INTRODUCTION — Initial treatment of patients with type 2 diabetes mellitus includes lifestyle changes focusing on diet, increased physical activity and exercise, and weight reduction, reinforced by consultation with a registered dietitian and diabetes self-management education, when possible. Monotherapy with metformin is indicated for most patients, and insulin may be indicated as initial treatment for those who present with catabolic features (polyuria, polydipsia, weight loss) [1]. The natural history of most patients with type 2 diabetes is for blood glucose concentrations to rise gradually with time. Most patients require continuous treatment in order to maintain normal or near-normal glycemia.

Treatment for hyperglycemia that fails to respond to initial monotherapy and long-term medication use in type 2 diabetes are reviewed here. Options for initial therapy and other therapeutic issues in diabetes management, such as the frequency of monitoring and evaluation for microvascular and macrovascular complications, are discussed separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Overview of general medical care in nonpregnant adults with diabetes mellitus".) (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM and Diabetes: Initial therapy for non-pregnant adults with type 2 DM and Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to metformin monotherapy and Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to sulfonylurea monotherapy.)

INDICATIONS FOR A SECOND AGENT — For most patients, we add a second medication when the individualized glycemic treatment goal is not achieved within three months with metformin plus lifestyle intervention. This is consistent with guidelines from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus guideline for medical management of hyperglycemia (figure 1) [1-3]. Target glycated hemoglobin (A1C) goals in patients with type 2 diabetes should be tailored to the individual, balancing the prospect of reduced microvascular complications with the adverse effects and cost of added treatments. Most younger patients without established complications should have an A1C goal of <7 percent (53 mmol/mol) (calculator 1), if this can be achieved without significant hypoglycemia, other side effects, or excessive medication burden (due to complexity or cost that may limit adherence). Older adults and those with comorbid conditions or limited life expectancy may have A1C targets up to 8 percent (64 mmol/mol), 8.5 percent (69 mmol/mol), or even higher due to limited likelihood of benefit from intensive therapy balanced against the side effects of medications [4]. Glycemic targets are reviewed in more detail separately. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.) (Related Pathway(s): Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to metformin monotherapy and Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to sulfonylurea monotherapy.)

In order to achieve an A1C goal <7 percent, the following glucose goals are conventionally proposed, but slightly higher levels may suffice [5,6]:

●Fasting glucose 80 to 130 mg/dL (4.4 to 7.2 mmol/L)

●Postprandial glucose (90 to 120 minutes after a meal) less than 180 mg/dL (10 mmol/L)

After a successful initial response to oral therapy, patients fail to maintain target A1C levels (<7 percent) at a rate of 5 to 10 percent per year (figure 2) [7-9]. An analysis from the United Kingdom Prospective Diabetes Study (UKPDS) found that 50 percent of "newly diagnosed" patients, identified clinically and originally managed with a single drug, required the addition of a second drug after three years; by nine years, 75 percent of patients needed additional medications to achieve the target fasting plasma glucose level <108 mg/dL (6 mmol/L) and a mean A1C value of 7 percent [10]. Whether patients with truly new-onset diabetes, identified through screening, behave similarly is unknown.

Among the factors that can contribute to worsening glycemia are:

●Decreased compliance with diet, exercise, or the medical regimen.

●Weight gain.

●An intercurrent illness.

●The use of medicines that can increase insulin resistance, interfere with insulin release, or increase hepatic glucose production, particularly glucocorticoids, atypical antipsychotics, and immunosuppressants (table 1) [11].

●Progression of the underlying diabetes disease process, including decreased insulin secretion and increased insulin resistance (eg, weight gain).

●Undiagnosed type 1 diabetes with gradual destruction of the pancreatic beta cells, sometimes referred to as "latent autoimmune diabetes in adults" (LADA). (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Latent autoimmune diabetes in adults (LADA)'.)

●The patient's health care team may not have made appropriate changes in therapy often enough or at all ("therapeutic inertia") [12-15]. A population-based study of over 7200 patients with type 2 diabetes demonstrated that many patients remain with A1C levels higher than ideal for years because changes in therapy to improve glycemic management were not made or were only made slowly [12]. Adherence to algorithms that dictate changes in treatment at designated intervals and computerized decision aids may improve A1C more efficiently than standard care [14,16,17].

OUR APPROACH — The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including addition of insulin as an option, or to switch to insulin (table 2). Our approach outlined below is largely consistent with American and European guidelines [1,2,18]. The guidelines emphasize the importance of individualizing the choice of medications for the treatment of diabetes, considering important comorbidities (cardiovascular disease [CVD], heart failure, or chronic kidney disease; hypoglycemia risk; and need for weight loss) and patient-specific factors (including patient preferences, needs, values, and cost). We also agree with the World Health Organization (WHO) guidelines that sulfonylureas have a long-term safety profile, are inexpensive, and are highly effective, especially when used as described below, with patient education and dose adjustment to minimize side effects [19]. Short-acting sulfonylureas are preferred to reduce the risk of hypoglycemia. (Related Pathway(s): Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to metformin monotherapy.)

Our selection of drugs described below is based upon clinical trial evidence and clinical experience in achieving glycemic targets, with the recognition that there is a paucity of high-quality, longer-term, head-to-head drug comparison trials, particularly trials with clinically important health outcomes (cardiovascular events, mortality).

In a network meta-analysis of 296 trials evaluating the effects of selected metformin-based combinations on A1C, mortality, and vascular outcomes, the greatest reduction in A1C was seen with the addition of glucagon-like peptide 1 (GLP-1) receptor agonists, premixed insulin, basal-bolus insulin, basal insulin, or prandial insulin (reductions in A1C ranging from -0.67 for prandial insulin to -1.33 percentage points for subcutaneous semaglutide) [20]. For patients at low cardiovascular risk, all treatments were similar to placebo for vascular outcomes. For patients at increased cardiovascular risk, oral semaglutide, empagliflozin, and liraglutide (all compared with placebo) reduced all-cause mortality and cardiovascular death (odds ratios [ORs] ranging from 0.5 to 0.87). Sodium-glucose co-transporter 2 (SGLT2) inhibitors, in general, had favorable effects on hospitalization for heart failure and progression of renal disease.

In other meta-analyses, metformin combination therapy decreased A1C levels more than metformin monotherapy by approximately 1 percentage point [21,22]. Most combinations similarly reduced A1C. There was moderate evidence favoring metformin plus a GLP-1 receptor agonist over metformin plus a dipeptidyl peptidase 4 (DPP-4) inhibitor for reducing A1C levels [21]. As expected, the use of thiazolidinediones, sulfonylureas, and insulin was associated with weight gain, while metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors were associated with weight loss or weight maintenance. Sulfonylureas were associated with higher rates of hypoglycemia.

Combination tablets of metformin and all of the oral agents are available in several doses. For patients who are doing well on these particular doses, the combination tablets offer the convenience of taking fewer pills. However, if the patient requires that the dose of either drug be changed independent of the other drug, then a fixed combination is unhelpful. In addition, the cost of the brand name combinations is substantially greater than taking the generic components individually.

Monotherapy failure — For patients who fail initial oral monotherapy, there are many available medication classes that can be used with metformin or in combination with each other if metformin is contraindicated or not tolerated. (Related Pathway(s): Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to metformin monotherapy and Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to sulfonylurea monotherapy and Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

Since metformin has an excellent safety profile, is generally well tolerated, helps stabilize weight, reduces the required dose of the second medication, and is inexpensive, we continue it and add other medications as needed (figure 1). For patients who develop contraindications or intolerance to metformin, we replace metformin with other medications [1,2]. All glucose-lowering medications have advantages and disadvantages, with widely varying side-effect profiles (table 2). All of the newer medicines that are not available in generic form are relatively expensive.

For patients with persistent hyperglycemia while taking metformin (2000 mg per day or a lower maximally tolerated dose), the choice of a second medication should be individualized based on efficacy, risk for hypoglycemia, the patient's comorbid conditions, impact on weight, side effects, and cost.

A1C >9 percent (74.9 mmol/mol) or persistent symptoms of hyperglycemia — In this circumstance, insulin or a GLP-1 receptor agonist are the suggested second-line medications, as they have been shown to have the best glycemic efficacy [20]. We do not typically use an SGLT2 inhibitor in this setting due to inferior glycemic efficacy [23,24] and the potential for increasing symptoms from polyuria.

Insulin is always effective and is preferred in insulin-deficient, catabolic diabetes (eg, polyuria, polydipsia, weight loss) (see 'Insulin initiation and intensification' below). While basal insulin has historically been the preferred medication to add to metformin when A1C is markedly elevated (even in the absence of catabolic symptoms), GLP-1 receptor agonists are very reasonable when type 1 diabetes is not likely. For patients with established atherosclerotic CVD (ASCVD) in particular, specific GLP-1 receptor agonists that have demonstrated cardiovascular benefit (liraglutide, semaglutide, or dulaglutide) may be preferred, assuming that they achieve the desired glycemic target. Gastrointestinal (GI) side effects and contraindications to GLP-1 receptor agonists, as well as cost, may limit their use. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Precautions and adverse effects'.)

●Insulin – While neutral protamine Hagedorn (NPH) insulin has been used commonly at bedtime to supplement oral hypoglycemic drug therapy, longer-acting insulin analogs, such as insulin glargine (once daily), detemir (once or twice daily), and degludec (once daily), added to oral agents are similarly effective for reducing A1C values and may cause marginally less nocturnal hypoglycemia depending on dosing and glycemic targets, but no significant difference in total or severe hypoglycemia, and with the important disadvantages of higher cost. These trials are reviewed separately. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Choice of basal insulin'.)

Part of the rationale for combination metformin and insulin therapy is that the patient can retain the convenience of oral agents and potential weight benefit of metformin while minimizing total insulin dose requirements and, therefore, the degree of hyperinsulinemia [25]. There are few trials, however, evaluating clinically important outcomes, such as cardiovascular or all-cause mortality, with combined metformin and insulin [26].

In several trials and a meta-analysis, glycemic management was equivalent or improved with metformin-insulin combinations compared with insulin monotherapy or with sulfonylurea-insulin combinations, with lower insulin doses and less weight gain (figure 3) [26-29]. In the United Kingdom Prospective Diabetes Study (UKPDS), the combination of insulin with metformin was also associated with significantly less weight gain than seen with twice-daily insulin injections or insulin combined with sulfonylureas [30]. This is consistent with other observations that metformin alone does not usually produce weight gain [8]. Combining insulin and sulfonylurea is usually not endorsed, as they have similar mechanisms of action (providing more insulin) and the same glucose-lowering effect can usually be achieved with a modestly higher dose of insulin alone.

●GLP-1 receptor agonists – Data supporting the selection of subcutaneous injection GLP-1 receptor agonists versus basal insulin (as add-on therapy to metformin) at this glycemic threshold are limited by the fact that most studies have neither performed this direct comparison nor exclusively enrolled patients with a high A1C. In addition, in some trials, insulin was often not adjusted as it could or should have been based on labeling and usual clinical practice [31,32]. With those caveats, it nonetheless appears that potent subcutaneous injection GLP-1 receptor agonists are at least as effective as basal insulin [33,34]. They have been compared with basal insulin in combination with metformin, often as a third agent added on to metformin and another oral glucose-lowering medication. In most of these trials, GLP-1 receptor agonists have achieved at least equivalent glycemic management as the addition of basal insulin with the added benefit of weight loss, rather than weight gain, as is often seen with basal insulin. In a 26-week trial that enrolled patients with A1C as high as 11 percent (mean A1C 8.3 percent), the reduction in A1C was greater with liraglutide (-1.33 versus -1.09 percentage points with glargine), with weight loss of 1.8 kg in the liraglutide arm and weight increase of 1.6 kg in the glargine arm [31]. These trials and trials evaluating metformin, a GLP-1 receptor agonist, and insulin are reviewed separately. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus".)

A1C ≤9 percent — To select a second medication, we use shared decision-making with a focus on beneficial and adverse effects within the context of the degree of hyperglycemia as well as a patient's comorbidities and preferences.

Established cardiovascular or kidney disease — For patients with existing cardiorenal abnormalities, a glucose-lowering medication with evidence of cardiorenal benefit should be added to metformin.

As examples:

●For patients in whom ASCVD predominates, particularly in the setting of higher A1C or motivation to lose weight, we typically prefer liraglutide, semaglutide, or dulaglutide, but SGLT2 inhibitors are good alternatives. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

●For patients in whom heart failure or chronic kidney disease (albuminuria [urine albumin excretion >200 mg/day] and estimated glomerular filtration rate [eGFR] <60 but ≥30 mL/min/1.73 m²) predominate, we prescribe a low dose of an SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin). In the setting of declining eGFR, the main reason to prescribe an SGLT2 inhibitor is to reduce progression of diabetic kidney disease (DKD); they should be prescribed at the lowest dose. For the treatment of hyperglycemia, SGLT2 inhibitors are not recommended for initiation with eGFR <30 to 45 mL/min/1.73 m², with some differences in each medication depending on the labeling. However, renal and cardiac benefits have been shown in patients with eGFR below this threshold. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'SGLT2 inhibitor' and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)

In the absence of randomized trials directly comparing cardiovascular outcomes of the GLP-1 receptor agonists and SGLT2 inhibitors, the following findings largely support our approach outlined above:

●When compared with placebo, the GLP-1 receptor agonists liraglutide, semaglutide, and dulaglutide demonstrated favorable atherosclerotic cardiovascular and renal outcomes, including a reduction in cardiovascular and overall mortality [35-42]. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

●When compared with placebo, the SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin have also demonstrated benefit for cardiorenal outcomes, especially for heart failure hospitalization, risk of kidney disease progression, and cardiovascular and overall mortality [35,41-47]. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

●The majority of patients in these cardiovascular outcomes trials had established CVD or DKD with severely increased albuminuria, and therefore, these are the primary indications for adding one of these drugs. Patients at high CVD risk but without a prior event might benefit, but the data (balancing benefits and harms) are less supportive [41]. Similarly, patients without severely increased albuminuria have some benefit, but the absolute benefits are greater among those with severely increased albuminuria.

●In a population-based cohort study (over 370,000 patients with type 2 diabetes) evaluating whether SGLT2 inhibitors or GLP-1 receptor agonists added to baseline diabetes therapy are associated with differential CVD benefits, the use of SGLT2 inhibitors compared with GLP-1 receptor agonists was associated with reductions in heart failure hospitalizations in patients with or without underlying CVD (rate difference for those with history of CVD, -4.97 events per 1000 person-years, 95% CI -6.55 to -3.39) [48]. For the other primary outcome (a composite of hospitalization for myocardial infarction or stroke), there was a small benefit with SGLT2 inhibitors in patients with a history of CVD (rate difference -2.47 events per 1000 person-years, 95% CI -4.45 to -0.50). There was no difference in CVD outcomes between the two classes in those without a history of CVD.

●Despite this small ASCVD benefit of SGLT2 inhibitors in some observational studies [48] and network meta-analyses [35], the benefit of GLP-1 receptor agonists on stroke observed in the semaglutide [36] and dulaglutide [39] cardiovascular outcomes trial, as well as their efficacy for overall diabetes management, leads many, including us, to favor them over SGLT2 inhibitors in the absence of heart failure or CKD [49].

Of note, SGLT2 inhibitors have decreasing glycemic efficacy as eGFR declines, particularly with eGFR <45 mL/min/1.73 m², and in this setting, an alternative (or an additional) agent may be necessary to achieve glycemic goals. GLP-1 receptor agonists are an alternative since glycemic benefit is independent of kidney function. In addition, GLP-1 receptor agonists have been shown to slow the rate of decline in eGFR and prevent worsening of albuminuria, albeit to a lesser degree than SGLT2 inhibitors. GLP-1 receptor agonists should be titrated slowly, monitoring for GI side effects, which could precipitate dehydration and acute kidney injury (AKI). (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Microvascular outcomes'.)

We avoid use of SGLT2 inhibitors in patients with frequent bacterial urinary tract infections or genitourinary yeast infections, low bone density and high risk for falls and fractures, foot ulceration, and factors predisposing to diabetic ketoacidosis (eg, pancreatic insufficiency, drug or alcohol use disorder) because of increased risk while using these agents. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Contraindications and precautions'.)

The treatment of hyperglycemia in the setting of nondialysis chronic kidney disease and eGFR <30 mL/min/1.73 m² is reviewed separately. In general, we tolerate higher glycemic targets, and, if medication is required, we prefer a short-acting, low-dose sulfonylurea (eg, glipizide), repaglinide, linagliptin, or cautious use of a GLP-1 receptor agonist or insulin. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Treatment' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Use in chronic kidney disease' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Clinical use of meglitinides'.)

Without established cardiovascular or kidney disease — The cardiovascular benefit of GLP-1 receptor agonists and SGLT2 inhibitors has not been firmly established in those without existing or high risk for ASCVD and, importantly, has not been demonstrated in those at low cardiovascular risk. For patients without established ASCVD or kidney disease who have persistent hyperglycemia while taking metformin (2000 mg per day or a lower maximally tolerated dose), we choose an alternative glucose-lowering medication guided by efficacy, patient comorbidities, preferences, and cost. As examples:

●Cost concerns – In this circumstance, sulfonylureas are reasonable second agents because they are inexpensive, effective, universally available, and have a long-term track record, including demonstration of reduced risk of microvascular complications. These benefits are offset by risks of hypoglycemia and weight gain. Sulfonylureas can be used safely and effectively with dose adjustment, even in people at risk of hypoglycemia, but this requires a bit more attention. We prefer a shorter-duration sulfonylurea or one with relatively lower risk for hypoglycemia (eg, glipizide, glimepiride), since longer-acting glyburide is associated with a higher risk of hypoglycemia, especially in older or frail patients. In addition, there are good data providing reassurance of the cardiovascular safety of these sulfonylureas. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

The glycemic efficacy of sulfonylureas in combination with other oral agents is illustrated by the findings of a meta-analysis of trials in which sulfonylureas were added to oral agents (predominantly metformin or thiazolidinediones) [50]. Compared with placebo, the addition of sulfonylureas to oral diabetes treatment lowered A1C by 1.62 percentage points. The clinical use, side effects, and concerns about the cardiovascular safety of sulfonylureas are reviewed separately. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)

●Risk of hypoglycemia – For patients in whom avoidance of any hypoglycemia is desirable, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, or, much less commonly, pioglitazone are options as they are associated with a low hypoglycemia risk.

●Weight concerns – When weight loss is a priority, medications that promote weight loss, such as GLP-1 receptor agonists or SGLT2 inhibitors, or medications that are weight neutral, such as DPP-4 inhibitors, may be selected as a second agent. SGLT2 inhibitors are associated with modest weight loss. With both medication classes, weight loss effects are stronger when the medication is combined with sustained efforts at dietary modification.

●NASH – For patients with nonalcoholic steatohepatitis (NASH), any drug that causes weight loss may be beneficial. In patients with diabetes mellitus and biopsy-proven NASH, pioglitazone has been shown to improve fibrosis as well as inflammation and steatosis. Although less well studied, liraglutide appears to improve liver biopsy evidence of NASH. SGLT2 inhibitors are also under investigation. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Patients with NASH and diabetes'.)

The potential benefits of these drugs must be balanced with their associated adverse effects. In particular, pioglitazone is not typically a first-choice agent due to adverse effects, including increased risk of weight gain, fluid retention, heart failure, fractures, and the potential increased risk of bladder cancer. It may play a role in the treatment of selected patients with severe insulin resistance, NASH (or nonalcoholic fatty liver disease), at low risk of fracture. Adverse effects of pioglitazone may be minimized by avoiding the 45 mg dose. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Patients with NASH and diabetes' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Safety' and "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Precautions and adverse effects'.)

Trials comparing other combinations are reviewed separately in the individual topics. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Glycemic efficacy' and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Glycemic efficacy' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Glycemic efficacy'.)

Dual agent failure — For patients who fail dual therapy, the options include:

●Insulin (starting or intensifying) – May simplify regimen by eliminating sulfonylureas or other relatively weak oral agents, such as DPP-4 inhibitors

●Two oral agents and a GLP-1 receptor agonist, but DPP-4 inhibitors and GLP-1 receptor agonists should not be combined [51]

●One oral agent (usually metformin), basal insulin, and a GLP-1 receptor agonist

●Many permutations of three oral agents (eg, metformin and short-acting sulfonylurea, plus SGLT2 inhibitor or DPP-4 inhibitor; many other combinations are possible, but, again, DPP-4 inhibitors and GLP-1 receptor agonists should not be combined [51])

Although guidelines suggest combining SGLT2 inhibitors and GLP-1 receptor agonists [1], we rarely do so given the absence of data showing additive cardiorenal benefit and increased patient burden (cost, polypharmacy, adverse effects). However, we do combine the medications in selected cases.

The choice of additional therapy should be individualized, as discussed above for patients with monotherapy failure, based on efficacy, glycemic target, risk of hypoglycemia, the patient's underlying comorbidities, impact on weight, side effects, and cost. (See 'Monotherapy failure' above.)

●For most patients who do not achieve target A1C with initial combination treatment, we suggest starting or intensifying insulin therapy or starting a GLP-1 receptor agonist (see 'Insulin initiation and intensification' below). In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally tapered and discontinued, while metformin is continued. In patients on a DPP-4 inhibitor who are starting a GLP-1 receptor agonist, the DPP-4 inhibitor should be discontinued.

●For appropriate patients with cardiorenal comorbidities, a GLP-1 receptor agonist or an SGLT2 inhibitor should be added to the regimen. Insulin dose requirements can decrease precipitously with the addition of these medications, requiring patient education and close follow-up with insulin dose adjustment in the short term to reduce the risk of hypoglycemia. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

In a meta-analysis of randomized trials evaluating the addition of a third agent in patients inadequately managed with two agents (predominantly metformin and a sulfonylurea or metformin and a thiazolidinedione), triple-agent combinations reduced A1C to a greater extent than two agents [52]. In trials lasting 52 to 54 weeks, the addition of thiazolidinediones, GLP-1 receptor agonists, or SGLT2 inhibitors to metformin and sulfonylurea reduced A1C to a similar extent. However, these trials did not directly compare the third-line agents with each other.

For patients who are not well managed on two oral agents, switching to insulin may be less expensive than adding a third oral or injectable agent, depending on which insulin and which third oral or injectable agent is selected.

Insulin initiation and intensification — If a decision has been made to add insulin to oral hypoglycemic therapy in patients with type 2 diabetes, a single daily dose of either insulin NPH or detemir given at bedtime or insulin glargine or degludec given in the morning or at bedtime is a reasonable initial regimen [1]. Metformin, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors can be continued when insulin is added, whereas sulfonylureas and pioglitazone are usually discontinued due to reduced efficacy in comparison with other combinations and to adverse effects [2]. Patients should measure blood glucose two to four times daily during insulin dose adjustment and when changes in daily activities (traveling, changes in diet or exercise pattern) or acute illness makes insulin adjustments necessary. The dose of basal or long-acting insulin may be adjusted every three to four days until fasting glucose targets are achieved. Once an insulin regimen is stable, less frequent glucose monitoring may suffice. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Titrating dose'.) (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults with type 2 DM.)

For patients who continue to have poor glycemic management on basal insulin after titration, diet and exercise patterns should be reviewed. Potential next steps include adding rapid-acting insulin before the largest meal and then two or three meals (if needed), adding a GLP-1 receptor agonist, or changing to premixed insulin twice daily (figure 4). Several premixed combinations of basal and prandial insulin or basal insulin and a GLP-1 receptor agonist are available. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Designing an insulin regimen' and "General principles of insulin therapy in diabetes mellitus" and "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus".)

Use of an intensive insulin regimen with multiple daily injections (MDI; similar to that used in type 1 diabetes) may be necessary in insulin-deficient type 2 diabetes. Patients with type 2 diabetes on MDI or with insulin deficiency may benefit from devices used more commonly in type 1 diabetes such as insulin pumps or continuous glucose monitors. (See "Continuous subcutaneous insulin infusion (insulin pump)" and "Glucose monitoring in the management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.)

MDI results in higher serum insulin concentrations and better glycemic management than that achieved with either an oral drug or basal insulin therapy alone [8]. MDI in type 2 diabetes may require large doses of insulin to overcome insulin resistance and can be associated with substantial weight gain (averaging 8.7 kg in one study) [25]. Patients with type 2 diabetes with generalized obesity or with central overweight, often with nonalcoholic fatty liver disease, frequently require insulin doses in the range of 65 to 100 units per day or much higher. This could prompt consideration of use of concentrated insulins, such as U-300 glargine or U-500 regular insulin. Concentrated insulin formulations deliver more potent insulins in smaller volumes, which is less cumbersome for patients and facilitates improved insulin absorption. (See "General principles of insulin therapy in diabetes mellitus", section on 'U-500 regular insulin' and "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs'.)

While use of concentrated insulins is often effective for glycemic management, the worsening obesity associated with high-dose insulin can result in progressively increasing insulin requirements. This phenomenon may then lead to reconsideration of addition of an insulin-sparing agent (eg, GLP-1 receptor agonist or thiazolidinedione) or bariatric surgery. (See 'Surgical treatment of obesity' below and "Nutritional considerations in type 2 diabetes mellitus".)

CARDIOVASCULAR AND OTHER OUTCOMES — In the decade following new guidance released in 2008, approved diabetes drugs were required by the US Food and Drug Administration (FDA) to be evaluated for cardiovascular disease (CVD) safety with large trials; however, these CVD safety studies were almost all relatively brief (usually approximately 2 years in duration), placebo controlled, and enrolled all or a majority of patients with preexisting CVD or at high cardiovascular risk, representing a minority of the type 2 diabetes population. The long-term benefits and risks of using one agent over another in the absence of diagnosed CVD or high atherosclerotic CVD (ASCVD) risk are unknown. Thus, the results of these trials are best applied only to such patients and not to all patients with type 2 diabetes [3,53]. Cardiovascular benefit has been demonstrated for some of these medications when taken in combination with metformin, but benefit has not been investigated in drug-naïve patients at low to moderate cardiovascular risk.

The cardiovascular effects of diabetes drugs (when data are available) are reviewed in the individual topics. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Insulin therapy in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

MEDICATIONS NOT USUALLY RECOMMENDED

●Alpha-glucosidase inhibitors – Acarbose and miglitol are not preferred second- or third-line medications, because of lower efficacy and generally poorer acceptability [2,54]. They can reduce A1C values slightly (0.5 to 1 percentage points) when taken in conjunction with any other form of therapy [55,56]. They act predominantly by lowering glucose concentrations after meals but may be poorly tolerated because of flatulence and other gastrointestinal (GI) side effects. However, if they are started at a low dose (25 mg before meals) and slowly increased, they can be effective in people who follow high-carbohydrate diets. (See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus".)

●Pramlintide – Pramlintide is a synthetic analog of human amylin that slows gastric emptying, reduces postprandial rises in blood glucose concentrations, and modestly improves A1C concentrations in patients with type 1 and type 2 diabetes when injected subcutaneously three times per day. Pramlintide is only approved for use in patients also taking prandial insulin, and therefore, it is not generally used in patients with type 2 diabetes. It also has frequent GI side-effects. (See "Amylin analogs for the treatment of diabetes mellitus".)

●Inhaled insulin – An inhaled form of rapid-acting insulin was available for a short time but was discontinued in 2007 for commercial reasons. In 2014, another inhaled insulin preparation was approved by the US Food and Drug Administration (FDA). Inhaled insulin causes a very rapid rise in serum insulin concentration (similar to that after subcutaneous rapid-acting insulins and faster than that after subcutaneous regular insulin). It is designed to be used to manage postprandial glucose levels. Inhaled insulin may cause a transient cough with each inhalation, and it requires pulmonary monitoring. It is used infrequently in patients with type 2 diabetes. (See "Inhaled insulin therapy in diabetes mellitus".)

●Colesevelam – Colesevelam is a bile acid sequestrant that lowers low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia (see "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bile acid sequestrants'). Colesevelam's mechanism of action to improve glycemia is uncertain [57]. One possibility is that bile acid sequestrants act in the GI tract to reduce glucose absorption.

Given the modest glucose-lowering effectiveness, expense, and limited clinical experience, we typically do not recommend colesevelam to improve glycemic management in patients with type 2 diabetes.

In a meta-analysis of five short-term trials (16 to 26 weeks) in patients with type 2 diabetes inadequately treated with oral agents or insulin, the addition of colesevelam compared with placebo modestly reduced A1C levels (mean difference 0.5 percentage points, 95% CI -0.6 to -0.4) [58]. The meta-analysis was limited by the high or unclear risk of bias in the individual trials.

Side effects can include constipation, nausea, and dyspepsia. In contrast to its effects on LDL cholesterol, colesevelam increases triglyceride concentrations by approximately 20 percent [59,60]. The clinical implications of this increase are unknown. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Apolipoprotein C-III'.)

●Bromocriptine – Bromocriptine is an ergot-derived dopamine agonist that has been used for over two decades for the treatment of hyperprolactinemia and Parkinson disease. (See "Management of hyperprolactinemia", section on 'Overview of dopamine agonists' and "Initial pharmacologic treatment of Parkinson disease", section on 'Age ≤65 years: dopamine agonist versus levodopa'.)

A quick-release formulation of bromocriptine has been approved by the FDA for the treatment of type 2 diabetes mellitus [61]. In short-term clinical trials in patients with type 2 diabetes mellitus, bromocriptine (up to 4.8 mg daily) as monotherapy or as adjunctive therapy to sulfonylureas was minimally effective in reducing A1C compared with placebo (mean difference 0.4 to 0.5 percentage points) [61,62]. Common side effects include nausea, vomiting, dizziness, and headache [63]. The mechanism of action in reducing blood sugar is unknown.

Given its modest glucose-lowering effect, very frequent GI side effects, and the availability of more effective drugs, we do not recommend bromocriptine for the treatment of type 2 diabetes.

SURGICAL TREATMENT OF OBESITY — Bariatric surgical procedures in patients with type 2 diabetes and obesity that result in sustained major weight loss have been shown to lead to remission of diabetes in a substantial fraction of patients. Surgical treatment of obesity is an option to treat type 2 diabetes in appropriate surgical candidates with [64,65]:

●Body mass index (BMI) ≥40 kg/m² (BMI ≥37.5 kg/m² in Asian Americans)

●BMI 35 to 39.9 kg/m² (BMI 32.5 to 37.4 kg/m² in Asian Americans) when hyperglycemia is inadequately managed by lifestyle measures and optimal medical therapy

Surgical treatment has also been endorsed in patients with type 2 diabetes with BMI 30 to 34.9 kg/m² if hyperglycemia has been inadequately managed despite optimal treatment with medications, especially if other obesity-related comorbidities are present. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education' and "Obesity in adults: Overview of management", section on 'Comprehensive lifestyle intervention'.)

There are a growing number of unblinded trials comparing bariatric surgery with medical therapy for the treatment of type 2 diabetes (see "Outcomes of bariatric surgery", section on 'Diabetes mellitus'). In a meta-analysis of trials comparing bariatric surgery with medical/lifestyle treatments for type 2 diabetes, surgery reduced weight and improved glycemia more effectively than medical/lifestyle interventions (median A1C reduction 2 versus 0.5 percentage points for conventional therapy) [64]. However, very few trials have long-term (>3 years) follow-up, and although observational data suggest improvement in micro- and macrovascular outcomes [66,67], there are no long-term, high-quality studies (randomized trials) on improvement in micro- and macrovascular complications. In addition, there is relapse of diabetes over time, with 35 to 50 percent of patients who initially achieved remission of diabetes experiencing a recurrence [65,68]. Remission of diabetes is generally defined as a return to "normal" measures of glucose metabolism (A1C <6.5 percent and fasting glucose <100 mg/dL [5.6 mmol/L]) without glucose-lowering medication for at least one year [69]. Nevertheless, bariatric surgery improves glycemia substantially and significantly more than medication therapy, and most patients have substantial improvement in glycemic management for at least 5 to 15 years after surgery.

Despite these impressive metabolic results, concerns remain about acute postoperative complications including the need for reoperations and rehospitalizations and rare, but potentially severe, adverse events; the long-term success rates in maintaining weight loss [64,70,71]; and the reproducibility of the results in patients with an extensive history of diabetes or with different surgical teams [72]. Some weight regain is typical within two to three years of bariatric procedures, and different bariatric procedures result in different levels of weight loss and corresponding reductions in glycemia. Bariatric surgery procedures are reviewed in detail elsewhere. (See "Bariatric procedures for the management of severe obesity: Descriptions" and "Bariatric surgery for management of obesity: Indications and preoperative preparation" and "Bariatric operations: Perioperative morbidity and mortality".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Diabetes mellitus in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Type 2 diabetes (The Basics)" and "Patient education: Treatment for type 2 diabetes (The Basics)")

●Beyond the Basics topics (see "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and "Patient education: Blood glucose monitoring in diabetes (Beyond the Basics)" and "Patient education: Preventing complications from diabetes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The foundation of treatment of patients with type 2 diabetes mellitus includes lifestyle changes focusing on diet, increased physical activity and exercise, and weight reduction, reinforced by consultation with a registered dietitian and diabetes self-management education. In the absence of contraindications, metformin is usually the initial pharmacologic therapy for most patients with type 2 diabetes. Initial management is discussed elsewhere. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

●After a successful initial response to oral therapy, the majority of patients fail to maintain target glycated hemoglobin (A1C) levels during the subsequent three to five years. For most patients, we recommend a second medication when the individualized glycemic treatment goal is not achieved with metformin plus lifestyle intervention (Grade 1B). This decision is based on A1C assay results typically performed every three to six months after initial therapy. (See 'Indications for a second agent' above.)

Most young patients without established complications should have an A1C goal of <7 percent (53 mmol/mol) (calculator 1) if this can be achieved without significant hypoglycemia or other side effects. An A1C goal of <7 percent, however, is not appropriate for all patients, especially older adults and those with comorbid conditions (see "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'). In addition, the goal is not practical for all patients, due to patient preferences and side effects of medications. Individualized glycemic goals are required for such patients.

●For patients who do not achieve their goal glycemia on initial oral therapy, there are many medication classes that are available and can be used with metformin. Options include a short-acting sulfonylurea (eg, glipizide, glimepiride), insulin, glucagon-like peptide 1 (GLP-1) agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors, repaglinide (if sulfonylurea not chosen as initial therapy), pioglitazone, and dipeptidyl peptidase 4 (DPP-4) inhibitors (figure 1). All of these medications have advantages and disadvantages (table 2). (See 'Monotherapy failure' above.) (Related Pathway(s): Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to metformin monotherapy and Diabetes: Therapy for non-pregnant adults with type 2 DM and an inadequate response to sulfonylurea monotherapy.)

●For patients with A1C >9 percent (74.9 mmol/mol) or with persistent symptoms of hyperglycemia, we suggest adding insulin or a GLP-1 receptor agonist (Grade 2B). While basal insulin has historically been the preferred medication to add to metformin when A1C is elevated (even in the absence of catabolic features), GLP-1 receptor agonists are a reasonable option when type 1 diabetes has been excluded. (See 'Without established cardiovascular or kidney disease' above.)

●For patients with A1C ≤9 percent, the choice of a second medication should be individualized based upon efficacy, risk for hypoglycemia, the patient's comorbid conditions, impact on weight, side effects, and cost. (See 'Without established cardiovascular or kidney disease' above.)

•For patients with existing cardiorenal comorbidities who have persistent hyperglycemia while taking metformin, we recommend adding a GLP-1 receptor agonist (liraglutide, semaglutide, or dulaglutide) or an SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin) that has demonstrated cardiorenal benefit (Grade 1B). To select a medication, we use shared decision-making with a focus on beneficial and adverse effects within the context of the degree of hyperglycemia as well as a patient's comorbidities and preferences. (See 'Established cardiovascular or kidney disease' above.)

The majority of patients in the cardiovascular and renal outcomes trials had established cardiovascular disease (CVD) or diabetic kidney disease (DKD) with severely increased albuminuria, and therefore, these are the primary indications for one of these drugs. Patients at high CVD risk but without a prior event might benefit, but the data are less supportive. Similarly, patients without severely increased albuminuria have some benefit, but the absolute benefits are greater among those with severely increased albuminuria.

•For patients without established cardiorenal disease who have persistent hyperglycemia while taking metformin, we choose an alternative glucose-lowering medication guided by efficacy, patient comorbidities, preferences, and cost. (See 'Without established cardiovascular or kidney disease' above.)

●For patients with inadequate glycemic management on dual therapy, the choice of additional therapy should be individualized similarly as for patients with monotherapy failure based upon efficacy, risk of hypoglycemia, the patient's underlying comorbidities, impact on weight, side effects, and cost. (See 'Dual agent failure' above.)

•For most patients who do not achieve target A1C with initial dual therapy, we suggest starting insulin or a GLP-1 receptor agonist (Grade 2B) (if neither already chosen as a second agent). In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally tapered and discontinued, while metformin is continued. In patients on DPP-4 inhibitors who are starting GLP-1 receptor agonist, the DPP-4 inhibitor is discontinued, while metformin is continued. (See 'Dual agent failure' above and 'Insulin initiation and intensification' above.) (Related Pathway(s): Diabetes: Initial therapy for non-pregnant adults with type 2 DM.)

An alternative is two oral agents and a GLP-1 receptor agonist, particularly in patients in whom weight loss or avoidance of hypoglycemia is a primary consideration. Of note, GLP-1 receptor agonists and DPP-4 inhibitors should not be combined. Another option for patients close to glycemic goals is three oral agents (eg, metformin, sulfonylurea plus: DPP-4 inhibitor, SGLT2 inhibitor, or pioglitazone). Although guidelines suggest combining SGLT2 inhibitors and GLP-1 receptor agonists, we rarely do so given the absence of data showing additive cardiorenal benefit and increased patient burden (cost, polypharmacy, adverse effects). However, we do combine the medications in selected cases.

●For selected patients with type 2 diabetes and obesity (appropriate surgical candidates with body mass index [BMI] ≥40 kg/m² or BMI 35 to 39.9 kg/m² when hyperglycemia is inadequately managed by lifestyle measures and optimal medical therapy), we suggest bariatric surgery (Grade 2B). Bariatric surgery may also be an option in patients with lower BMI (30 to 34.9 kg/m²) when hyperglycemia is inadequately managed by optimal medical therapy, especially when other obesity-related comorbidities are present. However, longer-term follow-up of clinically important endpoints, such as effects on micro- and macrovascular complications and mortality, is required before bariatric surgery procedures can be routinely recommended for the treatment of persistent hyperglycemia, resistant to multiple medications, in obesity-related type 2 diabetes. (See 'Surgical treatment of obesity' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.