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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: Mar 2012. | This topic last updated: Jun 15, 2011.

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 probably 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 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 blood glucose in type 2 diabetes mellitus" and "Overview of medical care in adults with diabetes mellitus".)

INDICATIONS FOR A SECOND AGENT — 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) [2-4]. An analysis from the United Kingdom Prospective Diabetes Study (UKPDS) found that 50 percent of patients 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 hemoglobin A1C (HbA1c) value [5].

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) [6]. The latter factor is particularly important in elderly patients who are taking multiple drugs.
  • Progression of the underlying disease process including insulin resistance and deficient insulin secretion causing type 2 diabetes.
  • 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) [7]. (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") [8-11]. 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 [8]. Adherence to algorithms that dictate changes in treatment at designated intervals and computerized decision aids may improve A1C more efficiently than standard care [10,12,13].

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 recommends testing A1C levels every three months and 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) [1,14]. In order to achieve the A1C goal, the glucose goals below are usually necessary:

  • Fasting glucose 70 to 130 mg/dL (3.89 to 7.22 mmol/L)
  • Postprandial glucose (90 to 120 minutes after a meal) <180 mg/dL (10 mmol/L)

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). In a meta-analysis of 140 trials and 26 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 one percentage point [15]. Most combinations similarly reduced A1C, but there was weak evidence favoring metformin plus a GLP-1 agonist over metformin plus a DPP-IV inhibitor for reducing A1C levels.

The ADA/EASD guidelines favor insulin or sulfonylurea as the second step, and insulin is preferred for patients whose A1C is further from target (>8.5 percent) or who have symptoms related to hyperglycemia. If target A1C is not achieved with metformin, and sulfonylurea or basal insulin, the ADA/EASD suggest starting or intensifying insulin therapy. In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally tapered and discontinued. The selection of drugs in the ADA/EASD consensus guideline (algorithm 1) was based upon clinical trial evidence and clinical experience in achieving glycemic targets, with the recognition that there is a paucity of many high quality head to head drug comparison trials [1].

Thiazolidinediones (TZDs) are not considered first choice agents due to the risk of CHF and fractures and expense. However, in certain clinical settings, such as especially high risk for hypoglycemia or intolerance of or contraindications to metformin or sulfonylureas, a TZD may be considered. As an example, in a patient who would be at particularly high risk if hypoglycemia occurred (eg, a construction worker) and inadequate glycemic control on metformin (A1C >7 but <8.5 percent), pioglitazone 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 [1,14]. Because of these risks, rosiglitazone was removed from the market in Europe, and its use in the United States is restricted. Subsequently, 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 US Food and Drug Administration, and Japanese regulators withheld action pending results of ongoing review of the data. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Summary' and "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Bladder cancer'.)

Glucagon-like peptide-1 (GLP-1) analogs are also considered second tier agents and 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. Meglitinides, DPP-IV inhibitors, pramlintide, and alpha-glucosidase inhibitors are not included in the ADA/EASD algorithm because of lower glycemic efficacy, relative expense, and for some agents, limited long-term safety data.

For those close to 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. For those further from target (A1C >8.5 percent) we prefer to add insulin, rather than an oral agent.

EFFICACY OF COMBINATION THERAPY

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, TZDs, meglitinides, alpha-glucosidase inhibitors, GLP-1 analogs, DPP-IV inhibitors) as add-on therapy to metformin, reductions in A1C with different classes of drugs ranged from 0.42 to 1.0 percentage points [16,17]. In one analysis, the reduction in A1C with sulfonylureas compared with placebo was greater than that of TZDs compared with placebo [16]. However, these trials did not directly compare different agents in combination with metformin.

As expected, the use of TZDs, sulfonylureas, and meglitinides was associated with weight gain, while GLP-1 analogs, alpha-glucosidase inhibitors, and DPP-IV inhibitors were associated with weight loss or no change [17]. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than placebo. Insulin was not included in one meta-analysis [17], although it is clearly the most effective and one of the least expensive of the anti-diabetic medications available.

These results demonstrate that add-on therapy in general is effective, and therefore the choice of a second agent depends upon additional factors, such as safety and cost. Insulin or sulfonylureas are the preferred second-line agents because of efficacy, side effect profile, long-term safety, and relative cost (algorithm 1). (See 'Combination oral and insulin therapy' below.)

Metformin plus sulfonylureas — Metformin has an additive glycemic effect when given in combination with a sulfonylurea [18-20]. In the US Multicenter Metformin Study, patients who were not well controlled on diet or glyburide alone were randomly assigned to metformin monotherapy, the addition of metformin to glyburide, or continuation of glyburide alone [20]. Treatment with metformin plus glyburide resulted in lower A1C levels than glyburide alone (7.1 versus 8.7 percent, respectively).

A sub-study within the UKPDS suggested that early addition of metformin to sulfonylurea therapy might increase the risk of diabetes-related death [21]. This finding was attributed by the investigators to be due to chance. These results require further study before firm conclusions can be made. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Metformin 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 "Sulfonylureas and meglitinides in the treatment of diabetes mellitus", section on 'Side effects'.)

Combination tablets of metformin and sulfonylureas 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 this brand name combination is substantially greater than taking the generic components individually.

Metformin plus thiazolidinediones — TZDs lower glycemic levels when given in combination with metformin. As an example, in a study of patients with inadequate glycemic control on metformin monotherapy, the addition of pioglitazone (30 mg daily) versus placebo resulted in significant improvement in A1C, fasting blood glucose values, and in measures of insulin sensitivity [22]. Specifically, the mean A1C values decreased by 0.6 percentage points in patients receiving metformin plus pioglitazone and increased by 0.2 percentage points in patients receiving metformin-placebo.

Combination tablets of pioglitazone and metformin are available in several doses [23].

The early addition of a TZD to metformin to achieve glycemic goals is favored by some [24,25] but not all [26], and is not included as a first tier option in the ADA/EASD consensus algorithm (algorithm 1) [1,14]. If a TZD is to be used in combination with metformin (or a sulfonylurea), pioglitazone is recommended because of the greater concern about atherogenic lipid profiles and a potential increased risk for cardiovascular events with rosiglitazone. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Cardiovascular Effects'.)

Metformin plus meglitinides — Meglitinides may also be given in combination with metformin, resulting in superior glycemic control than with either agent used as monotherapy [27,28]. A randomized two-year study of initial diabetic treatment comparing nateglinide/metformin or glyburide/metformin concluded that both regimens had similar efficacy in lowering A1C, but hypoglycemic events were more common in patients treated with glyburide/metformin (17.7 percent of patients versus 8.2 percent for nateglinide/metformin) [29]. Meglitinides are discussed in more detail separately. (See "Sulfonylureas and meglitinides in the treatment of diabetes mellitus", section on 'Meglitinides'.)

Meglitinides were not recommended by the ADA/EASD guidelines because of higher costs (currently only available as brand name drugs), compared to sulfonylureas, and more limited clinical data. However, 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 diabetics with end-stage renal disease", section on 'Meglitinides'.)

Other metformin combinations — Metformin can also be given in combination with exenatide (requiring twice daily injections), liraglutide (once daily injection), or with DPP-IV inhibitors. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus".) However, these combinations are generally not recommended unless patients are intolerant of or have contraindications to sulfonylureas and insulin. The GLP-1 based therapies are more expensive and long-term safety has not been established.

Sulfonylureas and thiazolidinediones — The TZDs have been studied in combination with metformin, sulfonylureas, and insulin (see 'Insulin' below and 'Metformin plus thiazolidinediones' above) [30-32]. The glycemic efficacy of TZDs in combination with a sulfonylurea is illustrated by the findings from a 16-week study of 560 patients with type 2 diabetes who had A1C values >8.0 percent despite sulfonylurea therapy [31]. Those receiving pioglitazone (15 or 30 mg) plus the sulfonylurea had significant decreases in A1C values compared with those receiving placebo plus the sulfonylurea (0.9 and 1.3 percentage points for the lower and higher dose of pioglitazone, respectively) [31]. Fasting plasma glucose concentrations also decreased significantly in the patients given pioglitazone.

Combination tablets of pioglitazone and glimepiride are available in several doses [23]. Although combination therapy may be more convenient than taking the drugs individually, the fixed-dose combinations offer less dosing flexibility, and are generally more expensive than using generic agents, when available, as separate pills. While these combinations result in short term improvements in glycemic control, long-term trials demonstrating improved outcomes are lacking.

If a TZD is to be used in combination with a sulfonylurea, pioglitazone is preferred. (See 'Metformin plus thiazolidinediones' above.)

Combination with alpha-glucosidase inhibitors — Acarbose and miglitol can reduce A1C values slightly (0.5 to 1.0 percentage points) when taken in conjunction with any other form of therapy [33,34]. They act predominantly by lowering glucose concentrations after meals but may be poorly tolerated because of flatulence and other GI side effects. The ADA/EASD consensus guidelines do not recommend these drugs as preferred second-line medications because of lower efficacy, poorer tolerance, and increased cost compared to the alternatives above [1]. (See "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus".)

INSULIN — Both patients and providers are often reluctant to initiate insulin therapy, despite its proven efficacy and cost advantage compared to many newer agents. Self-blame; concerns about life-restriction, weight gain, and hypoglycemia; and the patient's perception that insulin therapy is associated with worsening of diabetes are factors contributing to patient reluctance. An international survey of over 3600 nurses and doctors in 13 countries revealed that clinicians who delay initiating insulin therapy have also delayed initiating oral medication, and that specialists and opinion leaders are less likely to delay starting insulin [35].

Insulin is a reasonable choice for initial therapy in patients who present with symptomatic or poorly controlled diabetes, and is the preferred second-line medication for patients with A1C >8.5 percent or with symptoms of hyperglycemia despite initial therapy with metformin and life-style intervention. The 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.

Combination oral and insulin therapy — Patients with persistent hyperglycemia despite oral hypoglycemic therapy may add insulin to oral medication, or may stop the oral drug and begin insulin. Part of the rationale for combination oral hypoglycemic drug 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 [36]. In several studies of patients inadequately controlled with drugs alone, combination oral-insulin therapy resulted in equivalent glycemic control with less or no weight gain compared to several daily insulin injections (figure 2) [37-40].

While NPH 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 unknown long-term safety. (See "General principles of insulin therapy in diabetes mellitus", section on 'Human versus analogs' and "Insulin therapy in type 2 diabetes mellitus", section on 'Choice of insulin'.)

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 [41-44]. However, the combination of sulfonylurea and insulin is less efficacious and results in more weight gain than metformin and insulin (figure 2) [37]. Furthermore, insulin plus sulfonylurea have a similar mechanism 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. (See "Metformin in the treatment of diabetes mellitus", section on 'Lactic acidosis'.)

Metformin and insulin — In several studies, glycemic control was better with metformin-insulin combinations than with insulin monotherapy or with sulfonylurea-insulin combinations (figure 2) [37,45,46]. The combination of insulin with metformin is also associated with significantly less weight gain than seen with twice daily insulin injections or insulin combined with sulfonylureas [21]. This is consistent with other observations that metformin alone does not usually produce hyperinsulinemia or weight gain [3]. For these reasons and those noted above, we prefer combination metformin-insulin therapy to sulfonylurea-insulin therapy in individuals without contraindications to metformin. (See "Metformin in the treatment of diabetes mellitus", section on 'Lactic acidosis'.)

Thiazolidinediones and insulin — The addition of a TZD to insulin improves glycemic control compared with insulin monotherapy [47]. However, the combination of insulin plus either rosiglitazone or pioglitazone causes an increased incidence of heart failure and should be avoided in patients with heart failure [48]. In addition, both available TZDs have been associated with bone loss, and rosiglitazone may be associated with other cardiovascular risks, as described above. TZDs are also more expensive than metformin. (See "Thiazolidinediones in the treatment of diabetes mellitus".)

Insulin versus triple oral therapy — In patients who are not well-controlled on two oral agents, switching to insulin is usually less expensive than adding a third oral 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 [49]. Patients on three oral agents (a sulfonylurea, metformin and a TZD) 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.

Three oral agents can be considered in patients with A1C values that are not too far from goal [50,51]. 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 [50]. 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 [52].

These findings, combined with the greater concern about adverse cardiovascular events with TZDs, particularly rosiglitazone, favor the addition of insulin glargine over rosiglitazone. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Cardiovascular Effects'.)

The ADA/EASD guidelines recommend rapid addition of medications and transition to new regimens to achieve target glycemic goals [1]. In general this means the addition of insulin in patients who are not meeting goals with two oral agents. However, it is reasonable to try a third oral agent before starting insulin in patients who are close to glycemic goals and who prefer not to start insulin. In this situation, pioglitazone is preferred because of the greater concern about atherogenic lipid profiles and a potential increased risk for cardiovascular events with rosiglitazone. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'Cardiovascular Effects'.)

Insulin intensification — Diet and exercise patterns should be reviewed in patients whose glycemic control is poor despite initial 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 [3]. 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) [36]. 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".)

OTHER MEDICATIONS

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".)

Exenatide — Exenatide is a GLP-1 analog used as adjunctive therapy for patients with type 2 diabetes who are inadequately controlled on oral agents. The drug is administered subcutaneously twice daily or once weekly and thus, like insulin, requires injections.

Exenatide does not cause hypoglycemia unless it is administered with unadjusted doses of other diabetes medications. Unlike insulin, exenatide promotes weight loss but has a high rate of gastrointestinal side-effects including nausea, vomiting, and diarrhea. It is more expensive than insulin therapy. Exenatide use may be most appropriate for an overweight patient who is experiencing weight gain on oral agents. However, the long-term safety and efficacy of this therapy are not yet established. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Exenatide'.)

Liraglutide — Liraglutide is a GLP-1 analog that has been modified to non-covalently bind to serum albumin through a lipid side chain, resulting in slower degradation and allowing for once-daily subcutaneous dosing. It is available for use as monotherapy as an adjunct to diet and exercise or in combination with oral agents in adults with type 2 diabetes. It is not considered a first-line therapy. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Liraglutide'.)

Liraglutide does not cause hypoglycemia unless it is administered with unadjusted doses of other diabetes medications that can cause hypoglycemia, such as sulfonylureas or insulin. Unlike insulin, liraglutide promotes weight loss, in part probably because of its high rate of gastrointestinal side-effects including nausea, vomiting, and diarrhea. It is more expensive than insulin therapy. The long-term safety and efficacy of this therapy are not yet established. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Liraglutide'.)

DPP-IV inhibitors — Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous enzyme that deactivates a variety of other bioactive peptides, including glucagon-like peptide-1 and gastric inhibitory peptide; therefore, its inhibition could potentially affect glucose regulation through multiple effects. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'DPP-IV inhibitors'.)

Because of high cost, relatively weak effects on A1C, and limited clinical data, DPP-IV inhibitors cannot currently be recommended for routine use. They 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, the modest glucose lowering effectiveness, expense, and limited clinical experience with DPP-IV inhibitors may temper enthusiasm for these drugs. (See "Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'DPP-IV inhibitors'.)

Inhaled insulin — An inhaled form of rapid-acting insulin was available for a short time but was discontinued in 2007 for commercial reasons. Other inhaled insulin preparations are in clinical trials but are not currently available. (See "General principles of insulin therapy in diabetes mellitus", section on 'Inhaled insulin'.)

Colesevelam — Colesevelam is a bile acid sequestrant that lowers LDL cholesterol in patients with primary hypercholesterolemia. (See "Lipid lowering with drugs other than statins and fibrates", section on 'Bile acid sequestrants'.)

In short-term trials (16 to 26 weeks), colesevelam modestly reduced A1C levels (0.3 to 0.4 percentage points) in patients with type 2 diabetes inadequately treated with oral agents or insulin [53-56]. Colesevelam's mechanism of action to improve glycemic control is uncertain. One possibility is that bile acid sequestrants act in the gastrointestinal tract to reduce glucose absorption.

Side effects can include constipation, nausea, and dyspepsia. In contrast to its effects on LDL cholesterol, colesevelam increases triglyceride concentrations by approximately 20 percent [53,54]. The clinical implications of this increase are unknown. (See "Lipoprotein classification; metabolism; and role in atherosclerosis", section on 'Triglyceride rich lipoproteins and apo C-III'.)

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.

Bromocriptine — Bromocriptine is an ergot-derived dopamine agonist that has been used for over two decades for the treatment of hyperprolactinemia and Parkinson’s disease. (See "Treatment of hyperprolactinemia due to lactotroph adenoma and other causes", section on 'Dopamine agonists' and "Pharmacologic treatment of Parkinson disease", section on 'Dopamine agonists'.)

A new quick release formulation of bromocriptine (Cycloset) was approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus [57]. 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) [57,58]. Common side effects include nausea, vomiting, dizziness, and headache [59]. 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.

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SUMMARY AND RECOMMENDATIONS

Glycemic goals

Metformin monotherapy failure

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

    The addition of pioglitazone is an alternative option in individuals without risk factors for heart failure 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 plus thiazolidinediones' above.)

    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. (See 'Metformin plus meglitinides' above.)

Contraindications to metformin and sulfonylurea monotherapy failure — In individuals with contraindications to metformin, sulfonylureas are often first-line therapy. (See "Initial management of blood glucose in type 2 diabetes mellitus", section on 'Sulfonylureas'.)

  • In patients with inadequate glycemic control on sulfonylureas, with A1C >8.5 percent, we suggest switching to insulin (Grade 2B). (See 'Sulfonylureas and insulin' above.)
  • In patients with inadequate glycemic control on sulfonylureas (A1C >7 percent), with A1C close to target (≤8.5 percent), we suggest adding pioglitazone (Grade 2B). (See 'Metformin plus thiazolidinediones' above.)

    DPP-IV 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 clinical experience with DPP-IV inhibitors temper our enthusiasm for these drugs. (See 'DPP-IV inhibitors' above.)

Dual oral agent failure

  • 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 'Metformin and insulin' above.) An alternative that is less likely to work is three oral agents.

    However, three oral agents (metformin, sulfonylurea, pioglitazone) can be considered in patients with A1C values that are not too far from goal (A1C ≤8.5 percent). (See 'Insulin versus triple oral therapy' above.)

    A GLP-1 analog could also be considered as an add-on drug for overweight patients who are poorly controlled on maximal doses of two oral agents. However, long-term safety has not been established. (See 'Exenatide' above and 'Liraglutide' above.)

    A DPP-IV 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, and there are contraindications to pioglitazone. However, long-term safety has not been established. (See 'DPP-IV inhibitors' above.)

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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. 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.
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