Commentary

SGLT inhibitors present promising step for type 1 diabetes

SGLT inhibitors are a group of antihyperglycemic agents commonly used by patients with type 2 diabetes given their overall favorable metabolic and cardiovascular profile. In addition to their ability to lower blood glucose without increasing the risk for hypoglycemia, they can facilitate weight loss and reduce systolic blood pressure. SGLT2 inhibitors reduce major adverse cardiovascular events among high-risk patients and heart failure hospitalization, CV death and progression of chronic kidney disease in people with diabetes.

Four SGLT2 inhibitors — empagliflozin (Jardiance, Boehringer Ingelheim), dapagliflozin (Farxiga, AstraZeneca), canagliflozin (Invokana, Janssen) and ertugliflozin (Steglatro, Merck) — are FDA-approved for use in type 2 diabetes, but none is approved as an adjunctive treatment in type 1 diabetes, mainly due to increased risk for diabetic ketoacidosis (DKA). Recently, sotagliflozin, a combined SGLT1 and SGLT2 inhibitor, was rejected by the FDA. Sotagliflozin and dapagliflozin are approved for use in type 1 and type 2 diabetes in Europe.

Mechanism of action

The SGLT1 transporter is located in the enterocyte of the small intestine and in the distal part of the proximal renal tubule. Inhibition of SGLT1 helps to reduce postprandial glucose excursion and increase glycosuria. The SGLT2 transporter, located in the proximal renal tubule, reabsorbs 90% of the glucose filtered to the kidneys. SGLT2 inhibitors work by decreasing the renal threshold for glucose reabsorption, which in turn leads to increased glycosuria and subsequent improvement in plasma glucose level.

In a small study, dapagliflozin reduced the renal threshold for glucose excretion at a plasma glucose concentration lower than fasting plasma glucose (85-108 mg/dL). The calculation used in the study showed urine glucose excretion started at 21 mg/dL in patients with diabetes; however, the actual threshold could not be determined given that the calculated threshold is lower than the lowest plasma glucose in the study. Of note, the percent inhibition of renal glucose reabsorption by dapagliflozin at a plasma glucose level of 100 mg/dL was 20% in healthy people and 27% in those with type 2 diabetes.

Mohammad El-rifai

Similar results were found for empagliflozin. In another study, empagliflozin reduced the plasma glucose concentration at which urine glucose spillage started to less than 40 mg/dL. Other researchers showed that patients with type 1 diabetes might have a lower renal threshold and, hence, more urinary glucose excretion with the use of empagliflozin.

Although most of the therapeutic effects of SGLT2 inhibitors come from the glycosuric effect, this insulin-independent mechanism is the core cause of increased DKA incidence with these medications. This glucose-lowering effect leads to hypoinsulinemia and hyperglucagonemia, which in turn increases the body’s reliance on fatty acids and ketone bodies for energy and, hence, ketosis and possibly ketoacidosis in case of significant insulin insufficiency. Of note, an increased incidence of euglycemic DKA has been observed with SGLT inhibitor use, which can result in the delay of diagnosis and management by patients and providers and increased morbidity and mortality. The FDA has issued a warning about the possibility of DKA with the use of these agents in people with diabetes.

SGLT inhibition in type 1 diabetes

Given their insulin-independent glucose-lowering effects, SGLT inhibitors are an attractive option for use as an adjunctive treatment to insulin in type 1 diabetes. Several trials have assessed their efficacy and safety in this setting. All of these trials showed significant reduction in HbA1c, weight and systolic BP without increased risk for hypoglycemia. However, all showed increased risk for DKA. These findings were universal in all trials, including DEPICT, EASE and inTandem, evaluating the use of dapagliflozin, empagliflozin and sotagliflozin, respectively, in patients with type 1 diabetes. Of note, all trials were conducted before the introduction of the hybrid closed-loop insulin system, and, hence, no data are available regarding the efficacy and safety of SGLT inhibitors with this recent technology.

The EASE 3 trial used a unique lower dose of empagliflozin — 2.5 mg daily — currently unavailable, which showed comparable incidence of DKA with placebo. In comparison with placebo, empagliflozin 2.5 mg showed minimal yet significant benefit in HbA1c reduction, weight loss, systolic BP reduction and insulin total daily dose reduction; however, these benefits were not as great compared with higher empagliflozin doses.

Remaining questions

Although there was universal benefit with SGLT inhibitor use in regard to reduction in HbA1c, systolic BP and body weight, there was also a universal increase in DKA risk. Knowing that insulin deficiency is the main cause of DKA, this risk can be mitigated by sufficient insulin replacement and stopping the medication during stressful situations, which can lead to relative insulin deficiency due to severe insulin resistance. In the meantime, finding a way to achieve the glycemic and metabolic benefits of these medications without increasing DKA risk will be of huge benefit. A well-constructed detailed DKA mitigation strategy is needed since the current trials were conducted in highly selected patients with extensive education about DKA risks and management. Therefore, additional large studies with real-world methodology are needed.

Whether the benefits of SGLT inhibitor use in type 1 diabetes outweigh the risks is a matter of personal opinion. What we know is that these trials showed increased risk despite a study population of highly selected patients with extensive education about DKA risks and management and with tools. Therefore, additional large studies with real-world methodology are needed.

An important question to be answered is the safety of SGLT inhibitors as an adjunctive treatment with a hybrid closed-loop insulin system, which might present an increased risk for DKA based on how these systems work and the pharmacodynamics of SGLT inhibitors. The reduced renal threshold for glycosuria and urinary glucose excretion with SGLT inhibitors mean that the glycosuric effect will begin at a plasma glucose level that is lower than the hybrid closed-loop systems target. Currently, the only available hybrid closed-loop system is the Medtronic 670G, which has a target blood glucose level of 120 mg/dL, and insulin delivery is adjusted by the pump to maintain this target. This mean that patients who use this technology might have longer duration with blood glucose levels below 120 mg/dL due to the effect of SGLT inhibitors with concomitant decrease or suspension of insulin delivery by the pump and subsequent hyperglucagonemia — the essential cause of DKA. Given that, the use of SGLT inhibitors in patients using the system should be avoided until further studies are conducted in this group.

Although trials showed dose-dependent glycemic and metabolic benefits of SGLT inhibitors, a promising step might be to use lower doses for patients with type 1 diabetes, doses lower than those approved for type 2 diabetes. This should decrease DKA risk by minimizing the reduction in insulin total daily dose especially in thin patients with low to low normal BMI. These doses need to be evaluated in longer and larger studies knowing that people with type 1 diabetes might have more urinary glucose excretion with SGLT2 inhibitors than people with type 2 diabetes.

Disclosure: El-rifai reports no relevant financial disclosures.

SGLT inhibitors are a group of antihyperglycemic agents commonly used by patients with type 2 diabetes given their overall favorable metabolic and cardiovascular profile. In addition to their ability to lower blood glucose without increasing the risk for hypoglycemia, they can facilitate weight loss and reduce systolic blood pressure. SGLT2 inhibitors reduce major adverse cardiovascular events among high-risk patients and heart failure hospitalization, CV death and progression of chronic kidney disease in people with diabetes.

Four SGLT2 inhibitors — empagliflozin (Jardiance, Boehringer Ingelheim), dapagliflozin (Farxiga, AstraZeneca), canagliflozin (Invokana, Janssen) and ertugliflozin (Steglatro, Merck) — are FDA-approved for use in type 2 diabetes, but none is approved as an adjunctive treatment in type 1 diabetes, mainly due to increased risk for diabetic ketoacidosis (DKA). Recently, sotagliflozin, a combined SGLT1 and SGLT2 inhibitor, was rejected by the FDA. Sotagliflozin and dapagliflozin are approved for use in type 1 and type 2 diabetes in Europe.

Mechanism of action

The SGLT1 transporter is located in the enterocyte of the small intestine and in the distal part of the proximal renal tubule. Inhibition of SGLT1 helps to reduce postprandial glucose excursion and increase glycosuria. The SGLT2 transporter, located in the proximal renal tubule, reabsorbs 90% of the glucose filtered to the kidneys. SGLT2 inhibitors work by decreasing the renal threshold for glucose reabsorption, which in turn leads to increased glycosuria and subsequent improvement in plasma glucose level.

In a small study, dapagliflozin reduced the renal threshold for glucose excretion at a plasma glucose concentration lower than fasting plasma glucose (85-108 mg/dL). The calculation used in the study showed urine glucose excretion started at 21 mg/dL in patients with diabetes; however, the actual threshold could not be determined given that the calculated threshold is lower than the lowest plasma glucose in the study. Of note, the percent inhibition of renal glucose reabsorption by dapagliflozin at a plasma glucose level of 100 mg/dL was 20% in healthy people and 27% in those with type 2 diabetes.

Mohammad El-rifai

Similar results were found for empagliflozin. In another study, empagliflozin reduced the plasma glucose concentration at which urine glucose spillage started to less than 40 mg/dL. Other researchers showed that patients with type 1 diabetes might have a lower renal threshold and, hence, more urinary glucose excretion with the use of empagliflozin.

Although most of the therapeutic effects of SGLT2 inhibitors come from the glycosuric effect, this insulin-independent mechanism is the core cause of increased DKA incidence with these medications. This glucose-lowering effect leads to hypoinsulinemia and hyperglucagonemia, which in turn increases the body’s reliance on fatty acids and ketone bodies for energy and, hence, ketosis and possibly ketoacidosis in case of significant insulin insufficiency. Of note, an increased incidence of euglycemic DKA has been observed with SGLT inhibitor use, which can result in the delay of diagnosis and management by patients and providers and increased morbidity and mortality. The FDA has issued a warning about the possibility of DKA with the use of these agents in people with diabetes.

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SGLT inhibition in type 1 diabetes

Given their insulin-independent glucose-lowering effects, SGLT inhibitors are an attractive option for use as an adjunctive treatment to insulin in type 1 diabetes. Several trials have assessed their efficacy and safety in this setting. All of these trials showed significant reduction in HbA1c, weight and systolic BP without increased risk for hypoglycemia. However, all showed increased risk for DKA. These findings were universal in all trials, including DEPICT, EASE and inTandem, evaluating the use of dapagliflozin, empagliflozin and sotagliflozin, respectively, in patients with type 1 diabetes. Of note, all trials were conducted before the introduction of the hybrid closed-loop insulin system, and, hence, no data are available regarding the efficacy and safety of SGLT inhibitors with this recent technology.

The EASE 3 trial used a unique lower dose of empagliflozin — 2.5 mg daily — currently unavailable, which showed comparable incidence of DKA with placebo. In comparison with placebo, empagliflozin 2.5 mg showed minimal yet significant benefit in HbA1c reduction, weight loss, systolic BP reduction and insulin total daily dose reduction; however, these benefits were not as great compared with higher empagliflozin doses.

Remaining questions

Although there was universal benefit with SGLT inhibitor use in regard to reduction in HbA1c, systolic BP and body weight, there was also a universal increase in DKA risk. Knowing that insulin deficiency is the main cause of DKA, this risk can be mitigated by sufficient insulin replacement and stopping the medication during stressful situations, which can lead to relative insulin deficiency due to severe insulin resistance. In the meantime, finding a way to achieve the glycemic and metabolic benefits of these medications without increasing DKA risk will be of huge benefit. A well-constructed detailed DKA mitigation strategy is needed since the current trials were conducted in highly selected patients with extensive education about DKA risks and management. Therefore, additional large studies with real-world methodology are needed.

Whether the benefits of SGLT inhibitor use in type 1 diabetes outweigh the risks is a matter of personal opinion. What we know is that these trials showed increased risk despite a study population of highly selected patients with extensive education about DKA risks and management and with tools. Therefore, additional large studies with real-world methodology are needed.

An important question to be answered is the safety of SGLT inhibitors as an adjunctive treatment with a hybrid closed-loop insulin system, which might present an increased risk for DKA based on how these systems work and the pharmacodynamics of SGLT inhibitors. The reduced renal threshold for glycosuria and urinary glucose excretion with SGLT inhibitors mean that the glycosuric effect will begin at a plasma glucose level that is lower than the hybrid closed-loop systems target. Currently, the only available hybrid closed-loop system is the Medtronic 670G, which has a target blood glucose level of 120 mg/dL, and insulin delivery is adjusted by the pump to maintain this target. This mean that patients who use this technology might have longer duration with blood glucose levels below 120 mg/dL due to the effect of SGLT inhibitors with concomitant decrease or suspension of insulin delivery by the pump and subsequent hyperglucagonemia — the essential cause of DKA. Given that, the use of SGLT inhibitors in patients using the system should be avoided until further studies are conducted in this group.

PAGE BREAK

Although trials showed dose-dependent glycemic and metabolic benefits of SGLT inhibitors, a promising step might be to use lower doses for patients with type 1 diabetes, doses lower than those approved for type 2 diabetes. This should decrease DKA risk by minimizing the reduction in insulin total daily dose especially in thin patients with low to low normal BMI. These doses need to be evaluated in longer and larger studies knowing that people with type 1 diabetes might have more urinary glucose excretion with SGLT2 inhibitors than people with type 2 diabetes.

Disclosure: El-rifai reports no relevant financial disclosures.