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Management of persistent hyperglycemia in type 2 diabetes mellitus
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Management of persistent hyperglycemia in type 2 diabetes mellitus
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Sep 15, 2016.

INTRODUCTION — Initial treatment of patients with type 2 diabetes mellitus includes education, with emphasis on lifestyle changes including diet, exercise, and weight reduction when appropriate. Monotherapy with metformin is indicated for most patients, and insulin may be indicated for initial treatment for some [1]. Although several studies have noted remissions of type 2 diabetes mellitus that may last several years, most patients require continuous treatment in order to maintain normal or near-normal glycemia. Regardless of the initial response to therapy, the natural history of most patients with type 2 diabetes is for blood glucose concentrations to rise gradually with time.

Treatment for hyperglycemia that fails to respond to initial monotherapy and long-term pharmacologic therapy in type 2 diabetes is 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 blood glucose in adults with type 2 diabetes mellitus" and "Overview of medical care in adults with diabetes mellitus".)

INDICATIONS FOR A SECOND AGENT — We agree with the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus guideline for pharmacotherapy to control hyperglycemia in type 2 diabetes, which recommends testing glycated hemoglobin (A1C) levels every three months and the addition of a second medication when the treatment goal of A1C <7 percent with metformin plus lifestyle intervention is not achieved within three months (algorithm 1) [1,2]. We are aware that this A1C goal is not appropriate for all patients, especially older adults and those with comorbid conditions or limited life expectancy. Target A1C goals in patients with type 2 diabetes should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia. Glycemic targets are generally set somewhat higher for older patients and those with comorbidities or a limited life expectancy and little likelihood of benefit from intensive therapy. Glycemic targets are reviewed in more detail separately. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Glycemic targets'.)

In order to achieve an A1C goal <7 percent, the following glucose goals are usually necessary [3]:

Fasting glucose 135 to 150 mg/dL (7.5 to 8.3 mmol/L)

Postprandial glucose (90 to 120 minutes after a meal) 134 to 144 mg/dL (7.4 to 8 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 1) [4-6]. An analysis from the United Kingdom Prospective Diabetes Study (UKPDS) found that 50 percent of relatively new-onset patients identified clinically and originally controlled with a single drug required the addition of a second drug after three years; by nine years, 75 percent of patients needed multiple therapies to achieve the target A1C value [7]. Whether patients with truly new-onset diabetes, identified through screening, behave similarly is unknown.

Among the factors that can contribute to worsening glycemic control are:

Decreased compliance with diet, exercise, or the medical regimen, or weight gain.

An intercurrent illness or the ingestion of drugs that can increase insulin resistance, interfere with insulin release, or increase hepatic glucose production (table 1) [8]. The latter factor (ingestion of certain drugs) is particularly important in older patients who are taking multiple drugs.

Progression of the underlying disease process, including worsening insulin resistance and insulin secretion.

The patient may have 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") [9-12]. 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 control were not made or were only made slowly [9]. Adherence to algorithms that dictate changes in treatment at designated intervals and computerized decision aids may improve A1C more efficiently than standard care [11,13,14].

TREATMENT OPTIONS — The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including insulin, or to switch to insulin (table 2) [1,15]. We favor basal insulin or sulfonylurea as the second step, and insulin is preferred for patients whose glycated hemoglobin (A1C) is further from target (>8.5 percent) or who have symptoms related to hyperglycemia (algorithm 1).

Our selection of drugs is based upon clinical trial evidence and clinical experience in achieving glycemic targets, with the recognition that there is a paucity of high-quality, head-to-head drug comparison trials, particularly trials with clinically important health outcomes (cardiovascular events, mortality). In a meta-analysis of 179 trials and 25 observational studies evaluating the effects of oral or injectable diabetes medications as monotherapy and in combination with other oral agents or insulin on intermediate outcomes (A1C, body weight, lipid profiles), combination therapy decreased A1C levels more than monotherapy by approximately 1 percentage point [16]. Most combinations similarly reduce A1C [16,17]. In one meta-analysis, there was moderate evidence favoring metformin plus a glucagon-like peptide-1 (GLP-1) agonist over metformin plus a dipeptidyl peptidase-4 (DPP-4) inhibitor for reducing A1C levels [16]. The glycemic efficacy of some of the combinations is reviewed below. (See 'Glycemic efficacy' below.)

Metformin monotherapy failure — For patients who fail initial therapy, there are a number of agents that are available and can be used with metformin (table 2). We favor insulin or sulfonylureas as the preferred second-line agents because of efficacy, side-effect profile, long-term safety, and relative cost (algorithm 1).

Insulin is the preferred second-line medication for patients with A1C >8.5 percent or with symptoms of hyperglycemia despite initial therapy with metformin and lifestyle intervention.

For those close to A1C target, we prefer to add a shorter-duration sulfonylurea (such as glipizide, to reduce the risk of hypoglycemia compared with longer-acting sulfonylureas) rather than insulin.

Another reasonable alternative is the addition of repaglinide, which can be considered in individuals who do not reach glycemic goals with metformin, if there are contraindications to sulfonylureas or patient preference limits the use of insulin. Repaglinide is principally metabolized by the liver, with less than 10 percent renally excreted. Thus, it can be used safely in patients with chronic kidney disease. (See "Management of hyperglycemia in patients with type 2 diabetes and pre-dialysis chronic kidney disease or end-stage renal disease", section on 'Meglitinides'.)

GLP-1 receptor agonists may be appropriate to use in certain clinical settings, eg, when weight loss or avoidance of hypoglycemia is a primary consideration, the A1C level is close to target, and cost is not a major barrier. A prior history of myocardial infarction or stroke might also favor choosing liraglutide as the second drug to be added to metformin, based on the results of the liraglutide and cardiovascular outcomes study. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Empagliflozin may also be considered in patients with established cardiovascular disease (CVD). Although both liraglutide and empagliflozin appear to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes and established CVD, the balance between benefits and risks have not been examined in the long term. In addition, there are few data on benefits and risks in patients who have not had a major CVD event. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

DPP-4 inhibitors can be considered as add-on drug therapy for patients who are inadequately controlled on metformin. However, the modest glucose-lowering effectiveness, expense, and limited long-term clinical experience may temper enthusiasm for these drugs. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)

Thiazolidinediones are not considered first-choice agents, due to the risk of congestive heart failure (HF), fractures, and expense. However, in certain clinical settings, such as especially high risk for hypoglycemia or intolerance of or contraindications to sulfonylureas, a thiazolidinedione may be added. As an example, in a patient who would be at particularly high risk if hypoglycemia occurred (eg, a construction worker) and who has inadequate glycemic control on metformin (A1C >7 but <8.5 percent), pioglitazone (where available) could be used. The use of rosiglitazone is not recommended, because of the greater concern about its atherogenic lipid profiles and a potential increased risk for cardiovascular events [1,2]. In 2010, the European Medicines Agency suspended sales of rosiglitazone, owing to concern regarding cardiovascular safety and the availability of alternative therapies, including pioglitazone, that do not have the same concerns. In 2010, the US Food and Drug Administration (FDA) imposed marked restrictions on the prescribing of rosiglitazone because of concerns about increased risk of acute myocardial infarction and cardiovascular deaths. These restrictions were largely removed by the FDA in 2013, although the absence of an adverse effect of rosiglitazone on cardiovascular risk has not been excluded. In 2011, the French and German Medicines Agencies suspended the use of pioglitazone because of the potential increased risk of bladder cancer and the concern that the overall risks of pioglitazone exceed its benefits. The European Medicines Agency, the FDA, and Japanese regulators withheld action on pioglitazone pending results of ongoing review of the data. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Cardiovascular effects' and "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Safety'.)

Combination tablets of metformin and other 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 needs the dose of either drug to 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.

Sulfonylurea monotherapy failure — In individuals with contraindications to metformin, sulfonylureas are often first-line therapy. Shorter-acting sulfonylureas, such as glipizide, are less likely to cause hypoglycemia than the older, long-acting sulfonylureas and therefore are the preferred sulfonylureas, especially in older patients. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Sulfonylureas and meglitinides in the treatment of diabetes mellitus", section on 'Precautions and side effects'.)

In patients with inadequate glycemic control on sulfonylureas and with A1C >8.5 percent, we suggest switching to insulin. In patients who are intolerant or cannot take metformin for any reason and who have an A1C that is <8.5 percent but not at target on sulfonylurea alone, there are a number of agents that are available and can be used with a sulfonylurea. The choice of therapy should be individualized based upon patient characteristics, preferences, and costs. Options include thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors, alpha-glucosidase inhibitors, and insulin. All of these medications have advantages and disadvantages (table 2), and all of the newer medicines that are not available in generic form are relatively expensive. Hypoglycemia remains a risk when any of these medications are used in combination with a sulfonylurea. In general, sulfonylureas are tapered and stopped if insulin is added and especially if the insulin regimen includes preprandial rapid-acting insulin.

GLP-1 receptor agonists may be appropriate to use in combination with sulfonylureas in certain clinical settings, eg, when weight loss is a primary consideration and the A1C level is close to target. A prior history of myocardial infarction or stroke might also favor choosing liraglutide as the second drug, based on the results of the liraglutide and cardiovascular outcomes study. Empagliflozin may also be considered in patients with established CVD. (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 type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Pioglitazone is an option but can be associated with fluid retention, weight gain, and HF. DPP-4 inhibitors or SGLT2 inhibitors can be considered as add-on drug therapy to sulfonylureas in patients who have contraindications to metformin and pioglitazone. However, the modest glucose-lowering effectiveness, expense, and limited long-term clinical experience with these drugs temper our enthusiasm. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Candidates' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Candidates'.)

Dual agent failure — If target A1C is not achieved with metformin combined with sulfonylurea or basal insulin, we suggest starting or intensifying insulin therapy (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. Part of the rationale for combination metformin and insulin therapy is that by suppressing hepatic glucose production, the patient can retain the convenience of oral agents while minimizing total insulin requirements and therefore the degree of hyperinsulinemia [18].

Another option is two oral agents and a GLP-1 receptor agonist. It is reasonable to try a GLP-1 agonist before starting insulin in patients who are close to glycemic goals, who prefer not to start insulin, and in whom weight loss or avoidance of hypoglycemia is a primary consideration. In randomized trials comparing GLP-1 agonists with insulin in patients with type 2 diabetes inadequately controlled with metformin and sulfonylurea, there were similar reductions in A1C in the two groups. However, in some of the trials, the insulin was often not adjusted as aggressively as it could or should have been based on labeling and usual clinical practice. These trials are reviewed separately. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus".)

Another option is to try a third oral agent (eg, pioglitazone, DPP-4 inhibitor) before starting insulin in patients who are close to glycemic goals and who prefer not to start insulin [19,20]. This was illustrated in a study of 217 patients inadequately controlled on dual therapy with sulfonylureas and metformin, who were randomly assigned to receive either insulin glargine or rosiglitazone [19]. At study end (24 weeks), improvements in A1C (approximately 1.5 percentage points) were similar in both groups. However, insulin glargine was superior in reducing A1C values when baseline A1C values were >9.5 percent. Although insulin glargine was associated with more hypoglycemic events, there were fewer overall adverse events, significant improvements in the serum lipid profile, and it was less expensive. Subjects treated with insulin glargine also reported greater improvements in several health-related quality-of-life measurements [21]. These findings, combined with the greater concern about adverse cardiovascular events with thiazolidinediones, particularly rosiglitazone, favor the addition of insulin glargine over rosiglitazone. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Cardiovascular effects'.)

For patients who are not well controlled on two oral agents, switching to insulin is usually less expensive than adding a third oral or injectable agent. This was demonstrated in a study of 188 type 2 diabetic patients with inadequate glycemic control on two oral agents who were randomly assigned to receive a third oral agent or be switched to twice-daily insulin along with metformin [22]. Patients on three oral agents (a sulfonylurea, metformin, and a thiazolidinedione) had similar glycemic control but more side effects, a more atherogenic profile, and substantially higher costs than patients on twice-daily insulin along with metformin.

Insulin initiation and intensification — The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) have developed a flow diagram for initiating and titrating insulin in the management of type 2 diabetes (algorithm 2) [1]. The dose of insulin may be adjusted every three to four days until glycemic targets are achieved.

Diet and exercise patterns should be reviewed in patients whose glycemic control is poor despite insulin therapy. Insulin doses should then be adjusted to achieve target glycemic control. This will usually entail additional injections, often including short or rapid-acting insulin based on postprandial glucose readings (algorithm 2). Daily insulin doses typically exceed 65 to 100 units per day, and may sometimes be much higher, for obese type 2 diabetic patients to achieve near-normal glycemia. Patients should measure blood glucose two to four times daily and should only reduce their insulin dose if hypoglycemia develops.

Use of an intensive insulin regimen (similar to that used in type 1 diabetes) results in higher serum insulin concentrations and better glycemic control than that achieved with either an oral drug or conventional insulin therapy (basal insulin only) alone [5]. This regimen may require large doses of insulin to overcome insulin resistance and can be associated with significant weight gain (averaging 8.7 kg in one study) [18]. In addition to the directly deleterious effects of worsening obesity, it can also lead to partial noncompliance with therapy, particularly in women (see "Nutritional considerations in type 2 diabetes mellitus"). Insulin therapy is discussed in more detail elsewhere. (See "Insulin therapy in type 2 diabetes mellitus" and "General principles of insulin therapy in diabetes mellitus".)

GLYCEMIC EFFICACY — The glycemic efficacy of some of the commonly used combination regimens is reviewed here. Other combinations are reviewed separately in the individual topics. (See "Sulfonylureas and meglitinides in the treatment of diabetes mellitus", section on 'Glycemic efficacy' and "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 type 2 diabetes mellitus", section on 'Glycemic efficacy' and "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus" and "Amylin analogs for the treatment of diabetes mellitus".)

Combination with metformin — Several agents can be used as add-on therapy when metformin monotherapy fails (table 2). In meta-analyses of placebo-controlled trials evaluating different drugs (sulfonylureas, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, glucagon-like peptide-1 [GLP-1] agonists, dipeptidyl peptidase-4 [DPP-4] inhibitors) as add-on therapy to metformin, reductions in glycated hemoglobin (A1C) with different classes of drugs ranged from 0.42 to 1.0 percentage points [23,24]. In one analysis, the reduction in A1C with sulfonylureas compared with placebo was greater than that of thiazolidinediones compared with placebo [23]. However, these trials did not directly compare different agents in combination with metformin. As expected, the use of thiazolidinediones, sulfonylureas, and meglitinides was associated with weight gain, while GLP-1 agonists, alpha-glucosidase inhibitors, and DPP-4 inhibitors were associated with weight loss or no change [24]. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than placebo.

Insulin was not included in one meta-analysis [24], although it is clearly the most effective and one of the least expensive of the antidiabetic medications available. As an example, in a 24-week trial of insulin glargine versus sitagliptin in 515 patients with type 2 diabetes inadequately controlled with metformin monotherapy, there was a greater reduction in A1C in patients randomly assigned to glargine (-1.72 versus -1.13 percent) [25]. (See 'Combination oral and insulin therapy' below.)

The mechanism of action, dosing, monitoring, and adverse effects of metformin are reviewed separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)

Combination with sulfonylureas — The sulfonylureas have been studied in combination with metformin, thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, and insulin [26-28]. 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) [29]. 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 diabetes mellitus".)

Combination oral and insulin therapy — In several studies of patients inadequately controlled with oral agents, combination oral-insulin therapy resulted in equivalent glycemic control with less or no weight gain compared with several daily insulin injections (figure 2) [30-34]. While neutral protamine Hagedorn (NPH) insulin has been used commonly at bedtime to supplement oral hypoglycemic drug therapy, longer-acting insulins, such as insulin glargine (once daily) and detemir (once or twice daily), added to oral agents are similarly effective for reducing A1C values and may cause less nocturnal hypoglycemia, with the important disadvantages of higher cost and fewer long-term safety data. (See "Insulin therapy in type 2 diabetes mellitus".)

Metformin, GLP-1 agonists, DPP-4 inhibitors, and sodium-glucose co-transporter 2 (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 [15].

Metformin and insulin — Based upon the available evidence, we prefer combination metformin-insulin therapy to sulfonylurea-insulin therapy in individuals without contraindications to metformin. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Lactic acidosis'.)

In several trials and a meta-analysis, glycemic control was better with metformin-insulin combinations than with insulin monotherapy or with sulfonylurea-insulin combinations (figure 2) [30,34-36]. 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 [37]. This is consistent with other observations that metformin alone does not usually produce hyperinsulinemia or weight gain [5]. However, there are few trials with clinically important outcomes, such as cardiovascular or all-cause mortality [34].

Sulfonylureas and insulin — Sulfonylureas are the oldest class of oral hypoglycemic agents. Data from the UKPDS and meta-analyses of several randomized, placebo-controlled trials report modest but consistent benefits of combination sulfonylurea and insulin therapy compared with insulin monotherapy [38-41]. However, the combination of sulfonylurea and insulin is less efficacious and results in more weight gain than metformin and insulin (figure 2) [30]. Furthermore, insulin and sulfonylureas have similar mechanisms of action (providing more insulin), and the same glucose-lowering effect can usually be achieved, and at a lower cost, with a modestly higher dose of insulin alone. Thus, we prefer not to use combination sulfonylurea and insulin therapy.

Thiazolidinediones and insulin — The addition of a thiazolidinedione to insulin improves glycemic control compared with insulin monotherapy [42]. However, the combination of insulin plus either rosiglitazone or pioglitazone causes an increased incidence of heart failure (HF) and should be avoided in patients with HF [43]. In addition, both available thiazolidinediones have been associated with bone loss, and rosiglitazone may be associated with other cardiovascular risks, as described above. Thiazolidinediones are also more expensive than metformin. (See "Thiazolidinediones in the treatment of diabetes mellitus".)

GLP-1-based therapy and insulin — Short-term studies using glucagon-like peptide-1 (GLP-1) agonists or DPP-4 inhibitors (vildagliptin, alogliptin) in combination with basal insulin (glargine, detemir) have demonstrated safety and efficacy. These trials are reviewed separately. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus" and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)

CARDIOVASCULAR AND OTHER OUTCOMES — The long-term benefits and risks of using one combination over another are unknown. There is a paucity of high-quality, head-to-head drug comparison trials and trials with important clinical endpoints, such as effects on microvascular and macrovascular complications and mortality [17]. Many of the recently approved diabetes drugs are now being required by the US Food and Drug Administration (FDA) to prove cardiovascular disease (CVD) safety with large trials.

On the basis of these trials and other data, there does not appear to be an increased risk of adverse cardiovascular outcomes with metformin, insulin glargine, or short-term use of dipeptidyl peptidase-4 (DPP-4) inhibitors, used in combination with another oral agent. However, DPP-4 inhibitors may be associated with an increased risk of hospitalization for heart failure (HF).

Thiazolidinediones are associated with an increased risk of fluid retention and HF, and the use of rosiglitazone in particular is not recommended, because of the greater concern about its atherogenic lipid profiles and a potential increased risk for cardiovascular events.

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 "Insulin therapy in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sulfonylureas and meglitinides in the treatment of 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 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 type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

OTHER MEDICATIONS

Alpha-glucosidase inhibitors — Acarbose and miglitol can reduce glycated hemoglobin (A1C) values slightly (0.5 to 1.0 percentage points) when taken in conjunction with any other form of therapy [44,45]. They act predominantly by lowering glucose concentrations after meals but may be poorly tolerated because of flatulence and other gastrointestinal (GI) side effects. They are not preferred second-line medications, because of lower efficacy, poorer tolerance, and increased cost compared with the alternatives above [1,15]. (See "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus".)

Pramlintide — Amylin (also known as islet amyloid polypeptide) is a peptide hormone secreted by pancreatic beta cells in conjunction with insulin in response to nutrient stimuli (see "Pathogenesis of type 2 diabetes mellitus"). 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 insulin. It may be considered for patients with type 2 diabetes inadequately controlled on insulin who are overweight or experience weight gain refractory to lifestyle measures. This topic is discussed in detail elsewhere. (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 control postprandial glucose levels. (See "Inhaled insulin therapy in diabetes mellitus".)

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

Colesevelam is a bile acid sequestrant that lowers low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia (see "Lipid lowering with drugs other than statins and fibrates", section on 'Bile acid sequestrants'). Colesevelam's mechanism of action to improve glycemic control is uncertain [46]. 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) [47]. 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 [48,49]. The clinical implications of this increase are unknown. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Apolipoprotein C-III'.)

Bromocriptine — 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.

Bromocriptine is an ergot-derived dopamine agonist that has been used for over two decades for the treatment of hyperprolactinemia and Parkinson disease. (See "Pharmacologic treatment of Parkinson disease", section on 'Dopamine agonists' and "Management of hyperprolactinemia", section on 'Overview of dopamine agonists'.)

A quick release formulation of bromocriptine (Cycloset) was approved by the FDA for the treatment of type 2 diabetes mellitus [50]. 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) [50,51]. Common side effects include nausea, vomiting, dizziness, and headache [52]. The mechanism of action in reducing blood sugar is unknown.

SURGICAL TREATMENT OF OBESITY — Surgical treatment of obese patients with diabetes results in the largest degree of sustained weight loss (20 to 30 percent after one to two years) and, in parallel, the largest improvements in blood glucose control. There are a growing number of unblinded trials comparing bariatric surgery with medical therapy for the treatment of type 2 diabetes [53-60]. Remission of diabetes is generally defined as a glycated hemoglobin (A1C) level less than 6.5 percent without the use of diabetes medications. As examples:

In a two-year trial of 60 obese patients (body mass index [BMI] 30 to 40 kg/m2) with a history of type 2 diabetes diagnosed within the previous two years, subjects randomly assigned to laparoscopic banding with conventional therapy versus conventional therapy alone (education, lifestyle modification, pharmacologic therapy) experienced greater weight loss (20 versus 1.4 percent, respectively) and remission rates of diabetes (73 versus 13 percent, respectively) [53].

In another trial, 60 patients with obesity (BMI >35 kg/m2) and type 2 diabetes for at least five years were randomly assigned to gastric bypass, biliopancreatic diversion, or medical therapy (pharmacologic therapy, education, lifestyle modification) [54]. In the group assigned to conventional medical therapy, oral agents and/or insulin were titrated to achieve an A1C of <7 percent. At two years, diabetes remission occurred in a greater proportion of patients in the surgical groups (75, 95, and 0 percent for gastric bypass, biliopancreatic diversion, and medical therapy, respectively). The average time to normalization of fasting glucose and A1C levels for bypass and biliopancreatic diversion was 10 and 4 months, respectively. The reduction in average body weight was 33, 34, and 5 percent, respectively. However, there was no correlation between degree of weight loss and normalization of fasting glucose levels.

After five years of follow-up (53 patients), only 56 percent of patients in the surgical groups who had experienced diabetes remission at two years maintained it (7 of 15 [47 percent] in the gastric bypass group and 12 of 19 [63 percent] in the biliopancreatic diversion group) [61]. Compared with the medical group, patients in the surgical groups had significantly lower diabetes and cardiovascular medication use, serum lipids, and weight, although weight regain occurred in both surgical groups (+6.09 and +4.56 kg in the gastric bypass and biliopancreatic diversion groups, versus -1.05 kg in the medical group). Mean A1C levels were in a good range in all participants; however, they were significantly lower in the biliopancreatic diversion group (6.4 versus 6.7 and 6.9 percent in the gastric bypass and medical groups, respectively). The study was not powered to assess long-term diabetes complications.

In a one-year trial, 150 obese (BMI 27 to 43 kg/m2) patients with type 2 diabetes (mean duration approximately eight years) were randomly assigned to gastric bypass, sleeve gastrectomy, or intensive medical therapy [55]. After 12 months, the proportion of patients with A1C ≤6 percent (the primary endpoint) was higher in the surgical groups (42 and 31 percent compared with 12 percent in the medical group). The mean percentage weight loss was 28, 25, and 5 percent, respectively. At three years (137 patients), the proportion of patients with A1C ≤6 percent was 38, 24, and 5 percent for gastric bypass, sleeve gastrectomy, and medical therapy, respectively [62]. The use of glucose-lowering medications was lower in the surgical groups. The mean weight loss from baseline was 24.5, 21.1, and 4.2 percent, respectively.

In another one-year trial, 120 obese patients (BMI 30 to 39.9 kg/m2) with type 2 diabetes (mean duration nine years) who were participating in an intensive lifestyle and medically managed weight control program were randomly assigned to receive Roux-en-Y gastric bypass surgery while continuing the lifestyle program or to continue the lifestyle program alone [56]. The intensive lifestyle modification program was similar to the Action for Health in Diabetes (Look AHEAD) program. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus", section on 'Intensive lifestyle modification'.)

Medications were administered to achieve maximum control of glycemia and cardiovascular risk factors. After one year, a greater proportion of patients in the gastric bypass group achieved the composite outcome (A1C <7 percent, low-density lipoprotein [LDL] cholesterol <100 mg/dL, and systolic blood pressure less than 130 mmHg, 49 versus 19 percent, odds ratio [OR] 4.8, 95% CI 1.9-11.7). Among these outcomes, only achieving an A1C <7 percent was significant (75 versus 32 percent, OR 6.0, 95% CI 2.6-13.9). The mean percentage weight loss was 26.1 and 7.9 percent, respectively. Serious adverse events were more frequent in the gastric bypass group (22 versus 15 events), one of which involved a postoperative complication resulting in sepsis, stroke, leg amputation, and renal failure.

Despite these impressive short-term metabolic results, concerns remain about acute postoperative complications including need for reoperations and rehospitalizations and rare, but potentially severe, adverse events; the long-term success rates in maintaining weight loss [61,63]; and the reproducibility of the results in patients with an extensive history of diabetes or with a different surgical team [64]. 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. Longer-term follow-up of clinically important endpoints, such as effects on microvascular and macrovascular complications and mortality, are required before laparoscopic banding or other bariatric surgery procedures can be routinely recommended for the treatment of persistent hyperglycemia, resistant to multiple medications, in obesity-related type 2 diabetes. (See "Medical outcomes following bariatric surgery", section on 'Diabetes mellitus'.)

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: Diabetes mellitus type 2: Overview (Beyond the Basics)" and "Patient education: Diabetes mellitus type 2: Treatment (Beyond the Basics)" and "Patient education: Self-blood glucose monitoring in diabetes mellitus (Beyond the Basics)" and "Patient education: Preventing complications in diabetes mellitus (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

The treatment of patients with type 2 diabetes mellitus includes education, with emphasis on lifestyle changes including diet, exercise, and weight reduction when appropriate. 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 blood glucose 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. We recommend the addition of a second medication to achieve a treatment goal A1C of <7 percent (algorithm 1) (Grade 1B). This decision is typically made after two to three months of initial therapy. (See 'Indications for a second agent' above.)

We are aware that this goal 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"). In addition, the goal is not practical for all patients, due to patient preferences regarding combination therapy, particularly insulin therapy.

In patients with inadequate glycemic control on metformin and A1C >8.5 percent, we suggest adding insulin (Grade 2B). (See 'Metformin monotherapy failure' above.)

In patients with inadequate glycemic control on metformin (A1C >7.0 percent), with A1C close to target (≤8.5 percent), we suggest adding a short-acting sulfonylurea, such as glipizide (algorithm 1) (Grade 2B). (See 'Metformin monotherapy failure' above.)

The addition of repaglinide is an alternative option, which can be considered in individuals who do not reach glycemic goals with metformin, if there are contraindications to sulfonylureas or patient preference limits the use of insulin. (See 'Metformin monotherapy failure' above.)

Glucagon-like peptide-1 (GLP-1) receptor agonists may be appropriate to use in certain clinical settings, eg, when weight loss or avoidance of hypoglycemia is a primary consideration and the A1C level is close to target. (See 'Metformin monotherapy failure' above.)

The addition of pioglitazone (where available) is also an option in individuals without risk factors for heart failure (HF) or fracture, who do not reach glycemic goals with metformin alone, if there are contraindications to sulfonylureas or patient preference limits the use of sulfonylureas or insulin (algorithm 1). (See 'Metformin monotherapy failure' above.)

In individuals with contraindications to metformin, sulfonylureas are often first-line therapy. In patients with inadequate glycemic control on sulfonylureas, with A1C >8.5 percent, we suggest switching to insulin (Grade 2B). (See 'Sulfonylurea monotherapy failure' above.)

In patients who are intolerant or cannot take metformin for any reason and who have an A1C that is <8.5 percent but not at target on sulfonylurea alone, there are a number of agents that are available and can be used with a sulfonylurea. The choice of therapy should be individualized based upon patient characteristics, preferences, and costs. Options include thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors, alpha-glucosidase inhibitors, and insulin. All of these medications have advantages and disadvantages (table 2). The expense, side effects, and limited data on long-term safety make us cautious about suggesting the use of agents other than insulin. (See 'Sulfonylurea monotherapy failure' above.)

In individuals with inadequate glycemic control (A1C >7 percent) on two oral agents (usually metformin and sulfonylurea), we suggest switching to insulin (discontinue sulfonylurea and continue metformin) (Grade 2B). (See 'Dual agent failure' above and 'Metformin and insulin' above.)

Another option is two oral agents and a GLP-1 receptor agonist. It is reasonable to try a GLP-1 agonist before starting insulin in patients who are close to glycemic goals, who prefer not to start insulin, and in whom weight loss or avoidance of hypoglycemia is a primary consideration. (See 'Dual agent failure' above and "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Candidates'.)

An alternative that is less likely to work and is more expensive is three oral agents. However, three oral agents (eg, metformin, sulfonylurea, pioglitazone) can be considered in patients with A1C values that are not too far from goal (A1C ≤8.5 percent). (See 'Dual agent failure' above.)

A DPP-4 inhibitor or SGLT2 inhibitor may have a role as a third agent in those who cannot or will not take insulin when full doses of metformin and a sulfonylurea have not produced satisfactory metabolic control. However, long-term safety has not been established. (See 'Dual agent failure' above and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Candidates' and "Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus", section on 'Candidates'.)

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REFERENCES

  1. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32:193.
  2. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia 2008; 51:8.
  3. Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals. Diabetes Care 2014; 37:1048.
  4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
  5. United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310:83.
  6. U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995; 44:1249.
  7. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281:2005.
  8. Bressler P, DeFronzo RA. Drugs and diabetes. Diabetes Reviews 1994; 2:53.
  9. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004; 27:1535.
  10. Shah BR, Hux JE, Laupacis A, et al. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians? Diabetes Care 2005; 28:600.
  11. Ziemer DC, Doyle JP, Barnes CS, et al. An intervention to overcome clinical inertia and improve diabetes mellitus control in a primary care setting: Improving Primary Care of African Americans with Diabetes (IPCAAD) 8. Arch Intern Med 2006; 166:507.
  12. Grant RW, Buse JB, Meigs JB, University HealthSystem Consortium (UHC) Diabetes Benchmarking Project Team. Quality of diabetes care in U.S. academic medical centers: low rates of medical regimen change. Diabetes Care 2005; 28:337.
  13. Fanning EL, Selwyn BJ, Larme AC, DeFronzo RA. Improving efficacy of diabetes management using treatment algorithms in a mainly Hispanic population. Diabetes Care 2004; 27:1638.
  14. Grant RW, Cagliero E, Sullivan CM, et al. A controlled trial of population management: diabetes mellitus: putting evidence into practice (DM-PEP). Diabetes Care 2004; 27:2299.
  15. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140.
  16. Maruthur NM, Tseng E, Hutfless S, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med 2016; 164:740.
  17. Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA 2016; 316:313.
  18. Henry RR, Gumbiner B, Ditzler T, et al. Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-mo outpatient trial. Diabetes Care 1993; 16:21.
  19. Rosenstock J, Sugimoto D, Strange P, et al. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care 2006; 29:554.
  20. Lingvay I, Legendre JL, Kaloyanova PF, et al. Insulin-based versus triple oral therapy for newly diagnosed type 2 diabetes: which is better? Diabetes Care 2009; 32:1789.
  21. Vinik AI, Zhang Q. Adding insulin glargine versus rosiglitazone: health-related quality-of-life impact in type 2 diabetes. Diabetes Care 2007; 30:795.
  22. Schwartz S, Sievers R, Strange P, et al. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis. Diabetes Care 2003; 26:2238.
  23. Monami M, Lamanna C, Marchionni N, Mannucci E. Comparison of different drugs as add-on treatments to metformin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract 2008; 79:196.
  24. Phung OJ, Scholle JM, Talwar M, Coleman CI. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010; 303:1410.
  25. Aschner P, Chan J, Owens DR, et al. Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial. Lancet 2012; 379:2262.
  26. Kipnes MS, Krosnick A, Rendell MS, et al. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001; 111:10.
  27. Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia 2005; 48:1093.
  28. Zhang F, Xiang H, Fan Y, et al. The effects of sulfonylureas plus metformin on lipids, blood pressure, and adverse events in type 2 diabetes: a meta-analysis of randomized controlled trials. Endocrine 2013; 44:648.
  29. Hirst JA, Farmer AJ, Dyar A, et al. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia 2013; 56:973.
  30. Yki-Järvinen H, Ryysy L, Nikkilä K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1999; 130:389.
  31. Abraira C, Colwell JA, Nuttall FQ, et al. Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes. Diabetes Care 1995; 18:1113.
  32. Yki-Järvinen H, Kauppila M, Kujansuu E, et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1992; 327:1426.
  33. Chow CC, Tsang LW, Sorensen JP, Cockram CS. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care 1995; 18:307.
  34. Hemmingsen B, Christensen LL, Wetterslev J, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ 2012; 344:e1771.
  35. Wulffelé MG, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002; 25:2133.
  36. Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169:616.
  37. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854.
  38. Johnson JL, Wolf SL, Kabadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. A meta-analysis of the randomized placebo-controlled trials. Arch Intern Med 1996; 156:259.
  39. Wright A, Burden AC, Paisey RB, et al. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002; 25:330.
  40. Pugh JA, Wagner ML, Sawyer J, et al. Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A metaanalysis. Diabetes Care 1992; 15:953.
  41. Landstedt-Hallin L, Adamson U, Arner P, et al. Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure. Diabetes Care 1995; 18:1183.
  42. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001; 24:1226.
  43. US Food and Drug Administration. MedWatch the FDA Safety Information and Adverse Event Reporting Program - Avandia (rosiglitazone), April 2002. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154468.htm (Accessed on June 13, 2012).
  44. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med 1994; 121:928.
  45. Johnston PS, Feig PU, Coniff RF, et al. Long-term titrated-dose alpha-glucosidase inhibition in non-insulin-requiring Hispanic NIDDM patients. Diabetes Care 1998; 21:409.
  46. In Brief: A new indication for colesevelam. Med Lett Drugs Ther 2008; 50:33.
  47. Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus. Cochrane Database Syst Rev 2012; 12:CD009361.
  48. Fonseca VA, Rosenstock J, Wang AC, et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008; 31:1479.
  49. Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 2008; 168:1531.
  50. Bromocriptine (Cycloset) for Type 2 Diabetes. Med Lett Drugs Ther 2010; 52:97.
  51. Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs 1999; 8:1683.
  52. Gaziano JM, Cincotta AH, O'Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care 2010; 33:1503.
  53. Dixon JB, O'Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA 2008; 299:316.
  54. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012; 366:1577.
  55. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012; 366:1567.
  56. Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA 2013; 309:2240.
  57. Maggard-Gibbons M, Maglione M, Livhits M, et al. Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review. JAMA 2013; 309:2250.
  58. Gloy VL, Briel M, Bhatt DL, et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ 2013; 347:f5934.
  59. Courcoulas AP, Goodpaster BH, Eagleton JK, et al. Surgical vs medical treatments for type 2 diabetes mellitus: a randomized clinical trial. JAMA Surg 2014; 149:707.
  60. Puzziferri N, Roshek TB 3rd, Mayo HG, et al. Long-term follow-up after bariatric surgery: a systematic review. JAMA 2014; 312:934.
  61. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 2015; 386:964.
  62. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med 2014; 370:2002.
  63. Courcoulas AP, Belle SH, Neiberg RH, et al. Three-Year Outcomes of Bariatric Surgery vs Lifestyle Intervention for Type 2 Diabetes Mellitus Treatment: A Randomized Clinical Trial. JAMA Surg 2015; 150:931.
  64. Ludwig DS, Ebbeling CB, Livingston EH. Surgical vs lifestyle treatment for type 2 diabetes. JAMA 2012; 308:981.
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