SGLT2 inhibitors are being commonly used in the management of diabetes mellitus type 2. Apart from its modest effects on blood glucose, physicians prefer using these agents for other concomitant compelling indications. However, European diabetic experts have started using them in patients with diabetes mellitus type 1, while the FDA has rejected dapagliflozin (Forxiga, AstraZeneca), empagliflozin, and the combined SGLT2 and SGLT1 inhibitor - Sotagliflozin (Zynquista, Sanofi/Lexicon) in patients with Diabetes mellitus type 1. Till now, the European Union has approved dapagliflozin and sotagliflozin as an adjunct to insulin in the management of type 1 diabetes mellitus.

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What are the PROS and CONS of using SGLT2 inhibitors?

Although, the benefits of SGLT2 inhibitors, apart from their glycemic effects, are numerous.

Some of the benefits are enumerated here:

• Less hypoglycemia:

  • SGLT2 inhibitors have no effect on the pancreatic beta cells, insulin production, or insulin sensitivity.
  • Therefore, and since their action is glucose-dependent, they cause less hypoglycemia.
  • When the glucose load is less, they are less functional as less of the glucose will be filtered.

• SGLT2 inhibitors cause weight loss:

  • Since SGLT2 inhibitors prevent the glucose from getting reabsorbed into the blood, less of it is available for utilization.
  • The theoretical and observed weight loss in studies has been estimated as 13 kgs and 2.4 kgs respectively.

• Reduction in the blood pressure:

  • SGLT2 inhibitors lower the blood pressure by the process of osmotic diuresis.
  • When more glucose leaves the kidneys, more water goes with it.
  • This causes a reduction in the circulating blood volume resulting in a hypotensive effect.
  • Edematous hypertensive patients especially benefit from the use of these drugs via their diuretic effect.

• Cardiovascular benefits:

  • SGLT2 inhibitors have been shown to reduce the rates of hospitalization due to heart failure by 30 – 40 %.
  • Most of the beneficial effects are thought to be related to the diuretic effects of these drugs, however, other mechanisms must be playing some role.
  • Most authorities think that the cardiovascular effects are secondary to the shift of energy-efficient metabolism (from utilizing carbohydrates to fats).

• Renal protective effects:

  • SGLT2 inhibitors have been shown to reduce the progression of diabetic kidney disease by 30%.
  • This was shown in the CREDENCE trial which included patients with an eGFR of more than 30 ml/min and an ACR of more than 300 mg/gm despite treatment with an ACE inhibitor or ARB.

What are the CONS of SGLT2 inhibitors?

• Increased risk of infection:

  • SGLT2 inhibitors may increase the risk of genital mycotic infections like vulvovaginal mycotic infection, vulvovaginitis, vulvovaginal candidiasis, candida balanitis, and balanoposthitis.
  • Uncircumcised males and patients with a history of genital infections are at greater risk.
  • Their use has also been associated with the life-threatening infection - Necrotizing Fasciitis.

• Acute kidney injury:

  • Since, SGLT2 inhibitors cause volume depletion, patients with an unstable renal profile are at risk of acute kidney injury.
  • High-risk patients include heart failure, dehydration, patients on nephrotoxic agents, patients on diuretics, and those with very high blood sugars.

• Bone fractures:

  • SGLT2 inhibitors, canagliflozin, in particular, has been associated with the risk of bone fractures.
  • Patients who may be at high risk include moderate renal impairment, patients on glucocorticoids or other drugs that may cause osteopenia and osteoporosis.

• Diabetic Ketoacidosis:

  • SGLT2 inhibitors may cause euglycemic ketoacidosis.
  • The following groups of patients are at a high risk of developing euglycemic ketoacidosis:
    • patients who are insulin deficient
    • patients who discontinue insulin
    • alcoholics
    • strenuous activity or heavy exercise
    • Recent stroke, myocardial infarction, surgery, severe infection
    • Caloric restriction

• Miscellaneous effects:

  • SGLT2 inhibitors may cause hypotension, dyslipidemias, are associated with the risk of bladder cancers, and hypersensitivity reactions.

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Why the FDA rejected the use of SGLT2 inhibitors in patients with Type 1 Diabetes Mellitus?

The debate was put forth in front of the panelists after a few small scale studies and the frequent off-label use of SGLT2 inhibitors in patients with type 1 diabetes mellitus. The EASE 2 and EASE 3 trials were conducted to evaluate the safety and efficacy of empagliflozin at a dose of 10 mg, 25-mg, and 2.5 mg as an adjunct to insulin in patients with type 1 diabetes mellitus. The doses of empagliflozin were 10 and 25 mg in the EASE 2 trial while 2.5 mg was used in the EASE 3 trial.

The results of the empagliflozin intervention compared to placebo, were as follows:

• Reduction in HbA1c with 2.5/ 10/ 25 mg: -0.28%/ -0.54%/ -0.53% (all P < 0.0001) respectively

• Reduction in the mean weight with 2.5/ 10/ 25 mg: -1.8/ -3.0/ -3.4 kg (all P < 0.0001) respectively

• Reduction in total daily insulin dose with 2.5/ 10/ 25 mg: -6.4/-13.3/-12.7% (all P < 0.0001) respectively

• Reduction in the systolic blood pressure with 2.5/ 10/ 25 mg: -2.1/ -3.9/ -3.7 mmHg (all P < 0.05) respectively.

• Diabetic ketoacidosis occurred more frequently with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable to placebo when the dose was reduced to 2.5 mg (0.8%) and placebo (1.2%).

• In addition, the risks of genital infections were more frequent in the empagliflozin group, however, hypoglycemia in both the groups was comparable.

Based on the above data, the panelists and experts concluded:

• The data regarding the use of empagliflozin in T1DM is limited

• Most of them were nervous and not confident enough because of the risks of diabetic ketoacidosis

• The risks of postmarketing DKA might be much higher than what was seen in the study according to the experts.

• Most experts argued that the reduction in HbA1C was minimal especially at a dose of 2.5 mg of empagliflozin.

• The 1.8 kgs reduction in body weight and 2.1 mmHg reduction in the blood pressure was also considered as insignificant by most experts.

• Further large scale studies were recommended before the drug is approved by the FDA.

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Contrary to the FDA, the European Union has approved Dapagliflozin in the treatment of patients with T1DM as an adjunct to Insulin.

The European Union has approved dapagliflozin in T1DM.

Do all T1DM patients benefit from SGLT2 inhibitors?

The answer is clearly "NO". The European Union has categorized a subgroup of T1DM patients who may benefit from the use of Dapagliflozin. These include:

• An inadequate glycemic control despite optimal insulin therapy

• Obese type 1 Diabetic patients with a BMI (Body mass index) of 27 kg/m² or more

• Insulin requirement of the patient exceeds 0.5 units/kg of body weight

• Patients have undergone a structured education program that encompasses the following important points:

  1. Risk factors, signs and symptoms, and when to suspect diabetic ketoacidosis.

  2. How and when to monitor blood ketone levels

  3. What to do if the ketone levels are high

Furthermore, the HbA1C should be checked at 3 - 6 months. If the reduction in HbA1C is less than 0.3%, the use of SGLT2 inhibitors should be discontinued.

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The Final Words:

Although the data is currently limited regarding the use of SGLT2 inhibitors in T1DM patients, the risks of life-threatening diabetic ketoacidosis exist. Because of the prevailing uncontrolled blood sugars in T1DM, some may argue "we are already taking the risk", I still believe we should not be using it in our population for the following reasons:

• Patients with type 1 diabetes mellitus, in contrast to patients with insulin-dependent type 2 diabetes mellitus, require very small amounts of insulin. We should focus on adjusting the dose of insulin rather than adding another drug.

• Adding another drug may put the patient at risk of all the adverse effects of SGLT2 inhibitors and increase the cost of treatment.

• The addition of SGLT2 inhibitors might result in non-compliance to insulin leading to more frequent episodes of diabetic ketoacidosis.

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What is your opinion? 

Should we be following the advice of the European Union or the FDA?