Skip to main content

Sodium-glucose cotransporter-2 inhibitors in type 2 diabetes


Management of type 2 diabetes

SGLT2 inhibitors in type 2 diabetes management: Key evidence and implications for clinical practice

This review provides an overview of the current concerns and misconceptions on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes and provides an overview of their place within the diabetes management pathway.

Summary points
  • Based on the evidence for SGLT2 inhibitors summarized in the review, the authors developed a benefit/risk tool that can be used as a quick reference for clinicians in routine practice.
  • SGLT2 inhibitors reduce the reabsorption of glucose in the kidney in an insulin-independent manner, thereby increasing glucose excretion via urine.
  • Three SGLT2 inhibitors are approved in the UK: canagliflozin, dapagliflozin and empagliflozin. National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommend the use of SGLT2 inhibitors for first intensification of type 2 diabetes treatment after metformin failure.
  • Guidelines also note that SGLT2 inhibitors can be administered in combination with other anti-diabetic drugs, such as insulin and glucagon-like peptide-1 receptor antagonists.
  • Randomized controlled trials and real-world evidence have shown that SGLT2 inhibitors achieve and maintain glucose levels, are associated with weight loss (reduce visceral fat), and have cardio- and renoprotective effects.
  • SGLT2 inhibitors are generally well tolerated; however, there are some patient populations that may be at increased risk of adverse events.
  • Genital infections are a common adverse event with SGLT2 inhibitors. To achieve optimum treatment benefit, education on the risk of these and practical hygiene advice at the start of treatment are recommended.
  • There is conflicting evidence for the risk of lower limb amputation and bone fractures with SGLT2 inhibitors; however, high-risk individuals should avoid SGLT2 inhibitors. Preventative footcare advice and ongoing monitoring is recommended.
  • Patients receiving SGLT2 inhibitors may experience diabetic ketoacidosis, although this is rare. Diabetic ketoacidosis monitoring should be implemented when administering SGLT2 inhibitors.
  • SGLT2 inhibitors should be discontinued immediately in patients with acute illness or planned surgical procedures, but can be resumed following full recovery.

Wilding J et al. Diabetes Ther 2018. doi: 10.1007/s13300-018-0471-8

Practical approach to initiating SGLT2 inhibitors in type 2 diabetes

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are recommended in type 2 diabetes. This review describes their actions, adverse events, and a treatment algorithm.

Summary points
  • ​​​​​​​SGLT2 inhibitors reduce plasma glucose, body weight, and blood pressure, and are recommended as second/third-line treatments for patients with type 2 diabetes.
  • In the key EMPA-REG OUTCOME TRIAL, empagliflozin had cardio- and renal protective effects in patients with type 2 diabetes.
  • Hemodynamic effects may underlie its rapid onset of action; other benefits include weight loss, improved cardiac function and metabolic effects.
  • The overall incidence of adverse events is similar to those for other antidiabetic drugs; the most common is genitourinary tract infection.
  • Risks of dehydration and postural hypotension are higher in patients also receiving diuretics or drugs with gastrointestinal adverse events.
  • Regulatory agencies have issued warnings for increased risks of ketoacidosis and lower limb amputation for SGLT2 inhibitors.
  • Patients that may benefit with SGLT2 inhibitors have younger age, unimpaired renal function, cardiovascular disease, no genitourinary infection, overweight/obese, and/or hypertension.
  • Lower doses of SGLT2 inhibitors are recommended when starting treatment.
  • In patients with glycated hemoglobin (HbA1c) <8.5%, daily insulin doses should be reduced by 20% and sulfonylureas should be reduced or stopped; in those with HbA1c >8.5%, the insulin dose should be maintained.
  • Patients with symptoms of ketoacidosis should be monitored.
  • Concomitant diuretic treatment should be monitored and reconsidered according to the clinical situation.

Gomez-Peralta F et al. Diabetes Ther 2017; 8: 953–962. doi: 10.1007/s13300-017-0277-0

SGLT2-I in the hospital setting: Diabetic ketoacidosis and other benefits and concerns

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are frequently prescribed for outpatients. This review describes potential hospital usage, and the risks of euglycemic ketoacidosis in this setting.

Summary points
  • Meta-analysis data indicated no risk of hypoglycemia unless given with insulin or an insulin secretagogue. SGLT2 inhibitors could therefore be prescribed in hospital to patients not receiving these concomitant treatments.
  • SGLT2 inhibitors tend to have synergistic effects with other blood pressure treatments.
  • The US Food and Drug Administration issued a warning for ketoacidosis during SGLT2 inhibitor use.
  • Euglycemic ketoacidosis can result if patients have decreased glucose for energy expenditure and insulin deficiency, and can be difficult to diagnose.
  • Patients admitted to hospital have risk factors for SGLT2 inhibitor-associated ketoacidosis.
  • Worsening renal function without adjusted doses of SGLT2 inhibitors could increase the risk of ketoacidosis.
  • Other risks include genitourinary infection, and postural hypotension, which may be exacerbated by reduced oral intake.

Levine JA, Karam SL, Aleppo G. Curr Diab Rep 2017; 17: 54. doi: 10.1007/s11892-017-0874-3

SGLT2 inhibitors in the management of type 2 diabetes

An overview of sodium-glucose cotransporter-2 (SGLT2) inhibitors, their potential benefits and risks, and their effects on glucose and other metabolic parameters in patients with type 2 diabetes.

Summary points
  • SGLT2 inhibitors reduce glycated hemoglobin (HbA1c) concentrations by increasing urinary excretion of glucose and have been shown to cause a mild reduction in blood pressure and body weight.
  • The most recent American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement recommends SGLT2 inhibitors as a reasonable drug option if additional glucose-lowering effect is needed beyond metformin monotherapy.
  • The most common adverse effects with their use include an increase in urine volumes and voiding frequency, and genital mycotic infections, as well as reported cases of diabetic ketoacidosis.
  • SGLT2 inhibitors (specifically empagliflozin) are the first antidiabetic drug class linked to a reduction in major cardiovascular events.
  • It remains to be determined whether SGLT2 inhibitors should be considered preferred agents after metformin monotherapy in those with established cardiovascular disease.
  • Future investigations are needed to determine whether these agents should be used as initial monotherapy (instead of the standard approach using metformin), for diabetes prevention, and even in non-diabetic patients with cardiovascular disease or heart failure.
  • Because this class of drugs reduces albumin excretion, there is also some interest in their potential to improve renal outcomes in non-diabetic individuals with chronic kidney disease.

Monica Reddy RP, Inzucchi SE. Endocrine 2016; 53: 364–372. doi: 10.1007/s12020-016-0943-4

Combination therapy with GLP-1 analogues and SGLT2 inhibitors in the management of diabesity: The real world experience

Results from this retrospective cohort study show that combination therapy of glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors is a promising option for patients with diabesity.

Summary points
  • ‘Diabesity’ is a term describing obesity that leads to the development of type 2 diabetes.
  • Many conventional antidiabetic medications (eg, sulphonylureas, thiazolidinediones, meglitinides and insulin) are associated with considerable weight gain and are thus less suitable for overweight and obese patients.
  • GLP-1 agonists and SGLT2 inhibitors may be preferable in these patients because of their association with weight loss.
  • A small retrospective patient cohort study (n=37) demonstrated statistically significant reductions in glycated hemoglobin (HbA1c), body weight, body mass index, and total daily insulin requirements in patients with type 2 diabetes receiving combination treatment with a GLP-1 agonist and a SGLT2 inhibitor.
  • Combination therapy with GLP-1 and SGLT2 inhibitors is a promising option for patients with diabesity but randomised double-blind controlled trials are needed.

Deol H et al. Endocrine 2017; 55: 173–178. doi: 10.1007/s12020-016-1125-0

Contents