 

Empagliflozin (Jardiance®) 10 mg and 25 mg tablets

Dosing
Start with lower dose and increase after three months if metabolic control is not achieved.

Renal dose adjustments
The efficacy of SGLT2 inhibitors is dependent on adequate glomerular filtration. Urinary glucose excretion is about 50% lower in patients with CKD stage 3 (eGFR 30-60 ml/min) treated with SGLT2 inhibitors when compared with those with CKD stage 1 or 2 (eGFR >60 ml/min).42 The glucose lowering efficacy of these agents in patients with CKD is therefore expected to be attenuated.

Dapagliflozin:
No dose adjustment when eGFR >60 ml/min.
Has been studied in CKD stage 3 (eGFR 30-60 ml/min) but failed to demonstrate glycaemic superiority compared to placebo.24 Dapagliflozin should therefore not be used when the eGFR is <60 ml/min.

Empagliflozin:
No dose adjustment is necessary when eGFR >60 ml/min.
Only the higher 25mg dose has been studied in patients with an eGFR <60 ml/min24
Contraindicated when eGFR is <45 ml/min.

Canagliflozin:
No dose adjustment when eGFR is >60 ml/min.
Reduce the dose to 100mg if the patient is already using the drug and the eGFR decreases to 45-59 ml/min, but do not initiate therapy.
Contraindicated when eGFR is <45ml/mi.

Recommendations

Caveats: Neither the cost nor the exact registered indications for this class are known; these are general recommendations that may change depending on the product registration with the Medicines Control Council of South Africa.

  1. Monotherapy when metformin is not tolerated or contraindicated: SGLT2 inhibitors have not been compared directly against metformin in drug naive patients (they have been studied against placebo). The side-effect profile and need for careful patient selection is a limitation on its use in the primary health care setting. SGLT2 inhibitors are therefore not recommended as monotherapy for type 2 diabetes.
  2. Dual therapy as add-on to metformin or other 1st line drugs: SGLT2 inhibitors may be considered for dual therapy in selected patients, based on its glycaemic efficacy, negligible risk of hypoglycaemia and positive effect on weight loss.
  3. Triple therapy as add-on to any other 2 oral glucose lowering drugs: SGLT2 inhibitors may be considered for tripletherapyin selected patients, based on its glycaemic efficacy, negligible risk of hypoglycaemia and positive effect on weight loss.
  4. Add on to insulin: the addition of SGLT2 inhibitors to insulin is not recommended at primary health care level.
  5. Established cardiovascular disease: these patients should not be managed at primary health care level. The decision to use SGLT2 inhibitors in this situation should be made by a specialist (physician, cardiologist, endocrinologist).

Author: Aslam Amod
Editors: Zaheer Bayat, Ankia Coetzee, Nazeer A Mohamed, Joel ADave, Tanya Kinvig and Fraser J Pirie

References and Bibliography

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Drugs mentioned

NeoHealth® ID 17149 · updated 10/26/2021