Version October 2024
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 in the setting of very high glucose levels, eg, glycated hemoglobin [A1C] >9 percent) [1]. The natural history of most patients with type 2 diabetes is for blood glucose concentrations to rise gradually with time, requiring therapy intensification.
Treatments for hyperglycemia that fails to respond to initial monotherapy or 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: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite 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 and underscores the importance of avoiding delay in treatment intensification (figure 1) [1,2].
In some patients, early combination therapy is warranted for the kidney or heart protective benefit imparted by selected classes of glucose-lowering medications. (See 'Established cardiovascular or kidney disease' below and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Patient selection' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Patient selection'.)
Glycemic goals — Target 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 (eg, aged <65 years) 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 [3]. Glycemic targets are reviewed in more detail separately. (See "Glycemic management and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.) (Related Pathway(s): Diabetes: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite monotherapy.)
In order to achieve an A1C goal <7 percent, the following glucose goals are conventionally proposed, but slightly higher levels usually suffice [4,5]:
●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 therapy, 5 to 10 percent of patients per year no longer meet target A1C levels (<7 percent) (figure 2 and figure 3) [6-8].
●UKPDS – 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 [9].
●GRADE – In the GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness) trial, which compared the efficacy and longevity of four different medications (U-100 glargine, liraglutide, glimepiride, sitagliptin) added to metformin, all four medication combinations resulted in average A1C levels <7 percent, but 71 percent of participants had glycemic deterioration on the randomly assigned treatment (defined as an A1C ≥7 percent) over a mean follow-up of five years [10]. (See 'Without established cardiovascular or kidney disease' below.)
Causes of rising glycemia — Among the factors that can contribute to worsening glycemia are:
●Decreased adherence to diet, exercise, or the medical regimen.
●Weight gain.
●Progression of the underlying diabetes disease process, including decreased insulin secretion and increased insulin resistance (eg, due to weight gain).
●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].
●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 have A1C levels above goal for years owing to a delay in (or absence of) medication changes to improve glycemic management [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 have deterioration of glycemic management on 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 [1,2,18,19]. The guidelines emphasize the importance of individualizing the choice of medications for the treatment of diabetes, considering important comorbidities (including cardiovascular disease [CVD], heart failure (HF), diabetic kidney disease (DKD), 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 [20]. Short-acting sulfonylureas are preferred to reduce the risk of hypoglycemia. (Related Pathway(s): Diabetes: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite 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 are few high-quality, longer-term, head-to-head drug comparison trials, particularly trials examining clinically important health outcomes (cardiovascular events, mortality) in patients without existing or multiple risk factors for atherosclerotic CVD (ASCVD). (See 'Without established cardiovascular or kidney disease' below.)
●In the GRADE comparative effectiveness trial, basal insulin or a GLP-1 receptor agonist added to metformin maintained A1C <7 percent more effectively than a DPP-4 inhibitor or sulfonylurea [10]).
●In a network meta-analysis of 296 trials evaluating the effects of selected metformin-based combinations on A1C, mortality, and vascular outcomes in a heterogeneous group of patients with variable cardiovascular risk, 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) [21]. In patients at low cardiovascular risk, all treatments were similar to placebo for vascular outcomes. In 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 cotransporter 2 (SGLT2) inhibitors, in general, had favorable effects on hospitalization for HF and progression of kidney disease.
●In other meta-analyses, metformin combination therapy decreased A1C levels more than metformin monotherapy by approximately 1 percentage point [22,23]. Most combinations similarly reduced A1C. Moderate evidence favored metformin plus a GLP-1 receptor agonist over metformin plus a dipeptidyl peptidase 4 (DPP-4) inhibitor for reducing A1C levels [22]. 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 the generic components individually.
Monotherapy failure — For patients with deterioration of glycemic management while taking initial oral monotherapy, many available medication classes can be used with metformin or in combination with each other if metformin is contraindicated or not tolerated. (Related Pathway(s): Diabetes: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite 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, a GLP-1 receptor agonist, or a dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist are the suggested second-line medications, as they have been shown to have the best glycemic efficacy (algorithm 1) [21]. We do not typically use an SGLT2 inhibitor in this setting due to inferior glycemic efficacy [24,25] 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 an effective alternative to basal insulin when type 1 diabetes is not likely. However, no long-term studies have compared insulin and GLP-1 receptor agonists when the starting A1C is very high (eg, >9 percent). For patients with established ASCVD in particular, specific GLP-1 receptor agonists that have demonstrated cardiovascular benefit (liraglutide, semaglutide, or dulaglutide) may be preferred, provided 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-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on '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; to be removed from the United States market December 2024), 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. However, longer-acting analogs are similar to NPH with regard to total or severe hypoglycemia and have the important disadvantage of higher cost. These data 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 [26]. There are few trials, however, evaluating clinically important outcomes, such as cardiovascular or all-cause mortality, with combined metformin and insulin [27].
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 4) [27-30]. In the United Kingdom Prospective Diabetes Study (UKPDS), the combination of insulin with metformin was also associated with significantly less weight gain than twice-daily insulin injections or insulin combined with sulfonylureas [31]. This is consistent with other observations that metformin alone does not usually produce weight gain [7] and may result in modest weight loss [32]. 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 indicated based on labeling and usual clinical practice [33,34]. With those caveats, subcutaneous injection GLP-1 receptor agonists may be as effective as basal insulin in patients with initially high A1C levels [35,36].
GLP-1 receptor agonists have been compared with basal insulin in combination with metformin, often as a third agent added 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 [10]. In a 26-week trial that enrolled patients with A1C values 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 [33]. These trials are reviewed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)
●Dual-acting GLP-1 and GIP receptor agonist – Tirzepatide is a dual-acting GLP-1 and GIP receptor agonist with high glucose-lowering efficacy. In a 40-week trial that compared tirzepatide with semaglutide in 1878 participants with type 2 diabetes, tirzepatide conferred greater reduction in A1C and body weight [37]. Clinical data are not yet available to establish whether tirzepatide also provides the cardiovascular or kidney protective benefits shown for some GLP-1 receptor agonists. Trial data demonstrating the glycemic and weight loss efficacy of tirzepatide are reviewed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Clinical outcomes'.)
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. Data from small trials demonstrate substantial inter-individual variability in treatment response to specific medications for endpoints including glycemia and reduction in albuminuria [38,39], further underscoring the importance of individualized therapy.
Established cardiovascular or kidney disease — For patients with existing ASCVD, HF, or albuminuric DKD, a glucose-lowering medication with evidence of cardiac or kidney benefit should be added to metformin (algorithm 2).
As examples:
●ASCVD – For patients in whom ASCVD is the predominant comorbidity, particularly in the setting of higher A1C or motivation to lose weight, we typically prefer liraglutide, subcutaneous semaglutide, or dulaglutide. SGLT2 inhibitors with cardiovascular benefit (empagliflozin or canagliflozin) are good alternatives. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
●HF and/or DKD – For patients in whom HF or DKD (albuminuria [urine albumin excretion >200 mg/day] and estimated glomerular filtration rate [eGFR] <60 but ≥25 mL/min/1.73 m2) is the predominant comorbidity, 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 DKD. 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, cardiac and kidney benefits have been shown in patients with eGFR below this threshold. (See "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 and those from network meta-analyses [40-42] largely support our approach outlined above:
●When compared with placebo, the GLP-1 receptor agonists liraglutide, subcutaneous semaglutide, and dulaglutide demonstrated favorable atherosclerotic cardiovascular and kidney outcomes, including a reduction in cardiovascular and overall mortality [40,43-49]. (See "Glucagon-like peptide 1-based therapies 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 cardiovascular and kidney outcomes, especially for HF hospitalization, risk of kidney disease progression, and cardiovascular and overall mortality [40,48-54]. (See "Sodium-glucose cotransporter 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 medications. Patients at high CVD risk but without a prior event might benefit, but the data are less definitive [48]. Similarly, patients without severely increased albuminuria derive 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 HF 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) [55]. 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.
●Considering the small ASCVD benefit of SGLT2 inhibitors [40,41,55] and the benefit of GLP-1 receptor agonists on stroke observed in the semaglutide [43] and dulaglutide [46] cardiovascular outcomes trials, as well as their efficacy for overall diabetes management, many of us favor them over SGLT2 inhibitors in the absence of HF or DKD [56].
Of note, SGLT2 inhibitors, which are relatively weak glucose-lowering agents, have lower glycemic efficacy as eGFR declines, particularly with eGFR <45 mL/min/1.73 m2. In this setting, an alternative or 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, with monitoring for GI side effects, which could precipitate dehydration and acute kidney injury (AKI). (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Microvascular outcomes'.)
SGLT2 inhibitors should be used with caution in patients with frequent genitourinary yeast infections or other genitourinary conditions, 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). SGLT2 inhibitors should be held for three to four days prior to procedures, colonoscopy preparation, and with poor oral intake to prevent diabetic ketoacidosis. (See "Sodium-glucose cotransporter 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 CKD 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 linagliptin (which does not require renal dose adjustment), cautious use of a GLP-1 receptor agonist or insulin, a short-acting, low-dose sulfonylurea (eg, glipizide), or repaglinide. (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 — For most 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 suggest a GLP-1 receptor agonist or basal insulin based on the results of the GRADE trial, a comparative effectiveness study of commonly used classes of glucose lowering medications (algorithm 2) [10,57].
In the GRADE trial, choice of a second glucose-lowering medication was evaluated in 5047 patients with type 2 diabetes (A1C 6.8 to 8.5 percent [50.8 to 69.4 mmol/mol], mean body mass index [BMI] 34 kg/m2) and low baseline prevalence of cardiovascular or kidney disease [10]. Participants with hyperglycemia despite taking maximum tolerated doses of metformin were randomly assigned to treatment with U-100 glargine, liraglutide, glimepiride, or sitagliptin. Over a mean follow-up of five years, all four medications lowered A1C levels. The proportion of patients with A1C ≥7 percent was modestly lower with glargine (67.4 percent, hazard ratio [HR] 0.87, 95% CI 0.80-0.94 compared with the other three treatments combined) and liraglutide (68.2 percent, HR 0.84, 95% CI 0.78-0.91) than with glimepiride (72.4 percent, HR 1.01, 95% CI 0.93-1.09) or sitagliptin (77.4 percent, HR 1.37, 95% CI 1.27-1.48). The medications had a parallel effect on the secondary metabolic outcome, with 39 percent of glargine-treated participants exceeding A1C >7.5 percent compared with 46, 50, and 55 percent with liraglutide, glimepiride, and sitagliptin, respectively [10].
The proportion of individuals with weight gain of ≥10 percent was lowest in the liraglutide group (6.1 versus 13.1, 12.1, and 9.1 percent for glargine, glimepiride, and sitagliptin, respectively) [10]. The proportion of individuals with severe hypoglycemia was highest in the glimepiride group (2.2 versus 1.3, 1, and 0.7 percent for glargine, liraglutide, and sitagliptin, respectively). Liraglutide had the highest frequency of gastrointestinal side effects.
The treatment groups did not differ in the rate of the prespecified secondary micro- or macrovascular outcomes, including moderately or severely increased albuminuria, reduced kidney function, peripheral neuropathy, major adverse cardiovascular events (MACE), hospitalization for HF, cardiovascular mortality, or overall mortality [57,58]. However, there was a small reduction in the incidence of any CVD (defined as first incidence of MACE, hospitalization for unstable angina or HF, or revascularization in any arterial bed) with liraglutide (6.6 percent) compared with the other medications (9, 9.2, and 9.6 percent for insulin, glimepiride, and sitagliptin, respectively; HR 0.7, 95% CI 0.6-0.9 for liraglutide compared with the other three medications combined).
The GRADE trial was designed and launched prior to the availability of SGLT2 inhibitors. SGLT2 inhibitors have lower glycemic efficacy compared with basal insulin and GLP-1 receptor agonists [21]. The cardiovascular benefit of SGLT2 inhibitors has not been demonstrated in those at low cardiovascular risk.
Shorter-term trial data also support selection of the dual-acting GLP-1 and GIP receptor agonist tirzepatide as a second glucose-lowering agent, particularly in individuals for whom substantial body weight loss is a treatment goal. Trial data for tirzepatide are reviewed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Clinical outcomes'.)
For patients who are opposed to injection therapy and/or who decline or cannot tolerate GLP-1 receptor agonists or insulin, GRADE demonstrated that other available medications also effectively reduce A1C. The choice of an alternative glucose-lowering medication is guided by efficacy, patient comorbidities, preferences, side effects, and cost (algorithm 2).
●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 modest 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) [59]. 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, 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, a dual-acting GLP-1 and GIP receptor agonist (tirzepatide), 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. Weight loss effects are stronger when the medication is combined with sustained efforts at dietary modification.
●Metabolic dysfunction-associated steatohepatitis (MASH) – For patients with MASH, any drug that causes weight loss should theoretically be beneficial. In patients with diabetes mellitus and biopsy-proven MASH, pioglitazone has been shown to improve fibrosis as well as inflammation and steatosis. GLP-1-based therapies also appear to improve liver biopsy evidence of MASH. These studies are reviewed in detail separately. (See "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Patients with MASH 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, HF, fractures, and the potential increased risk of bladder cancer. It may play a role in the treatment of selected patients with steatotic liver disease or severe insulin resistance who are at low risk for heart failure or fractures. (See "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Patients with MASH and diabetes' and "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Safety' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Adverse effects'.)
Trials comparing other combinations are reviewed separately in the individual topics. (See "Glucagon-like peptide 1-based therapies 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 cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Glycemic efficacy'.)
Dual agent failure — For patients who have deterioration of glycemic management on 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 or dual-acting GLP-1 and GIP receptor agonist, but DPP-4 inhibitors and GLP-1/dual-acting receptor agonists should not be combined [60].
●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 [60]).
Although guidelines suggest combining SGLT2 inhibitors and GLP-1 receptor agonists [1], we do not usually add an SGLT2 inhibitor to GLP-1 receptor agonist therapy for hyperglycemia alone given the absence of data showing additive cardiovascular and kidney benefit and increased patient burden (cost, polypharmacy, adverse effects). However, we do combine the medications if strong indications exist for each class (eg, a patient with type 2 diabetes, obesity, A1C >9 percent, and severely elevated albuminuria).
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-based therapy (see 'Insulin initiation and intensification' below). In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally discontinued, while metformin is continued. In patients on a DPP-4 inhibitor who are starting a GLP-1 receptor agonist or dual-acting GLP-1 and GIP receptor agonist, the DPP-4 inhibitor should be discontinued.
●For appropriate patients with cardiovascular and kidney 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-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose cotransporter 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 [61]. 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, and tirzepatide imparted even greater A1C reduction. However, these trials did not directly compare the third-line agents with each other. Moreover, only the GRADE study was of sufficient duration to determine long-term glycemic effects.
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 [62]. Patients should measure blood glucose at appropriate times, and usually once to twice per day, depending on the insulin used and timing of administration. For example, if bedtime NPH is used, it should be adjusted based on fasting glucose levels. More frequent self-monitoring should be implemented 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 'Monitoring and dose titration'.) (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 5). 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-based therapies 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 ambulatory 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 [7]. MDI in type 2 diabetes may require high doses of insulin to overcome insulin resistance and can be associated with substantial weight gain (averaging 8.7 kg in one study) [26]. Patients with type 2 diabetes with generalized obesity or with central overweight, often with steatotic liver disease, frequently require insulin doses in the range of 65 to 100 units per day or much higher. Although the total daily dose of insulin may be high, the insulin dose per kilogram is less remarkable. High daily insulin requirements may 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 'Bariatric (metabolic) surgery' below and "Medical nutrition therapy for type 2 diabetes mellitus".)
CARDIOVASCULAR AND OTHER OUTCOMES — In the decade following new US Food and Drug Administration (FDA) guidance released in 2008, approved diabetes drugs were required to be evaluated for cardiovascular disease (CVD) safety with large trials. The vast majority of these CVD safety studies were placebo-controlled and enrolled all or a majority of patients with pre-existing 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 less clear. Thus, the results of these trials are most applicable to patients similar to the trial population and not to all patients with type 2 diabetes [2,63]. Cardiovascular benefit has been demonstrated for some of these medications when taken in combination with metformin, but benefit has not been definitively established in drug-naïve patients at low to moderate cardiovascular risk. (See 'Without established cardiovascular or kidney disease' above.)
The cardiovascular effects of each diabetes drug (when data are available) is 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-based therapies 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 cotransporter 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 safety'.)
MEDICATIONS NOT USUALLY RECOMMENDED
●Alpha-glucosidase inhibitors – Acarbose and miglitol are not preferred second- or third-line medications, because of generally poor tolerance due to gastrointestinal side effects that do not lessen over time and low glucose-lowering effectiveness [2,64]. They can reduce A1C values slightly (0.5 to 1 percentage points) when taken in conjunction with any other form of therapy [65,66]. 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 approved and 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 [67]. One possibility is that bile acid sequestrants act in the GI tract to reduce glucose absorption.
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) [68]. 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 [69,70]. The clinical implications of this increase are unknown. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Apolipoprotein C-III'.)
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.
●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 'Initial therapy'.)
A quick-release formulation of bromocriptine has been approved by the FDA for the treatment of type 2 diabetes mellitus [71]. 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) [71,72]. Common side effects include nausea, vomiting, dizziness, and headache [73]. 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.
BARIATRIC (METABOLIC) SURGERY — In patients with type 2 diabetes and obesity, bariatric and metabolic surgical procedures that result in sustained, major weight loss have been shown to lead to at least temporary remission of diabetes in a substantial fraction of patients and reduced glycemia and need for medications in almost all patients. Bariatric surgical procedures are targeted at weight loss in the setting of obesity; the term "metabolic surgery" is used when a major goal of surgery is to improve diabetes or other metabolic diseases (eg, metabolic dysfunction-associated steatotic liver disease).
Patient selection — Surgical treatment of obesity is an option to treat type 2 diabetes in appropriate surgical candidates with [74]:
●Body mass index (BMI) ≥40 kg/m2 (BMI ≥37.5 kg/m2 in individuals with Asian ancestry)
●BMI 35 to 39.9 kg/m2 (BMI 32.5 to 37.4 kg/m2 in individuals with Asian ancestry) 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 (or ≥27.5 kg/m2 in individuals with Asian ancestry) if hyperglycemia has been inadequately managed despite optimal treatment with medications, especially if other obesity-related comorbidities are present, and is now recommended by the ADA [75]. Given the availability of increasingly potent GLP-1-based therapies such as tirzepatide and lack of comparative effectiveness data for bariatric surgery and these potent agents, we review these options with our patients and engage in shared decision-making. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education' and "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Indications'.)
Outcomes — Unblinded trials have compared 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 body weight and improved glycemia more effectively than medical/lifestyle interventions (median A1C reduction 2 versus 0.5 percentage points for conventional therapy) [74].
●Diabetes remission – An international group of experts convened by the American Diabetes Association (ADA) defines diabetes remission as an A1C <6.5 percent sustained for at least three months following discontinuation of any glucose-lowering medications [76]. In a prospective observational study of 316 patients with type 2 diabetes who previously participated in a trial of surgery versus medical/lifestyle therapy, diabetes remission (A1C ≤6.5 percent for three months without medication) at three years was achieved in 37.5 and 2.6 percent of patients, respectively [77]. Among participants who underwent extended follow-up, the rate of diabetes remission after bariatric surgery (n = 166) was 18.2 percent at seven years and 12.7 percent at 12 years, whereas after medical/lifestyle therapy (n = 96), the remission rate reached zero by 12 years [78]. These results are similar to other studies that have reported diabetes relapse in 35 to 50 percent of patients who initially achieved remission after surgery [75,79].
Nevertheless, bariatric surgery improves glycemia substantially and significantly more than medication therapy, and most patients have marked improvement in glycemic management for at least 5 to 15 years after surgery [78].
●Diabetes-related complications – Although observational data suggest improvement in micro- and macrovascular outcomes after bariatric surgery and/or diabetes remission [80-84], there are no long-term, high-quality studies (randomized trials) of micro- and macrovascular complications. The effects of bariatric surgery on diabetes-related complications are reviewed in detail elsewhere. (See "Outcomes of bariatric surgery", section on 'Diabetic complications'.)
Risks and concerns — 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, as well as the long-term success rates in maintaining weight loss [74,85,86]. Some weight regain is typical within two to three years of bariatric procedures, and different procedures result in different levels of weight loss and corresponding reductions in glycemia. Bariatric surgical 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: Early (fewer than 30 days) 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" and "Society guideline links: Diabetic kidney disease".)
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 5th to 6th 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 10th to 12th 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: Glucose monitoring in diabetes (Beyond the Basics)" and "Patient education: Preventing complications from diabetes (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Indication for a second agent – 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 glycated hemoglobin (A1C) assay results (calculator 1) typically performed every three to six months after initial therapy. After a successful initial response to lifestyle intervention and oral therapy, the majority of patients do not maintain target A1C levels during the subsequent three to five years. (See 'Indications for a second agent' above.)
●Monotherapy failure – For patients who do not achieve their goal glycemia on initial oral therapy, many medication classes are available that can be used with metformin. Options include glucagon-like peptide 1 (GLP-1) receptor agonists, a dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (tirzepatide), sodium-glucose co-transporter 2 (SGLT2) inhibitors, short-acting sulfonylureas (eg, glipizide, glimepiride), repaglinide (if sulfonylurea not chosen as initial therapy), insulin, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone (figure 1 and table 2). For patients with persistent hyperglycemia while taking a maximally tolerated dose of metformin, 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. (See 'Monotherapy failure' above.) (Related Pathway(s): Diabetes: Medication selection for non-pregnant adults with type 2 DM and persistent hyperglycemia despite monotherapy.)
●A1C >9 percent – For patients with A1C >9 percent (74.9 mmol/mol), we suggest adding insulin, a GLP-1 receptor agonist, or a dual-acting GLP-1 and GIP receptor agonist (Grade 2B). These agents have been shown to have the best glycemic efficacy (algorithm 1). (See 'A1C >9 percent (74.9 mmol/mol) or persistent symptoms of hyperglycemia' above.)
•Catabolic symptoms – Insulin is always effective and is preferred in catabolic diabetes (eg, polyuria, polydipsia, weight loss) or when distinguishing between type 1 and type 2 diabetes is difficult.
•Existing cardiovascular disease or high atherosclerotic cardiovascular disease (ASCVD) risk – For patients with established ASCVD or high ASCVD risk, specific GLP-1 receptor agonists that have demonstrated cardiovascular benefit (liraglutide, subcutaneous semaglutide, or dulaglutide) are preferred, assuming that they achieve the desired glycemic target.
•Without catabolic symptoms or ASCVD disease – For patients without either catabolic symptoms or existing cardiac disease, a GLP-1 receptor agonist or dual-acting GLP-1 and GIP receptor agonist may be favored when weight loss is important. Gastrointestinal (GI) side effects, contraindications, and cost may limit their use.
●A1C ≤9 percent – For patients with A1C ≤9 percent, the choice of a second medication should be individualized primarily based upon the presence of cardiovascular or kidney comorbidities (algorithm 2). (See 'Without established cardiovascular or kidney disease' above.)
•Cardiovascular and/or kidney comorbidities – For patients with existing cardiovascular and kidney comorbidities who have persistent hyperglycemia while taking metformin, we recommend adding a GLP-1 receptor agonist (liraglutide, subcutaneous semaglutide, or dulaglutide) or an SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin) that has demonstrated cardiovascular and kidney 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 (algorithm 2). (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.
•Absence of ASCVD, heart failure (HF), or DKD – For patients without established cardiovascular or kidney disease who have persistent hyperglycemia while taking metformin, we suggest a GLP-1 receptor agonist or basal insulin (Grade 2C). For patients who are opposed to injection therapy and/or who decline or cannot tolerate GLP-1 receptor agonists or insulin, other available medications also effectively reduce A1C. The choice of an alternative glucose-lowering medication is guided by efficacy, patient comorbidities, preferences, side effects, and cost. (algorithm 2). (See 'Without established cardiovascular or kidney disease' above.)
●Dual agent failure – 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-based therapy (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 a GLP-1 receptor agonist or dual-acting GLP-1 and GIP 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 or dual-acting GLP-1 and GIP receptor agonist, particularly for patients in whom weight loss or avoidance of hypoglycemia is a primary consideration. These GLP-1-based therapies should not be combined with DPP-4 inhibitors. 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 do not usually add an SGLT2 inhibitor to GLP-1 receptor agonist therapy for management of hyperglycemia alone, given the absence of data showing additive cardiovascular and kidney benefit and increased patient burden (cost, polypharmacy, adverse effects). However, we do combine the medications if strong indications exist for each class (eg, a patient with type 2 diabetes, obesity, A1C >9 percent, and severely elevated albuminuria).
●Obesity class II or III – 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. Patients seeking bariatric surgery should be counseled to develop coping skills, eliminate maladaptive behavior, and understand the risks and benefits of the surgery. (See 'Bariatric (metabolic) surgery' above and "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Preoperative counseling'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.
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