The goals in caring for patients with diabetes mellitus are to eliminate symptoms and to prevent, or at least slow, the development of complications. Microvascular (ie, eye and kidney disease) risk reduction is accomplished through control of glycemia and BP; macrovascular (ie, coronary, cerebrovascular, peripheral vascular) risk reduction, through control of lipids and hypertension, smoking cessation, and aspirin therapy; and metabolic and neurologic risk reduction, through control of glycemia.
A recommendation in the ADA's Standards of Care in Diabetes—2025 stresses that quality improvement initiatives and interprofessional teams are important “for supporting sustainable and scalable process changes that improve quality of care and health outcomes.”
Management of diabetes includes the following:
Ideally, blood glucose should be maintained at near-normal levels (preprandial levels of 90-130 mg/dL and HbA1c levels <7%). However, focus on glucose alone does not provide adequate treatment for patients with diabetes mellitus. Treatment involves multiple goals (ie, glycemia, lipids, BP).
The ADA's Standards of Care in Diabetes—2025 supports less stringent HbA1c targets for older adults with diabetes, as follows:
As discussed in the Prognosis section, there are pros and cons to aggressive glycemic control in persons with diabetes, with such tight control apparently being valuable, for example, for microvascular and macrovascular disease–risk reduction in patients with recent-onset disease, no known cardiovascular diseases, and a longer life expectancy. It seems to be not as beneficial in patients with known cardiovascular disease, a longer duration of diabetes (15 or more years), and a shorter life expectancy,
A study from the ACCORD Study Group found that setting the treatment target for HbA1c below 6% in high-risk patients resulted in reduced 5-year nonfatal myocardial infarctions but nonetheless was linked to greater 5-year mortality.
Review of blood glucose logs must be part of any diabetes management plan.
The care of patients with type 2 diabetes mellitus has been profoundly shaped by the results of the United Kingdom Prospective Diabetes Study (UKPDS). This landmark study confirmed the importance of glycemic control in reducing the risk for microvascular complications and refuted previous data suggesting that treatment with sulfonylureas or insulin increased the risk of macrovascular disease. Major findings of the UKPDS are displayed in the images below.
Significant implications of the UKPDS findings include the following:
According to a 2018 guidance statement by the American College of Physicians (ACP), “Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes.” The ACP said that this higher target is aimed at helping patients benefit from glycemic control while avoiding the adverse effects—associated with low blood sugar, medication burden, and costs—of stricter targets. The ACP stated that evidence does not indicate that medication therapy to reduce the HbA1c level to 7% or less results in reduced mortality or in decreased macrovascular complications, such as heart attack or stroke, compared with a reduction to about 8%.
However, experts from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) have expressed skepticism about the higher target, noting that the guidance statement does not take into account the cardiovascular disease benefits of newer drugs, which themselves frequently reduce HbA1c levels. In response, a coauthor of the ACP statement observed that other guidelines have also not specifically accounted for these newer medications in their recommended HbA1c levels and that research on such drugs has primarily been in patients either with cardiovascular disease or at high risk for developing it.
In a 2021 joint consensus statement from the ADA, the Endocrine Society, the European Association for the Study of Diabetes, and Diabetes UK, the term “remission,” as it applies to type 2 diabetes, is defined as the presence of an HbA1c level below 6.5% at least 3 months after glucose-lowering pharmacotherapy has been halted. This applies whether the remission has been achieved by way of lifestyle, bariatric surgery, or other means.
Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type 2 diabetes. Drug classes used for the treatment of type 2 diabetes include the following:
Metformin is the only biguanide in clinical use. Another biguanide, phenformin, was taken off the market in the United States in the 1970s because of its risk of causing lactic acidosis and associated mortality (rate of approximately 50%).
A nested case-control analysis found that, as with other oral antidiabetic drugs, lactic acidosis during metformin use is very rare and is associated with concurrent comorbidity.
The ADA’s Standards of Care in Diabetes describes metformin as effective and safe, stating that “as first-line therapy [it] has beneficial effects on A1C, is weight neutral, does not cause hypoglycemia, and reduces cardiovascular mortality.” Gastrointestinal intolerance, the result of bloating, abdominal discomfort, and diarrhea, is the drug’s principal side effect.
Metformin lowers basal and postprandial plasma glucose levels. Its mechanisms of action differ from those of other classes of oral antidiabetic agents; metformin works by decreasing hepatic gluconeogenesis. It also decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
In the UKPDS, metformin was found to be successful at reducing macrovascular disease endpoints in patients with obesity. The results with concomitant sulfonylureas in a heterogeneous population were conflicting, but overall, this drug probably improves macrovascular risk.
Kooy et al found improvements in body weight, glycemic control, and insulin requirements when metformin was added to insulin in patients with type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, reduced risk of macrovascular disease was evident after a follow-up period of 4.3 years. These results support continuing metformin treatment after the introduction of insulin in patients with type 2 diabetes mellitus.
The ADA points out that there may be an association between long-term metformin use and vitamin B12 deficiency, so that consideration should be given to periodically assessing persons treated with metformin—particularly those with anemia or peripheral neuropathy—for vitamin B12 levels.
GLP-1 agonists (ie, semaglutide, exenatide, liraglutide, dulaglutide) mimic the endogenous incretin GLP-1; they stimulate glucose-dependent insulin release, reduce glucagon, and slow gastric emptying. Animal data suggest that these drugs prevent beta-cell apoptosis and may in time restore beta-cell mass. The latter property, if proven in humans, would have tremendous therapeutic potential.
In addition to their use in controlling blood sugar, GLP-1 agonists have attracted a great deal of attention as aids to weight loss. For example, the semaglutide product sold under the brand name Wegovy has been FDA approved for weight loss in persons with obesity as well as in individuals who have overweight and, along with it, weight-related comorbidities. However, the semaglutide product Ozempic, while approved for the treatment of type 2 diabetes, has not been approved for weight reduction.
In December 2017, the FDA approved once-weekly semaglutide SC (Ozempic), a GLP-1 receptor agonist, as a glycemic control–improvement agent in adults with type 2 diabetes. It is administered as a subcutaneous injection once weekly.Meant as an adjunct to diet and exercise, semaglutide was approved following eight phase-3a studies (the SUSTAIN trials).
Semaglutide SC gained approval from the US Food and Drug Administration (FDA) in January 2020 for risk reduction of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and heart disease.Results from the 2-year randomized study SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) led to approval for the new indication. In the trial, 3297 adults with type 2 diabetes and established cardiovascular disease (CVD) received either injectable semaglutide or placebo, in addition to stand-of-care therapy.
Risk for the primary composite outcome—first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke—for patients treated with semaglutide SC was a significant 26% below that for placebo patients. However, cardiovascular risk reduction primarily resulted from declines in nonfatal stroke (39%) and nonfatal myocardial infarction (26%), with cardiovascular death rates being similar between the semaglutide and placebo patients.
In January 2025, the indications for semaglutide’s use were again expanded to include, in adults with type 2 diabetes mellitus and chronic kidney disease, risk reduction for sustained decline in the estimated glomerular filtration rate (eGFR), for end-stage kidney disease, and for cardiovascular death.
In September 2019, the FDA approved the first oral GLP-1 receptor agonist, a form of semaglutide available under the brand name Rybelsus. It is administered as a once-daily oral tablet. Approval of the oral tablet was based on results from the phase-3 PIONEER trials (n=9543). The trials included head-to-head studies of oral semaglutide compared with sitagliptin (DPP-4 inhibitor), empagliflozin (SGLT-2 inhibitor), and liraglutide 1.8 mg (GLP-1 agonist). A1c reduction was found with oral semaglutide, as well as, via a secondary endpoint, body weight reduction.
For adults at high risk for major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke), the FDA, in October 2025, approved a new indication for Rybelsus, to reduce the risk of these events. Approval of the new indication followed the outcome of a randomized, double-blind, parallel-group, placebo-controlled trial in patients aged 50 years or older, with established CVD and/or chronic kidney disease; the occurrence of MACE was significantly reduced in patients on Rybelsus.
A comparison by Bunck et al of 1 year's therapy with either exenatide or insulin glargine in metformin-treated patients with type 2 diabetes found that exenatide provided significantly greater improvement in beta-cell function. Reduction in HbA1c was similar with the two drugs. Beta-cell function and glycemic control returned to pretreatment values following discontinuation of exenatide or insulin glargine, suggesting that long-term treatment is required to maintain the beneficial effects of these drugs.
Exenatide received FDA approval for type 2 diabetes in 2005.
The addition of exenatide in patients receiving insulin glargine as basal insulin helps to improve glycemic control without the risk of increased hypoglycemia or weight gain. This benefit, however, is accompanied by a significant increase in adverse events such as nausea, diarrhea, vomiting, and headache.
Exenatide has greater ease of titration (only two possible doses, with most patients progressing to the higher dose) than does insulin. Although the original product requires twice-daily injections, a long-acting exenatide formulation that is given once weekly
