Narrowing the Scope of Antidiabetic Treatment Options Utilizing Patient-Specific Factors

The abundant antidiabetic treatment options for glucose-lowering medications can make an individualized pharmacologic approach to treatment arduous.

The American Diabetes Association recommends metformin as the initial treatment for type 2 diabetes. As long as it is tolerated and there are no contraindications present, metformin should be continued, and other glucose-lowering agents may be added to the metformin-based treatment regimen when necessary. The decision-making process for adjunctive therapy options should be guided using a patient-centered approach. Patient-specific characteristics to consider upon initiating combination therapy include cardiovascular comorbidities, hypoglycemia risk, weight impact, cost, side effect profile, and patient preferences. With such an extensive array of medications available for managing type 2 diabetes, ambiguity in the approach to pharmacologic treatment is standard amongst clinicians. Treatment options that postulate maximum glycemic control, vascular improvement, and mortality benefits should be selected in every patient.

A clinical research and evidence-based medicine unit in Thessaloniki, Greece, aimed to provide a comprehensive overview of currently available literature. Therefore, the team conducted a systematic review and network meta-analysis to comparatively analyze the effectiveness of 21 glucose-lowering drugs used in managing type 2 diabetes. This analysis included data from randomized trials with an intervention duration of at least twenty-four weeks. Glucose-lowering potential, vascular outcomes, and mortality were assessed in over 320,470 patients.

Data were synthesized from 453 trials to assess 21 glucose-lowering interventions from 9 different medication classes. Analyzed randomized controlled trials included the following interventions: 134 investigating monotherapies, 296 exploring add-on therapies with metformin, and 23 comparing monotherapies to add-on therapies with metformin.

In treatment-naïve patients at low cardiovascular risk, there were no clinically significant differences in hemoglobin A1c reductions when metformin was compared with other therapy options, excluding dipeptidyl peptidase-4 (DPP-4) inhibitors. The most substantial decreases in hemoglobin A1c levels were obtained when metformin-based treatments with adjunct insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were used. In 298 trials that assessed background metformin-based therapy in low cardiovascular risk patients, there were no clinically significant differences between therapy options in vascular outcomes and mortality. Patients with an increased cardiovascular risk receiving background metformin-based treatment were also analyzed throughout 21 clinical trials. Oral semaglutide, empagliflozin, liraglutide, dapagliflozin, and extended-release exenatide were shown to reduce all-cause mortality, with semaglutide, empagliflozin, and liraglutide further reducing cardiovascular death in this patient population. In addition, stroke odds were reduced with subcutaneous semaglutide and dulaglutide. Hospitalization due to heart failure and end-stage renal disease was lower with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Subcutaneous semaglutide increased diabetic retinopathy, while canagliflozin demonstrated a higher occurrence of amputations.

Additional drug-specific factors to consider before initiating therapy in adults with type 2 diabetes are cost, renal effects, and side effect profiles. The cost of metformin is relatively low; however, it is contraindicated in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m². Gastrointestinal side effects are also familiar with metformin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The cost of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is neutral, and their initiation or dose increases should be executed with caution due to the potential risk of acute kidney injury. The specific glucagon-like peptide-1 receptor agonist, liraglutide, has shown benefits in the progression of diabetic kidney disease. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are costly, increase low-density lipoprotein (LDL) cholesterol levels, and require renal dose adjustments. Canagliflozin, empagliflozin, and dapagliflozin demonstrate a clear progression of diabetic kidney disease. Canagliflozin possesses an FDA-approved indication for managing chronic kidney disease and a black box warning for amputation risk. Despite the requirement of renal dose adjustments, thiazolidinediones (TZDs) are generally not recommended for use in patients with renal impairment due to fluid retention potential. Insulin procures the highest antihyperglycemic efficacy. Human insulin is low in cost with subcutaneous and inhaled routes of administration. Insulin analogs are high in cost and are only available via the subcutaneous route. Therefore, lower doses of insulin are required with reduced estimated glomerular filtration rates (eGFR). Insulin dosing is titrated/tapered based on clinical responses. Injection site reactions and hypoglycemic risk should also be monitored.

When treatment goals are not achieved in patients with type 2 diabetes, the escalation of treatment should not be delayed. Instead, the reevaluation of treatment regimen and adherence should occur every three to six months, with proper adjustments being made to integrate further beneficial medication options based on patient-specific factors.

Practice Pearls:

• Maximum glycemic control is achieved with the concomitant use of metformin with insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs).
• In patients at low cardiovascular risk, all antidiabetic treatment options proved to be equally effective concerning vascular outcomes.
• Metformin-based combination therapy has been shown to reduce all-cause mortality in type 2 diabetes.

References for “Narrowing the Scope of Antidiabetic Treatment Options Utilizing Patient-Specific Factors”:
Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes. Ann Intern Med. June 2020: doi:10.7326/M20-0864

Pharmacologic Approaches to Glycemic Treatment: <em>Standards of Medical Care in Diabetes—2020</em> Diabetes Care. 2020;43

Bernice Ford, 2021 PharmD Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences