Guidelines for Oral Pharmacotherapy of Type 2 Diabetes

Diabetes mellitus is the seventh leading cause of death in the United States and affects 25.8 million Americans, with up to 27% of those 65 years and older being affected. In the United States, 11 distinct classes of oral antidiabetic agents are approved by the US Food and Drug Administration for the treatment of hyperglycemia in diabetes mellitus. There are 14% of patients with diabetes who currently take both oral agents and insulin and 58% who take oral medications only.

This report is based on a systematic review focused on head-to-head monotherapy and dual therapy. Combination therapies with more than 2 agents were not included in the review, and data on α-glucosidase inhibitors such as acarbose were excluded.

Metformin should be the initial drug for most patients with type 2 diabetes refractory to lifestyle modifications, with a second drug added if needed.
Specific recommendations in the new guidelines are:
Recommendation 1: When diet, exercise, weight loss, and other lifestyle modifications have not adequately improved hyperglycemia, clinicians should add oral pharmacologic therapy in patients with type 2 diabetes (grade: strong recommendation, high-quality evidence).

Recommendation 2: For most patients with type 2 diabetes, initial pharmacologic therapy should be monotherapy with metformin (grade: strong recommendation; high-quality evidence).

Recommendation 3: When lifestyle modifications and monotherapy with metformin fail to control hyperglycemia, clinicians should add a second drug to metformin (grade: strong recommendation; high-quality evidence).

Overall adverse effects were fewer with metformin than with sulfonylureas, and high-quality evidence showed that risk for dangerous levels of hypoglycemia was higher with sulfonylureas than with metformin or thiazolidinediones. In addition, the combination of metformin plus sulfonylureas is associated with 6-fold greater risk for hypoglycemia than the combination of metformin plus thiazolidinediones. When used as monotherapy, the risk for hypoglycemia with metformin and thiazolidinediones was similar, based on moderate-quality evidence.

Evidence was insufficient regarding any efficacy difference among various medications across subgroups of adults based on age, sex, or race.

The ACP recommended generic metformin because of its better efficacy and fewer adverse effects than most other available medications, lack of associated weight gain, and lower cost.

"Metformin is associated with an increased risk for gastrointestinal side effects. Thiazolidinediones are associated with an increased risk for heart failure, and both rosiglitazone and pioglitazone are contraindicated in patients with serious heart failure."

ACP has produced a summary of the guideline for patients: 

"AMERICAN COLLEGE OF PHYSICIANS"

STUDY HIGHLIGHTS:

• The guideline addressed the comparative effectiveness of medications for type 2 diabetes in adults 18 years and older for intermediate outcomes (hemoglobin A1c [HbA1c], lipids, weight); long-term outcomes (mortality, cardiovascular morbidity, and microvascular endpoints such as retinopathy and nephropathy); and safety across subgroups, in particular, those 65 years and older.
• The quality of randomized controlled trials was evaluated with use of Jadad criteria, and observational studies were assessed with the Guide for Conducting Comparative Effectiveness Reviews.
• Key findings were summarized for individual outcome measures to derive the final recommendations.

Intermediate outcomes:

• For HbA1c levels, 104 head-to-head comparisons were examined, and most drug agents were found to be similar in efficacy, reducing HbA1c levels by an average of 1 percentage point.
• Metformin was reported in 3 pooled studies to be more efficacious than DPP-4 inhibitors.
• All dual therapy regimens were more efficacious than monotherapy and reduced HbA1c levels by an average of 1 percentage point more than monotherapy.
• The combination of metformin with another agent was better than metformin monotherapy.
• Metformin with a sulfonylurea was more efficacious than with a DPP-4 inhibitor or thiazolidinedione.
• 79 studies with head-to-head comparisons of effect on weight were reviewed.
• Monotherapy with metformin was more effective for weight loss than with thiazolidinediones, sulfonylureas, or DPP-4 inhibitors.
• Metformin monotherapy was more effective for weight loss than combination therapy, with a mean difference of 2.2 kg.
• Metformin plus a sulfonylurea was favored vs metformin plus a thiazolidinedione.
• 74 head-to-head studies of oral therapy on lipids were examined.
• Diabetes therapies had a small to moderate effect on lipid levels: 5 to 10 mg/dL for low-density lipoprotein (LDL) cholesterol, 3 to 5 mg/dL for high-density lipoprotein (HDL) cholesterol, and 10 to 30 mg/dL for triglycerides.
• Compared with metformin monotherapy, dual therapy did not show a benefit for LDL cholesterol control.
• The combination of metformin with sulfonylurea was favored vs metformin plus a thiazolidinedione for LDL control.
• For HDL cholesterol levels, combination therapy was superior to metformin monotherapy.
• The data on triglyceride lowering were variable: metformin monotherapy was more effective than sulfonylurea monotherapy, and different combinations had slightly different effects of reductions of 10 to 25 mg/dL.

Long-term outcomes:

• The quality of evidence for long-term outcomes was poor to moderate.
• For mortality and cardiovascular morbidity, 5 randomized controlled trials and 11 observational studies showed lower all-cause mortality rates for metformin monotherapy vs sulfonylureas.
• Evidence for other comparisons was unclear or insufficient.
• Only 2 studies examined nephropathy and showed pioglitazone as superior to metformin monotherapy for reducing the albumin-to-creatinine ratio.

Comparative safety:

• No evidence showed an adverse effect of hyperglycemia for any class of medication.
• Pooled results showed a greater risk for hypoglycemia from sulfonylureas compared with metformin (OR, 4.60) and thiazolidinedione (OR, 3.88).
• Evidence was insufficient to show any difference among therapies for liver damage and macular edema.
• For congestive heart failure, 5 observational studies showed superiority of metformin vs sulfonylureas.
• The evidence across subgroups for efficacy and safety of one medication vs another was unclear and insufficient.

ACP recommendations:

• The ACP recommends oral therapy for type 2 diabetes when lifestyle modification fails to improve hyperglycemia. A goal of an HbA1c level of 7% or lower is reasonable for many, but not necessarily all, patients and should be based on individual assessment.
• The ACP recommends that clinicians prescribe monotherapy with metformin as a first-line treatment in most patients with type 2 diabetes, except when there are contraindications.
• A second oral agent is recommended when metformin and lifestyle modifications fail to control hyperglycemia.

by

AKSHAYA SRIKANTH

Pharm.D Internee

Hyderbad, India