Diabetes management: Beyond The Basics

Over the past decade, the management of type 2 diabetes has transitioned from an emphasis on tight glycemic control to a focus on individualized treatment for each patient that seeks to balance the risk for hyperglycemia against the risk for hypoglycemia.

The importance of avoiding hypoglycemia has been demonstrated in recent clinical trials that have revealed an association between hypoglycemia and mortality resulting from cardiovascular events. The 2019 American Diabetes Association Standards of Medical Care in Diabetes includes recommendations derived from these recent findings. For individuals with cardiovascular disease (CVD) or multiple cardiovascular risk factors, appropriate choices for second-line therapy should include agents with proven efficacy in improving cardiovascular outcomes. In addition, these guidelines continue to stress the use of agents that minimize the risk for both hypoglycemia and weight gain.1 

The guidelines also emphasize that glycemic thresholds should be modified in accordance with the individual patient’s profile and risk factors. Strict control of A1c is no longer viewed as an appropriate goal for all patients. It is important that clinicians be aware that controlling blood glucose concentrations, in itself, has minimal effect on CVD risk. Decisions regarding treatment and target glycemic thresholds should consider such factors as how often patients experience hypoglycemia. The association between chronic mood disorders and hypoglycemia should be assessed in the individual patient. Clinicians should note the increased likelihood of hypoglycemia in individuals of advancing age, who experience age-related declines in renal function and hepatic-enzyme activity. These factors can lengthen hospital stays and increase medical costs.1

In the effort to balance the risk for hyperglycemia against that for hypoglycemia, patients must be highly involved in all aspects of their care, including diet, exercise, and medication adherence. Clinicians must have the knowledge necessary to counsel their patients, who must participate in self-monitoring of blood glucose, be attentive to symptoms of hypoglycemia, and take appropriate action to address hypoglycemia.1 

Clinicians must respond to episodes of hypoglycemia or factors that elevate the risk of hypoglycemia by first switching from oral agents associated with the greatest risk of hypoglycemia, such as sulfonylureas, to newer classes and newer forms of agents such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2).1 

Mechanism of Action of Glucose Lowering Drugs

Given the high risk of hypoglycemia with insulin and insulin secretagogues, such as sulfonylureas and meglitinides, newer classes of drugs have been developed that decrease hyperglycemia without the risk of hypoglycemia.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces hyperglycemia by stimulating insulin production only in the presence of elevated glucose levels. However, in patients with type 2 diabetes, the production of incretins is significantly reduced.2 As GLP-1 is only able to stimulate insulin release when blood glucose concentrations are above fasting levels, the actions of GLP-1 are self-terminating and unlikely to induce hypoglycemia.3 Additionally, GLP-1 also improves metabolic control by inhibiting glucagon secretion, slowing gastric emptying and the absorption of glucose, and suppressing appetite.4 Some evidence suggests that GLP-1 may also promote beta-cell proliferation and reduce beta-cell apoptosis. The proliferation of beta cells may improve glucose homeostasis over time as approximately 50% of beta-cell mass is lost in patients with type 2 diabetes.5,6 Currently approved GLP-1 receptor agonists include dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide, the first oral agent in the class.

Sodium-glucose cotransporter-2 (SGLT2) is a glucose transporter found in the early portion of the renal tubule. In patients with diabetes, expression of SGLT2 is upregulated, leading to enhanced glucose reabsorption and worsening hyperglycemia. SGLT2 inhibitors reduce glucose absorption in the kidneys, which results in the excretion of excess glucose in the urine and the reduction of blood glucose levels. SGLT2 inhibitors act independently of pancreatic beta cells but are dependent on kidney function. The glycemic efficacy of this class of drugs decreases with falling glomerular filtration rates (GFR).7 

References:

  1. American Diabetes Association. Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(suppl 1):S90-S102.
  2. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-705.
  3. Meloni AR, DeYoung MB, Lowe C, et al. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes, Obesity, and Metabolism. 2013;15:15-27.
  4. Goldenberg RM, Steen O. Semaglutide: review and place in therapy for adults with type 2 diabetes. Canadian JDiabetes. 2019;43:136-145.
  5. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940.
  6. Wajchenberg BL. Beta-cell failure in diabetes and preservation by clinical treatment. Endocrine Reviews. 2007;28(2):187-218.
  7. Novak LM, Kruger D. Bolstering your armamentarium with SGLT2 inhibitors. Nurse Practitioner. 2017;42(10):28-34.