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In adults with type 2 diabetes, different glucose-lowering drugs have similar effects. Metformin manages blood sugar levels better than, or as well as, other drugs.

Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA. 2016;316:313-24.

Review questions

In adults with type 2 diabetes, how well do different types of glucose-lowering drugs work? What are the side effects of these drugs?

Background

Type 2 diabetes is a disease that increases your blood sugar levels. Over time, high blood sugar levels can lead to other serious health problems such as kidney failure, vision loss, and heart disease. Some people with type 2 diabetes can control their blood sugar levels using exercise and diet. Many people will also need to use drugs to help manage their diabetes. There are many different types of drugs that can be used to treat diabetes, and these work in different ways. Some drugs are used alone, and some are used together with 1 or 2 other drugs. We need to know how well these drugs work compared with one another and if they have side effects.

How the review was done

The reviewers found 301 studies (randomized controlled trials) that were published up to March 2016.

• The studies included 118,094 adults with type 2 diabetes. People were mostly between 50 and 60 years of age, and a little over half were men. Studies of pregnant women were excluded.
• -glucosidase inhibitors (e.g., acarbose).
• 177 studies tested single drugs (monotherapy), 109 studies tested metformin plus another drug (dual therapy), and 29 studies tested metformin plus a sulfonylurea plus another drug (triple therapy).
• People were followed for at least 24 weeks.

Studies were combined using a type of analysis that lets you compare treatments even if they were not compared directly in the individual trials.

What the researchers found

Compared with metformin alone (monotherapy):

• -glucosidase inhibitors had similar effects for deaths from cardiovascular causes;
• all glucose-lowering drugs had similar effects for deaths from any cause;
• -glucosidase inhibitors increased hemoglobin A_1c (HbA_1c) levels, a measure of average blood sugar control;
• SGLT-2 inhibitors, basal insulin, GLP-1 receptor agonists, and meglitinides had similar HbA_1c levels;
• sulfonylureas, basal insulin, and meglitinides had higher risks for hypoglycemia (blood sugar that is too low);
• thiazolidinediones and DPP-4 inhibitors had lower risks for hypoglycemia; and
• -glucosidase inhibitors had similar risks for hypoglycemia.

Compared with metformin + a sulfonylurea (dual therapy):

• metformin + another glucose-lowering drug (thiazolidinedione, DPP-4 inhibitor, SGLT-2 inhibitor, GLP-1 receptor agonist, or meglitinide) had similar effects for deaths from cardiovascular causes or from any cause;
• metformin + basal insulin had similar effects for deaths from any cause;
• metformin + any other glucose-lowering drug had similar HbA_1c levels; and
• metformin + any other glucose-lowering drug had lower risks for hypoglycemia.

Compared with metformin + a sulfonylurea + a thiazolidinedione (triple therapy):

• metformin + a sulfonylurea + another glucose-lowering drug (DPP-4 inhibitor, SGLT-2 inhibitor, basal insulin, or GLP-1 receptor agonist) had similar effects for deaths from cardiovascular causes or from any cause;
• -glucosidase inhibitor increased HbA_1c levels;
• metformin + a sulfonylurea + another glucose-lowering drug (DPP-4 inhibitor, SGLT-2 inhibitor, basal insulin, or GLP-1 receptor agonist) had similar HbA_1c levels;
• metformin + a sulfonylurea + a GLP-1 receptor agonist had lower risks for hypoglycemia; and
• metformin + a sulfonylurea + another glucose-lowering drug (DPP-4 inhibitor, SGLT-2 inhibitor, or basal insulin) had similar risks for hypoglycemia.

Conclusions

In adults with type 2 diabetes, different glucose-lowering drugs had similar effects for death. Metformin alone was better than or similar to other glucose-lowering drugs for managing blood sugar levels. Combining other drugs with metformin had varied effects.

Effects of glucose-lowering drugs for treating people with type 2 diabetes

CV = cardiovascular; DPP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; Hb = hemoglobin; SGLT-2 = sodium-glucose-linked cotransporter 2.

*Studies were combined using a type of analysis that lets you compare treatments even if they were not compared directly in the individual trials.

†Drugs not assessed for death from CV disease: monotherapy with basal insulin or GLP-receptor agonists; dual therapy with metformin plus either basal insulin or α-glucosidase inhibitors, and triple therapy with metformin plus sulfonylureas plus either α-glucosidase inhibitors or meglitinides.

‡Drugs not assessed for death from any cause: dual therapy with metformin plus α-glucosidase inhibitors and triple therapy with metformin plus sulfonylureas plus either α-glucosidase inhibitors or meglitinides.

§Drugs not assessed for HbA_1c levels: triple therapy with metformin plus sulfonylureas plus meglitinides.

||Drugs not assessed for hypoglycemia: triple therapy with metformin plus sulfonylureas plus either meglitinides or α-glucosidase inhibitors.