SGLT2 Inhibitors: Entering the new era in diabetes management

Diabetes is a leading health concern with a current estimate of 415  million world population afflicted with the disease. According to the International Diabetes Federation, an estimated 4.9 million people died as a result of diabetes in 2014.

Diabetes and metabolic risk factors frequently occur as a cluster, making it difficult to control glycemia (blood glucose levels) without affecting one or more of the associated risk factors of hypertension, obesity, and hyperlipidemia as evident by the treatment-limiting side effects of many available antidiabetes agents.

Need for optimal management of glycemia in patients with type 2 diabetes has long been recognized. The results from UKPDS 35 trials, show that the incidence of secondary diabetic complications was significantly associated with glycaemia. Each 1% reduction in mean HbA1c was associated with reductions in risk of 21% for deaths related to diabetes, 14% for myocardial infarction and 37% for microvascular complications.

The mainstay of treatment of patients with type 2 diabetes includes modifications in lifestyle (diet and exercise), oral antidiabetic agents, and insulin therapy. The major aims are not only to improve glycemic control, reduce weight, and improve the quality of life of these patients but also to reduce the long-term cardiovascular risk.

Management of type 2 diabetes has evolved significantly and rapidly over the past several decades. One of the newest additions to antidiabetic therapy is a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with a unique mechanism that targets the kidney’s ability to reabsorb filtered glucose.

The sodium–glucose cotransporters (SGLTs), provide new therapeutic targets to reduce hyperglycaemia in patients with diabetes. SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors escalate urinary glucose excretion. The insulin-independent mechanism of action of SGLT2 inhibitor seems to offer glucose-lowering efficacy with low risk of clinically significant hypoglycaemia a common complication with most oral antidibetic agents. Notably, lowering of plasma glucose with SGLT2i is accompanied by a urinary loss of calories (glucose), suggesting a shift toward negative net energy balance unlike other antidiabetic agents.

SGLT2 Inhibitors work differently from other, non-insulin, diabetes therapeutics which increase insulin production in the pancreas or affect metabolism.  They act in the kidneys to reduce the re-absorption of glucose into the bloodstream. These are potential add-on therapies to current diabetes treatments.

In the last few years, several molecules were developed to specifically target SGLT2s. Currently there has been 4 drugs approved by FDA in the class category including canagleiflozin, dapaglfilozin, empagliflozin and ertugliflozin for use as monotherapy when diet and exercise are inadequate and when metformin is not tolerated and can also be utilized as an add-on to other glucose-lowering agents, including insulin.

In addition to providing glycemic control, this class has beneficial effects associated on lowering the blood pressure (added advantage in patients with diabetes and hypertension), weight loss, and potential cardiovascular benefits.

Dapagliflozin a highly selective inhibitor of the renal sodium-glucose cotransporter-2. The near absence of hypoglycemia and an insulin-independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes.

Glycemic Efficacy

Clinical trials of SGLT2 inhibitors versus oral antidiabtic agents showed similar-to-favorable glycemic control in  type 2 diabetes mellitus. A number of studies also examined the efficacy of SGLT2 inhibitors as add-on therapy. Adding an SGLT2 inhibitor to an antidiabetic regimen including but not limiting to insulin led to a greater A1C reduction without a significant increase in hypoglycemia risk.

Reductions in BP and Weight

The main nonglycemic effects include blood pressure reduction and weight loss. Several clinical trials show positive effects that SGLT2 inhibitors significantly reduced blood pressure

by approximately 3 to 5 mmHg and weight by roughly 4 to 6 pounds. The BP-lowering effect is most likely due to osmotic diuresis, which is believed to contribute to the initial weight loss as well. Gradual weight loss is thought to be caused by a reduction in adipose tissue as well as calorie loss through glycosuria. These additional benefits of SGLT2 inhibitors are theorized to contribute to positive outcomes on cardiovascular diseases.

Possible positive cardiovascular outlook

Many clinical trials have shown cardiovascular benefits from gliflozins. It is, however, premature to conclude that this benefit is a drug-class effect of SGLT2 inhibitors; future studies will help determine this.

In December 2016, as a result of empagliflozin’s potential cardiovascular benefits, the FDA approved an expanded indication for empagliflozin to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.

Safety Concerns

The most common adverse reactions associated with SGLT2 inhibitors are polyuria and genitourinary infections and volume depletion.

SGLT2 inhibitors increase the risk of hypoglycemia when they are used concurrently with insulin and insulin secretagogues. To minimize the risk of hypoglycemia, the doses of insulin and insulin secretagogue should be reduced upon initiation of SGLT2 inhibitors.

Place in Therapy

2015 update from ADA (American diabetes association) and European Association for the Study of Diabetes (EASD) and the 2017 ADA diabetes care guidelines have classified SGLT2 inhibitors as second-line agents after metformin.

The American Association of Clinical Endocrinologists and the American College of Endocrinology AACE/ACE placed SGLT2 inhibitors as third-line treatment after metformin and glucagon-like peptide-1 receptor agonists. Therefore, per the AACE/ACE guidelines, SGLT2 inhibitors are preferred to alternative antidiabetic drugs.

Patient Counseling

Patients should be counseled to report symptoms of ketoacidosis, hypotension, UTI (urinary tract infection), and genital mycotic infections. Clinicians should advise patients to maintain adequate fluid intake because decreased oral intake or increased loss of fluids can potentially lead to AKI (acute kidney injury). In addition, patients must be informed of common side effects, such as increased urination, increased thirst, nausea, and constipation.

Conclusion

The use of SGLT2 inhibitors is becoming more prominent in the treatment of type 2 diabetes mellitus because of additional benefits such as low hypoglycemia risk, decreased mortality secondary to cardiovascular events, and efficacy in lowering BG (Blood Glucose) concentrations, body weight, and BP.