Introduction:
Diabetes is a leading cause of cardiovascular (heart) and renal (kidney) disease. Many drugs are available for type 2 diabetes mellitus (Type 2 DM) (e.g., insulin, metformin, sulfonylureas, glitazones). However, their drawbacks include limited effectiveness against DM-related cardiovascular disease (CVD). Moreover, some may also increase the risk of CVD-related deaths. As a result, the United States Food and Drug Administration (US FDA) recently approved sodium-glucose transporter (SGLT) inhibitors, a new class of glucose-lowering compounds (as Type 2 DM is a state of increased blood glucose). Since their introduction, SGLT inhibitors have become the mainstay of type 2 DM treatment. They also have beneficial effects on the heart and kidneys.
What Are SGLT and SGLT Inhibitors?
Glucose is the source of energy for metabolic processes in cells. It is a polar (charged) molecule that cannot be transported across the plasma membrane. Therefore, carrier proteins called glucose transporters are needed for the uptake. The sodium-glucose co-transporters (SGLTs, also called sodium glucose-linked transporters) are responsible for glucose transport.
SGLT1 reabsorbs most of the dietary glucose in the intestine. On the other hand, SGLT2 does the maximum glucose reabsorption in the kidney. Therefore, SGLT2 and SGLT1 are responsible for all renal glucose reabsorption.
What Is the Mechanism of Action of SGLT2 Inhibitors?
SGLT2 inhibitors (also called gliflozins) are antidiabetic agents that act on the SGLT-2 proteins expressed in the kidney to:
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Prevent the reabsorption of filtered glucose.
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Decrease the renal threshold for glucose (RTG; the glucose concentration above which the kidneys begin to remove it into the urine).
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Promote urinary glucose excretion.
Further, SGLT2 inhibitors also regulate specific physiological (normal body) functions, which include decreasing renal intraglomerular (glomerulus is an important part of the kidney) pressure (it is an important determinant of kidney disease) and reducing the heart's pressure.
What Are the Approved SGLT2 Inhibitors and Their Indications?
Canagliflozin: Canagliflozin was the first approved SGLT-2 inhibitor for type 2 DM patients.
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It can also decrease CVD adverse events in type 2 DM subjects with underlying cardiovascular illnesses.
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It further minimizes the risk of end-stage renal disease (ESRD, a condition in which kidneys stop functioning permanently, leading to regular long-term dialysis or a kidney transplant) and hospitalization due to heart failure (HF).
Dapagliflozin: After getting FDA approval in 2014, it was indicated in adult patients with type 2 DM as an adjunct to diet and exercise.
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Other indications include minimizing the hospitalization attributed to HF due to cardiovascular risk factors and decreasing the risk of CVD deaths.
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It is also indicated to decrease the risk of glomerular filtration rate (GFR; a measure of proper kidney function) decline, ESRD, and hospitalization for HF in chronic kidney disease (CKD) patients at risk of progressive disease.
Empagliflozin: It is indicated in adult patients with type 2 DM to improve blood glucose control in addition to diet and exercise. Further, it is advised to decrease the risk of cardiovascular adverse events in type 2 DM patients and minimize the risk of mortality and HF hospitalization in adult subjects.
Ertugliflozin: The latest SGLT-2 inhibitor approved by the FDA was Ertugliflozin in 2017. It is indicated for adult type 2 DM patients to improve blood glucose control in addition to diet and exercise.
What Are the Adverse Effects Associated With SGLT-2 Inhibitors?
SGLT-2 inhibitors during pregnancy can cause fetal risk (during the second and third trimesters). SGLT-2 inhibitor use during lactation is also not advocated. Further, studies have not assessed their use in liver disease. Other adverse effects are:
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Canagliflozin: Genital fungal infections in females (most common), urinary tract infections (UTIs), increased urination, genital fungal infections in males, increased thirst, constipation, nausea, and vaginal pruritus (itching).
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Dapagliflozin: Genital fungal infections in females (most common), nasopharyngitis (inflammation of the nose and pharynx), UTIs, back pain, nausea, influenza, dyslipidemia (deranged blood lipid levels), constipation, and pain in legs and arms.
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Empagliflozin: UTIs (most common), genital fungal infections in females and males, upper respiratory tract infections, increased urination, dyslipidemia, joint pain, and nausea.
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Ertugliflozin: Genital fungal infections in females (most common), UTIs, headaches, vaginal pruritus, increased urination, nasopharyngitis, back pain, weight loss, and increased thirst.
Patients receiving dialysis are contraindicated from treatment with any of the SGLT-2 inhibitors. An absolute contraindication is hypersensitivity reactions, such as allergy, anaphylaxis, or angioedema, to any of the four agents.
What Is the Role of SGLT2 Inhibitors in Improving Heart and Kidney Function?
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Heart: The SGLT2 inhibitor class shows a cardioprotective (heart protection) effect in diabetic patients. Moreover, it also persists in nondiabetic patients. As a result, SGLT2 inhibitors are approved for the treatment of HF. There is no direct evidence of the effects of SGLT2 inhibitors on the kidneys or heart. However, animal studies suggest an indirect effect on cardiac receptors.
The sympathetic nervous system (SNS; maintains heart rate and blood pressure) plays an important role in the pathogenesis of HF. As a result, many drugs that reduce HF chances partly inhibit SNS activity. Various studies show evidence of SNS inhibition with SGLT2 inhibitors.
- Kidneys:
- Different trials have shown that SGLT2 inhibitors produce a reduction in the progression of CKD in diabetic and nondiabetic patients. Still, it is unclear in what areas the inhibitors stop the natural progression of kidney disease
The beneficial renal and cardiac effects of SGLT2 inhibitors are observed within a few months after therapy in large cardiovascular trials. However, the effects are not only due to blood glucose control; (other mechanisms likely contribute). SGLT2 inhibitors do not induce the effects of other antidiabetic drugs, including increased body weight. Furthermore, SGLT2 inhibition reduces body weight. It is done by shifting substrate utilization from carbohydrates to lipids, thereby reducing body fat. Body fat is also used for ketone body formation in the liver. As a result, it provides additional energy substrates to improve heart and kidney function. By decreasing blood glucose levels and body weight, SGLT2 inhibitors improve beta-cell function (beta cells of the pancreas produce insulin, and insulin deficiency causes DM).
Conclusion:
SGLT2 inhibitors possess a remarkable ability to lower the progression of heart and kidney disease (especially heart disease) in type 2 DM patients. However, a thorough clinical evaluation is important to determine if SGLT-2 treatment is suitable for the patient. Furthermore, childbearing females should be informed about the potential risks to the fetus.
