Strategies for Diabetes Management: Using Newer Oral Combination Therapies Early in the Disease

Joel Zonszein, Per Henrik Groop

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations


Introduction: The duration of uncontrolled type 2 diabetes mellitus (T2DM) can adversely impact small and large vessels, eventually leading to microvascular and macrovascular complications. Failure of therapeutic lifestyle changes, monotherapy, and clinical inertia contribute to persistent hyperglycemia and disease progression. The aim was to review the complex pathophysiology of type 2 diabetes and how different oral agents can be used effectively as first-line therapy in combination with metformin, as well as in patients not achieving glycemic goals with metformin therapy. Methods: For this review, a non-systematic literature search of PubMed, NCBI, and Google Scholar was conducted. Results: New oral agents have made it possible to improve glycemic control to near-normal levels with a low risk of hypoglycemia and without weight gain, and sometimes with weight loss. Early combination therapy is effective and has been shown to have a favorable legacy effect. A number of agents are available in a single-pill combination (SPC) that provides fewer pills and better adherence. Compared with adding a sulfonylurea, still the most common oral combination used, empagliflozin has been shown to decrease cardiovascular (CV) events in a dedicated CV outcome study, and pioglitazone has been effective in reducing the risk of secondary CV endpoints, whereas sulfonylureas have been associated with an increased risk of CV disease. In those failing metformin, triple oral therapy by adding a non-metformin SPC such as empagliflozin/linagliptin or pioglitazone/alogliptin is a good option for reducing glycated hemoglobin (HbA1c) without significant hypoglycemia. Conclusion: Clinicians have a comprehensive armamentarium of medications to treat patients with T2DM. Clinical evidence has shown that dual or triple oral combination therapy is effective for glycemic control, and early treatment is effective in getting patients to goal more quickly. Use of SPCs is an option for double or triple oral combination therapy and may result in better adherence.

Original languageEnglish (US)
Pages (from-to)621-639
Number of pages19
JournalDiabetes Therapy
Issue number4
StatePublished - Dec 1 2016


  • DPP-4 inhibitors
  • Early combination therapy
  • Hyperglycemia
  • Hypoglycemia
  • Oral glucose-lowering agents
  • SGLT2 inhibitors
  • Single-pill combination
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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