Promising New Agents for Managing Diabetes

Strategies for Treating Diabetes
Strategies for Treating Diabetes

Prevalence of type 2 diabetes mellitus (T2DM) has dramatically increased worldwide, from 153 million people in 1980 to 347 million in 20081—a trend that is expected to continue, with predictions of 439 million cases by 2030.2

The goal of type 2 diabetes therapy is to achieve tight glycemic control, which reduces the microvascular complications that lead to CVD and stroke.3 However, more than half of patients treated with current therapies fail to achieve the American Diabetes Association's recommended target of less than 7% glycated hemoglobin (HbA1C),4,5 suggesting that these therapies are inadequate. A recently published article by Basile3 reviews the role of a new class of agents—sodium glucose cotransporter 2 (SGLT2) inhibitors—in improving glycemic control and reducing diabetes-related vascular disease.

Pathogenesis of T2DM and Limitations of Current Therapies

Type 2 diabetes results from "progressive b-cell dysfunction in the presence of chronic insulin resistance, leading to a progressive decline in plasma glucose control."3 Disruptions in signaling pathways involved in glucose homeostasis result in increased glucagon secretion, reduced incretin response, increased endogenous glucose production, and increased renal glucose reabsorption.3

RELATED: Endocrine Disorders Resource Center

Current pharmacotherapies act either by increasing insulin sensitivity or stimulating insulin secretion.3 Sulfonylurea insulin secretagogues (eg, glipizide) and nonsulfonylurea insulin secretagogues (eg, nateglinide) increase insulin secretion by closing potassium channels on the surface of pancreatic b cells.6 Metformin decreases hepatic glucose output and sensitizes peripheral tissues to insulin.6 The thiazolidinediones (pioglitazone, rosiglitazone) increase insulin sensitivity in peripheral tissue and decrease hepatic glucose production.6 The a-glucosidase inhibitors inactivate the enzyme that breaks down complex carbohydrates, slowing absorption and flattening the postglycemic curve,6 while incretin mimetics and incretin enhancers (eg, sitagliptin) stimulate glucose-dependent insulin secretion and decrease glucagon secretion.6

Current therapies do not always provide adequate glycemic control7 and have side effects, such as hypoglycemia, weight gain, fluid retention, and gastrointestinal symptoms, which compromise adherence.8 Newer therapies under investigation seek to achieve superior glycemic control with fewer adverse effects.

SGLT2 Inhibitors: Mechanism of Action


SGLT2 (sodium-glucose co-transporter 2) inhibitors target the renal system, which plays an important role in glucose homeostasis by mediating the reabsorption of glucose from the glomerular filtrate.3 Invokana (canagliflozin; Janssen) was the first of this class of drugs to be approved while other SGLT2 inhibitors are still in development.

SGLT2 is located in the proximal tubule of the nephron and responsible for maintaining glucose levels in the body by recovering filtered glucose in the kidneys. They account for approximately 90% of renal glucose reabsorption.9 Reabsorption of glucose from the glomerular filtrate increases in proportion to plasma glucose concentration, until maximum transport capacity of the tubules is reached, above which excess glucose is lost in the urine.3 

RELATED: Endocrine Disorders Resource Center

SGLT2 inhibitors reduce the capacity of the proximal tubule to reabsorb glucose from the glomerular filtrate, leading to increased urinary glucose excretion, thereby reducing hyperglycemia.9 As they work independently of insulin, their efficacy is also independent of b-cell function or insulin resistance.10

Potential Clinical Applications

SGLT2 inhibitors "have the potential to reduce CV risk in patients with T2DM not only through beneficial effects on glycemic control, but also via beneficial effects on body weight, blood pressure, lipids, and serum uric acid."3

SGLT2 inhibitors have demonstrated effectiveness in weight reduction in patients with type 2 diabetes, both as monotherapy and in combination with metformin, pioglitazone, or insulin.3 Even moderate weight loss in patients with type 2 diabetes has been associated with improvement in CV risk factors, such as hyperglycemia, hypertension, and inflammatory markers.11 SGLT2 inhibitors have also been associated with reductions in blood pressure and uric acid.3

The author concludes that SGLT2 inhibitors "can be used either early or late in the disease process to reduce hyperglycemia by reducing renal glucose reabsorption and increasing urinary glucose excretion." The author notes that "inhibiting SGLT2 and exposing the nephron to an increased sodium and glucose load may have a greater impact on CV risk than presently perceived." Large studies are underway to investigate the impact of this new class of agents on CV outcomes in patients with T2DM.


1. Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2•7 million participants. Lancet. 2011;378(9785):31-40.

2. Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet. 2011;378(9786):169-181.

3. Basile JN. The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM). J Diabetes Complications. 2013;27(3):280-286.

4. American Diabetes Association. (2012). Executive summary: Standards of medical care in diabetes—2012. Diabetes Care. 35(Suppl 1):S4-S10.

5. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004;291(3):335-342.

6. Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam Physician. 20091;79(1):29-36.

7. Wallace TM, Matthews DR. Poor glycaemic control in type 2 diabetes: a conspiracy of disease, suboptimal therapy and attitude. QJM. 2000;93(6):369-374.

8. Schernthaner G, Barnett AH, Betteridge DJ, et al. Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis. Diabetologia. 2010;53(7):1258-1269.

9. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5-14.

10. Zhang L, Feng Y, List J, et al. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab. 2010;12(6):510-516.

11. Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care. 2004;27(8):2067-2073.


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