Drugs that are now available for the treatment of type 2 diabetes include metformin,1 sulfonylureas,2 SGLT2 inhibitors,3,4 DPP-4 inhibitors,5 meglitinides,6 thiazolidinediones,7 insulin,8 and GLP-1 receptor agonists.9 The American Diabetes Association and the European Association for the Study of Diabetes issued a consensus report that outlines goals of treatment to guide clinical decisions regarding the preferred choice of type 2 diabetes medication for given circumstances.10 While the primary goals are control of glycemia and reduction of cardiovascular risk, the report also emphasizes the importance of patient involvement in the management of their diabetes to optimize adherence.
Factors to Consider
Patients and providers need to consider several factors when selecting a hypoglycemic agent.10 These include:
- HbA1C target
- Presence of cardiovascular disease, heart failure, and/or renal disease
- Need for weight loss
- Risk of hypoglycemia
- Side effects of specific medications
- Acceptability of a given regimen and its mode of administration
- Cost and access to specific medications
The American Diabetes Association recommends metformin monotherapy as the initial treatment for type 2 diabetes.11 Metformin is an oral medication that is safe, effective, and inexpensive. It may also reduce the risk of cardiovascular disease. Patients can remain on metformin as long as it is tolerated if it is not contraindicated. Over time, many people need more than one medication to achieve their HbA1C target. Other medications can be added to metformin as needed.
Insulin may be added to metformin if there is ongoing unintended weight loss, symptoms of hyperglycemia, or HbA1C or blood glucose levels are very high (>10% or ≥300 mg/dL, respectively).11 Insulin is known to be effective in cases of severe hyperglycemia but may not be needed indefinitely if glucose levels can be stabilized.
If oral medications are preferred, severe hyperglycemia can also be controlled with sulfonylureas.12 Sulfonylureas have the added benefit of a lower cost than other hypoglycemic medications.11
Heart or Kidney Disease
For people with atherosclerotic cardiovascular disease, heart failure, or kidney disease, SGLT2 inhibitors or GLP-1 receptor agonists may be considered as the first add-on to existing glucose-lowering treatment, as long as the selected individual drug in these classes has specific benefits for the person’s condition.11 If these medications are not tolerated, are contraindicated, or if they do not adequately lower HbA1C, other medications that can be offered include DDP-4 inhibitors, basal insulin, thiazolidinediones, and sulfonylureas. Thiazolidinediones should be avoided in patients with heart failure.
If the HbA1C target is not achieved after three months, metformin can be combined with any of the following medications: sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGL2 inhibitors, GLP-1 receptor agonists, or insulin.11
Maloney et al, conducted a meta-analysis of 24 hypoglycemia drugs comparing glycemic control, weight changes, and hypoglycemic risk.13 Important differences were seen among and within each different drug class on these parameters. The best choice of a specific medication regimen is often based on these drug-specific differences and patient preferences.
Palmer et al. conducted a systematic review and meta-analysis comparing clinical outcomes among patients using different type 2 diabetes medications.14 The primary outcome measure was cardiovascular mortality. Secondary measures included all-cause mortality, adverse events, myocardial infarction, stroke, HbA1C, hypoglycemia, and body weight. Metformin was associated with lower or comparable HbA1C compared to any other drug class. There was no significant difference with respect to cardiovascular or all-cause mortality among the different drug classes. Individual drugs within the drug classes have been shown to be cardio- or renal-protective.
Metformin is the drug of choice to initiate pharmacotherapy for type 2 diabetes. Multiple other medications with different modes of action and administration have been developed to lower blood glucose and reduce cardiovascular risk. As type 2 diabetes is a progressive disease, most people will rely on multiple drug regimens that over time need to be combined for maximum benefit. The choice of medications depends on co-existing medical conditions, target HbA1C, and patient preferences.
- Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675.
- Khunti K, Chatterjee S, Gerstein HC, Zoungas S, Davies MJ. Do sulphonylureas still have a place in clinical practice? Lancet Diabetes Endocrinol. 2018;6(10):821-832.
- Zhang X-L, Zhu Q-Q, Chen Y-H, et al. Cardiovascular safety, long-term non-cardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients With type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc. 2018;7(2).
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
- Esposito K, Chiodini P, Maiorino MI, Bellastella G, Capuano A, Giugliano D. Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open. 2014;4(6):e005442.
- Drugs for type 2 diabetes. Med Lett Drugs Ther. 2019;61(1584):169-178.
- Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106-1118.
- Erpeldinger S, Rehman MB, Berkhout C, et al. Efficacy and safety of insulin in type 2 diabetes: meta-analysis of randomised controlled trials. BMC Endocr Disord. 2016;16(1):39.
- Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524-536.
- Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.
- American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98-S110.
- Babu A, Mehta A, Guerrero P, et al. Safe and simple emergency department discharge therapy for patients with type 2 diabetes mellitus and severe hyperglycemia. Endocr Pract. 2009;15(7):696-704.
- Maloney A, Rosenstock J, Fonseca V. A model based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes: comparison of treatment effects at therapeutic doses. Clin Pharmacol Ther. 2019;105(5):1213-1223.
- 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(3):313-324.