SGLT2 inhibitors

SGLT-2 inhibitors (SGLT2i) were developed as novel oral antidiabetic agents for the treatment of type 2 diabetes mellitus (type 2 DM) and were first approved by the EMA in the European Union in 2012 (DAZ online 2012) and for the first time in the USA in 2013. They are based on a new mode of action that enables blood glucose control independently of the insulin effect, thus opening up a new therapeutic approach in diabetes therapy.

SGLT2i are also the first modern oral antidiabetics with proven efficacy for cardiovascular risk reduction in patients with type 2 DM (Zinman B et al. 2015). A result that until then could not be clearly demonstrated even with strict blood glucose control (HbA1c ≤6%) with other antidiabetic drugs (Duckworth et. al. 2009, The ACCORD Study Group 2008, The ACCORD Study Group 2016). Due to the additional beneficial effects on progression, prognosis, hospitalization rate and quality of life in chronic heart and kidney disease in several landmark clinical trials, the scope of application of these substances has since been greatly expanded beyond diabetes treatment and now also extends to the treatment of cardiovascular and renal diseases even without the presence of type 2 DM (cardiorenal syndrome, chronic renal failure CKD and all forms of heart failure HF regardless of ejection fraction).

And even beyond this, there are currently potential new beneficial effects as a component for treatment options, e.g. for obesity (van Ruiten CC et al. 2022), metabolic syndrome, treatment of non-alcoholic metabolic fatty liver (NASH) and metabolic-associated steatohepatitis (MASH).

The subject of research is the significance of SGLT-2 inhibitors for the prevention and treatment of neurovascular and neurodegenerative diseases (Pawlos A et al. 2021) such as:

• Stroke (Tsai W-H et. al. 2021, Chang S-N et. al. 2023)
• Parkinson's disease (Kim HK et.al. 2024)
• Cognitive dysfunction (Rizzo MR et. al. 2022, Shourav MI et.al. 2024)
• Dementia (Srijanth V et.al. 2020, Esterline R et. al. 2020).

The strong correlation between type 2 DM and the risk of developing these diseases as well as the suspected pleiotropic effects of SGLT2i suggest a possible efficacy. Further areas of application could arise for this substance class in the future, particularly in the field of neurology.

SGLT2i are based on a new mode of action that differs fundamentally from insulin and other oral antidiabetics. SGLT2i are based on the selective reversible inhibition of the sodium-dependent glucose transporter SGLT-2 (sodium-glucose co-transporter 2) in the proximal tubule of the kidney. This leads to increased excretion of glucose (glucosuria) and, as the co-transport of sodium is also inhibited, to increased excretion of sodium in the urine (natriuresis). The inhibition is selective for the SGLT-2 transporter. The SGLT-1 transporter is not inhibited. However, the inhibition of SGLT2 is not complete and is also partially compensated by the SGLT-1 transporter further distally in the renal tubule. Therefore, hypoglycemia or electrolyte shifts do not occur.

In the proximal tubule of the kidney, over 90% of the previously filtered glucose is physiologically reabsorbed by SGLT-2 and the remaining 10% by SGLT-1, which is located somewhat further distally. In healthy people, therefore, no glucose is excreted in the urine under normal conditions. Glucose is only excreted in the urine when the renal threshold is exceeded at elevated blood glucose levels of more than 180 mg/dl or 10 mmol/l on average.

The inhibition of SGLT-2 leads to increased excretion of glucose in the urine, thereby lowering the blood glucose level and reducing HbA1c. Depending on the level of the baseline value, around 50-80 g of glucose per day can be variably excreted via this mechanism and HbA1c can be variably reduced by 0.6-0.9% (depending on blood glucose concentration and GRF) (Ferranini E. 2016).

As glucose is excreted and is not introduced into the cell and metabolized as with insulin action, weight loss can also be achieved. In contrast, antidiabetic drugs that are based on insulin action or support or enhance the secretion and action of insulin (insolinotropic substances, e.g. sulphonylureas) usually lead to weight gain.
The daily calorie loss due to glucosuria is around 250-400 kcal, the average weight loss is around 2-4 kg over 12 months (Ferranini E. 2016). SGLT2i only leads to increased excretion of glucose, glucose uptake is not inhibited! Reactively increased glucose intake with food therefore presumably limits the effect with regard to weight loss.

The effect of SGLT2i is independent of the effect of insulin and therefore also causes a reduction in blood glucose in the case of insulin resistance. It can also be assumed that the blood glucose level also lowers the insulin level and increases the glucagon effect. SGLT2i therefore counteract insulin resistance and the negative effects of high insulin levels. Due to their positive effects on insulin resistance and weight, they are therefore more suitable than insulin, also as part of a therapy for people suffering from metabolic syndrome and obesity (when lifestyle changes and metformin alone do not lead to the desired reduction in blood glucose levels).

In contrast to blood glucose lowering with insulin or drugs that act via the insulin mechanism, there is no risk of hypoglycemia. SGLT2i can therefore be combined well with other antidiabetic drugs (especially metformin) without increasing the risk of hypoglycaemia. However, when combined with insulin and other insulinotropic substances, there is still a risk of hypoglycemia (although a combination with SGLT2i can at least reduce the dose of insulin and thus reduce the risk of hypoglycemia).

The direct effect on the blood glucose level results in its use as an antidiabetic substance in the treatment of type 2 diabetes mellitus. SGLT2i were initially approved exclusively for the treatment of type 2 diabetes.

In addition to glucose reabsorption, SGLT2i also block the reabsorption of sodium (sodium cotransport) and therefore also lead to increased sodium excretion (natriuresis) in the urine. Natriuresis together with osmotic diuresis due to glucosuria also lead to a reduction in intravascular blood volume, blood pressure and a reduction in the volume load (preload and afterload) on the heart. This explains, at least in part, the positive effect that SGLT2i has on the heart. Due to this effect, SGLT2i can reduce blood pressure by approx. 4-6 mmHg (even more in the case of severe arterial hypertension) (Ferranini E. 2016). In patients with pre-existing micro- and macroalbuminuria, albumin excretion can also be reduced by 30-40% (Ferranini E. 2016). The nephroprotective effect of SGLT2i, which is attributed, among other things, to altered haemodynamics at the nephron with vasoconstriction of the afferent arterioles, vasodilation of the efferent arterioles, reduction of glomerular filtration pressure (improvement or restoration of tubuloglomerular feedback, TGF) and decrease in hyperfiltration, is presumably also associated with these effects (Ferranini E. 2016). This can also lead to a reversible decrease in GFR at the start of therapy with SGLT2i, which within limits should be seen as part of these nephroprotective effects and not as a sign of worsening renal function.

In addition, there are a number of effects that cannot be explained by the direct effect of SGLT2i on blood glucose levels or the long-term improvement in blood glucose, as these effects are independent of the presence of type 2 DM and are already recognizable shortly after the start of therapy. These pleiotropic effects are currently the subject of intensive research. These include Reduced insulin and increased glucagon effect, shift from anabolic to catabolic metabolic state, improved fatty acid oxidation, improved mitochondrial function and energy metabolism, reduced oxidative stress, improved iron metabolism, increase in hematocrit with improved oxygen supply to the heart and kidneys, reduction in sympathetic tone, reduced RAAS activation, overall improved hemodynamics and reduced inflammation and fibrosis (for the cardiorenal effect, see also Zelniker TA, Braunwald E. 2022).

Type 2 diabetes mellitus (type 2 DM), heart failure (HF), chronic kidney disease (CKD) according to guidelines:

Treatment of type 2 DM (ESC guidelines, cardiovascular disease and type 2 DM) (Marx et al 2025).

Type 2 DM is treated after prior risk evaluation:

without atherosclerotic cardiovascular disease (ASCVD) or end-organ damage and with low to moderate risk (≤10% calculated 10-year risk ASCVD score/SCORE2 diabetes) treatment with metformin (class IIa 'should be considered') or SGLT2i if metformin is not tolerated in addition to lifestyle changes (dietary changes, diet and exercise or if these are not sufficient).

without atherosclerotic cardiovascular disease (ASCVD) or end-organ damage, but at high risk (≥10% calculated 10-year risk ASCVD score/SCORE2 diabetes), treatment with metformin or SGLT2i or GLP-1-RA should be considered for prevention or to reduce cardiovascular risk. Class IIb C recommendation ('may be considered')

with very high risk (multiple risk factors) or with ASCVD Class IA recommendation for SGLT2i, GLP-1-RA for cardiovascular risk reduction independent of glucose control, HbA1c, in addition to standard therapy

ESC guidelines for patients with type 2 DM with heart failure (HF): to improve prognosis, hospitalization, quality of life in chronic HF (all forms of HF: HFpEF, HFmrEF, HFrEF) Class IA recommendation for SGLT2i (dapagliflozin or empagliflozin) independent of blood glucose control and HbA1c, independent of concomitant blood glucose lowering medication in addition to standard therapy. For additional blood glucose control, if necessary, it is recommended to use substances with a neutral effect on cardiovascular risk (Glp-1-RA, siragliptin, linagliptin, metformin, possibly also insulin (insulin glargine, insulin degludec) class IIa).

Patients with type 2 DM and chronic kidney disease (CKD): to reduce the cardiovascular risk and the risk of progression of CKD and kidney failure SGLT2i class I and others in addition to standard therapy regardless of blood glucose and HbA1c.

It is recommended to switch antidiabetic medication without a proven beneficial cardioprotective effect to antidiabetic medication with a proven cardioprotective effect (class 1C recommendation).

Other antidiabetic medications should only be used additionally if blood glucose control is not sufficiently possible with class 1 medication (Marx N et al 2023).

Treatment of HF (ESC Guidelines Update 2024)(Böhm M et al 2024): SGLT2i (dapagliflozin, empagliflozin) is the first and only heart failure therapy with a proven significant mortality benefit for the entire spectrum of left ventricular ejection fraction (LVEF).
Class I-A recommendation for SGLT2i for all forms of heart failure across the entire spectrum of ejection fraction and independent of HbA1c.

Treatment of chronic kidney disease (CKD)(ESC Guidelines and KDIGO Guidelines 2024)

• SGLT2i (empagliflozin, dapagliflozin) recommended with class 1A recommendation in patients with type 2 DM and chronic kidney disease (CKD) with eGFR ≥20 ml/min/1.73m2 to reduce the risk of cardiovascular disease, worsening renal function and renal failure.
• SGLT2i 1A Recommendation also for CKD with eGFR ≥ 20 ml/min/1.73m2 with albuminuria ACR (albumin/creatine ratio) ≥ 200 mg/g (≥ 20 mg/mmol) or HF regardless of the level of albuminuria.
• SGLT2i 2B recommendation for CKD with eGFR 20-45 ml/min/1.73m2 with albuminuria ACR (Albumin/Creatine Ratio) ≤ 200mg/g (≤ 20 mg/mmol).

SGLT2i form an additional pillar alongside standard therapy for CKD.

Reversible decrease in GFR at the start of therapy should not generally lead to discontinuation or interruption of SGLT2i/close monitoring. (Note: treatment/co-treatment by an experienced nephrologist is the best option, especially with low eGFR, as there is a risk of acute renal failure if the eGFR falls too sharply).

SGLT2i can slow down the progression of CKD and delay terminal renal failure! This protective function is still present even with a low eGFR.

In cardio-renal syndrome, SGLTi offer the advantage that they can provide additional volume relief without the renal side effects of the usual diuretics in the case of a balancing act between cardiac decompensation due to volume loading and the risk of impaired renal function due to excessive diuresis caused by diuretics.

Treatment of NAFLD (updated S2k guideline DGVS 2022) (Roeb E, et. al. 2022). Use of SGLT2i can be considered (e.g. empagliflozin or dapagliflozin) in patients with NAFLD without cirrhosis and type 2 DM due to favorable effects (significant improvement in liver fat content and additional positive effects from cardiovascular and renal endpoint studies)(Recommendation: open recommendation, strong consensus).

The most common side effect is an increased risk of genital and urinary tract infections due to glucosuria. The risk can be reduced by good hygiene and care measures. Infections are rare and can generally be treated well with the usual treatment measures.

A serious adverse effect or complication is Fournier's gangrene, a necrotizing fasciitis of the perineum, which occurs very rarely. The risk is increased in patients with immunodeficiency of any cause, poor general health and nutritional status, alcoholism, drug addiction, smoking, advanced age, obesity and others. The disease is life-threatening and requires immediate surgical treatment and debridement.

Complication: Atypical ketoacidosis, very rare but potentially life-threatening! When treated with SGLT2i, ketoacidosis can occur even with only slightly elevated or normal blood glucose levels! Very important and requires special attention in terms of clinic and diagnosis!

Ketoacidosis is very likely if the following symptoms occur: nausea, vomiting, anorexia, abdominal pain, severe thirst, difficulty breathing, confusion, unusual tiredness, drowsiness, loss of consciousness.

Risk is increased in situations with increased endogenous insulin requirement or relative insulin deficiency, such as major surgical interventions (fasting, stress), especially major surgical interventions and bariatric surgery, but also diagnostic procedures that require fasting, low-calorie diets or fasting and dietary changes, especially with reduced carbohydrate intake, low-carb diets, malabsorption, severe fluid loss and excessive physical exertion, excessive alcohol consumption, or acute serious illnesses such as infections, gastroenteritis, myocardial infarction, stroke, etc.etc.
Even with combination treatment of SGLT2i with insulin, reducing the insulin dose can lead to an increased risk of ketoacidosis. Therefore, strict monitoring of blood glucose levels and possibly ketone bodies and increased awareness of symptoms is necessary!

Diagnosis: monitoring of ketone body concentration in blood (ketone body determination in urine not sufficient), pH≤7.3; serum bicarbonate ≤15mmol/l; anion gap ≥12mmol/l.

Immediate discontinuation of SGLT2i and treatment in case of ketoacidosis!

Pause treatment in case of infections and acute illnesses as well as in case of dietary changes, etc. Discontinuation possible 3 days before surgery. (AVP, Arneiverordnung in der Praxis Volume 50(1), March 2023) (patients should be informed about possible ketoacidosis, risk situations and symptoms!)

At the start of treatment, there may be a temporary, reversible increase in serum creatinine and a reduction in eGFR = part of the mode of action and the nephroprotective effect through osmotic diuresis and TGF. In patients with severely impaired renal function, close monitoring and treatment by an experienced nephrologist is recommended (clinical data and studies, as well as guidelines and benefit assessment for the treatment of CKD with low eGFR refer to dapagliflozin and empagliflozin; see Summary of Product Characteristics for the respective product).

Ertugliflozin is not recommended for use at eGFR ≤45 ml/min, and treatment with ertugliflozin should not be given or discontinued at eGFR ≤30 ml/min (see information for healthcare professionals Steglatro, version 2024). Only the treatment of type 2 DM from the age of 18 is specified as an indication (see Steglatro information for healthcare professionals, version 2024)

SGLT2i should not be used in type 1 diabetes mellitus, as the risk of life-threatening ketoacidosis is too high.

SGLT2i are not to be used in patients under 18 years of age (no data available). Exception: dapagliflozin and empagliflozin for type 2 DM approved from 10 years of age (Forxiga®, AstraZeneca, as of 2024; ^Jardiance®, Boehringer Ingelheim Lilly, as of 2023).

Ertugliflozin only from the age of 18 (information for healthcare professionals ^Steglatro®, MSD, as of 2024)

SGLT2i should not be used in case of hypersensitivity to one of the active ingredients or other components of the medication. Contains lactose compound, therefore not to be used in patients with rare hereditary galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption (see relevant product information)

Monopreparations:

• Empagliflozin (^Jardiance®) (approval 2014)
• Dapagliflozin (^Forxiga®) (approval 2012)
• Ertugliflozin (^Steglatro®) (approval 2018)
• Canagliflozin (^Invokana®) (no longer on the market in Germany)
• Sotagliflozin (^Zynquista®) (originally approved in 2019 as an add-on therapy for type 1 diabetes in combination with insulin in severely overweight patients) Non-selective, dual SGLT inhibitor inhibits SGLT-1 and SGLT-2; no longer on the market in Germany due to high risk of potentially life-threatening diabetic ketoacidosis; only approved in the USA for individual indications in heart failure and type 2 diabetes)

Combination preparations: (fixed-dose combinations are of secondary importance, as there is only a secondary indication and a specific additional benefit has not yet been sufficiently proven in studies for fixed-dose combinations):

• ^Xigduo® dapagliflozin/metformin
• ^Glyxambi® empagliflozin/linagliptin (dipeptidyl peptidase-4 (DDP-4) inhibitor)
• ^Steglujan® ertugliflozin/sitagliptin (dipeptidyl peptidase-4 (DDP-4) inhibitor)

1. AVP Medication Prescribing in Practice (3/2023) Volume 50(1).
2. Böhm M et al. (2024) Commentary on the Focused Update 2023 of the ESC Guidelines 2021 on the diagnosis and treatment of acute and chronic heart failure. Cardiology (online) https://doi.org/10.1007/s12181-023-00655-8
3. Chang S-N et al. (2023) Sodium-Glucose Cotransporter-2 Inhibitor Prevents Stroke in Patients With Diabetes and Atrial Fibrillation. J Am Heart Assoc (online) 12:e027764. DOI: 10.1161/JAHA.122.027764
4. DAZ online. EU approval. New antidiabetic drug dapagliflozin 2012. DAZ online (2012); 04.12.2012.
5. Duckworth W et al. for the VADT Investigators (2009) Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med 360:129-39.
6. Esterline R et al. (2020) A role of sodium glucose cotransporter 2 inhibitors (SGLT2is) in the treatment of Alzheimer's disease? Int Rev Neurobiol 155:113-140.
7. Ferrannini E (2017) Sodium-Glucose Co-Transporters and their Inhibition: Clinical Physiology. Cell Metab Rev 26:27-38.
8. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International 2024;105(Suppl.45)S117-S314.
9. Kim HK et al. (2024) SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients with Type 2 Diabetes. Neurology 103(8):e209805. doi: 10.1212/WNL.0000000000209805.
10. Marx N et al. 2023 ESC Guidlines for the management of cardiovascular disease in patients with diabetes: Developed by the task force on the management of cardiovadcular disease in patients with diabetes of the European Society of Cardiology (ESC). Europ Heart J, 44(39),4043-4140.
11. Pawlos A et al. (2021) Neuroprotective effect of SGLT2 inhibitors. Molecules 26(23):7213. doi: 10.3390/molecules26237213.
12. Rizzo MR et al. (2022) Cognitive impairment and type 2 diabetes mellitus: Focus of SGLT 2 inhibitors treatment. Pharmacol Res https://doi.org/10.1016/j.phrs.2022.106062
13. Roeb E et al. (2022) Updated S2k guideline non-alcoholic fatty liver disease of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS).Z Gastroenterol 60:1346-1521.
14. Shourav MI et al. (2024) Effects of Sodium-Glucose- Co-transporter 2 Inhibitors on Cognition in Patients with Diabetes: A systenatic review and Meta-analysis. Neurology 102(17Suppl.1). https://doi.org/10.1212/WNL.0000000000205318.
15. Srijanth V et al. (2020) Type 2 diabetes and cognitive dysfunction - towards effective management of both comorbidities. Lancet Diabetes Endocrinol 8(6):535-545.
16. The ACCORD Study Group. (2016) Nine-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes. Diabetes Care 39(5):701-708.
17. The ACCORD Study Group. (2008) Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 358:2545-259.
18. Tsai W-H et al. (2021) Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Scientific 11:15364. https://doi.org/10.1038/s41598-021-94945-4.
19. Zelniker TA, Braunwald E. (2020) Mechanisms of cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors. JACC State-of-the-Art Review. J Am Coll Cardiol. 422-34.
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21. van Ruiten CC et al. (2022) Effects of dapagliflozin and combination therapy with exenatide on food-cue induced brain activation in patients with type 2 diabetes. J Clin Endocrinol Metab. (online) doi:10.1210/clinem/dgac043
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Brief articles on the topic in the German Medical Journal:

SGLT2 inhibitors improve exercise capacity and quality of life in heart failure patients. German Medical Journal, Medicine, News, 05/2024 https://www.aerzteblatt.de/nachrichten/150943/SGLT2-Inhibitoren-verbessern-koerperliche-Leistungsfaehigkeit-und-Lebensqualitaet-von-Herzinsuffizienzpatienten

SGLT2 inhibitors could protect against dementia and Parkinson's disease, Medizin, News, 09/2024; https://www.aerzteblatt.de/nachrichten/154478/SGLT2-Inhibitoren-koennten-vor-Demenz-und-Parkinson-schuetzen

Guckel D, Sohns C. Diabetes mellitus and atrial fibrillation: Increased cardiac risk, focused therapy concepts
Dtsch Arztebl 2024; 121(13). https://www.aerzteblatt.de/archiv/240000/Diabetes-mellitus-und-Vorhofflimmern-Erhoehtes-kardiales-Risiko-fokussierte-Therapiekonzepte

Barley RD. Type 2 diabetes: Positive effects of SGLT2 inhibitors on heart and kidney also in routine use
Dtsch Arztebl 2023; 120(11): A-478 / B-412. https://www.aerzteblatt.de/archiv/230347/Typ-2-Diabetes-Positive-Effekte-von-SGLT2-Hemmern-auf-Herz-und-Niere-auch-in-Routineanwendung

Hofmann-Aßmus. In heart failure and kidney disease: SGLT-2 inhibition twice as good
Dtsch Arztebl 2024; 121(8): A-553 https://www.aerzteblatt.de/archiv/238655/Bei-Herzinsuffizienz-und-Nierenerkrankung-SGLT-2-Hemmung-doppelt-gut

König R. NAFLD, NASH and cirrhosis: Diabetes also damages the liver. Dtsch Arztebl 2023; 120(26): A-1175. https://www.aerzteblatt.de/archiv/232480/NAFLD-NASH-und-Zirrhose-Diabetes-schaedigt-auch-die-Leber

Schwenger V. SGLT2 inhibitors and concomitant diseases: protection for kidney and heart. Dtsch Ärztebl 2022; 119:27-28. https://www.aerzteblatt.de/archiv/226140/SGLT2-Inhibitoren-und-Begleiterkrankungen-Schutz-fuer-Niere-und-Herz

Schwenger V, Larus J, Mahfoud F, Remppis BA. Cardiorenal syndrome: cardiac and renal insufficiency simultaneously in focus. Perspectives in cardiology.
Dtsch Arztebl 2022; 119(24). https://www.aerzteblatt.de/archiv/225735/Kardiorenales-Syndrom-Herz-und-Niereninsuffizienz-gleichzeitig-im-Fokus