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. 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.
INDICATIONS FOR A SECOND AGENT — After a successful initial response to oral therapy, patients fail to maintain target glycated hemoglobin (A1C) levels (<7 10="" 50="" 5="" 75="" a1c="" a="" achieve="" addition="" after="" an="" analysis="" at="" ba1c="" by="" controlled="" diabetes="" drug="" found="" from="" hemoglobin="" kingdom="" multiple="" needed="" nine="" of="" originally="" p="" patients="" per="" percent="" prospective="" rate="" required="" second="" single="" study="" target="" that="" the="" therapies="" three="" to="" united="" value.="" with="" year.="" years="">
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. 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).
●The patient's health care team may not have made appropriate changes in therapy often enough or at all ("therapeutic inertia") . 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. Adherence to algorithms that dictate changes in treatment at designated intervals and computerized decision aids may improve A1C more efficiently than standard care.
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 a1c="" achieve="" achieved="" are="" below="" glucose="" goal="" goals="" in="" intervention="" is="" lifestyle="" metformin="" months.="" nbsp="" necessary:="" not="" order="" p="" percent="" plus="" the="" three="" to="" usually="" with="" within="">
●Fasting glucose 70 to 130 mg/dL (3.89 to 7.22 mmol/L)
●Postprandial glucose (90 to 120 minutes after a meal) <180 class="nowrap" nbsp="" span="" style="white-space: nowrap;">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. We favor 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. 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. 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.
If target A1C is not achieved with metformin, and sulfonylurea or basal insulin, we suggest starting or intensifying insulin therapy. In patients on sulfonylureas and metformin who are starting insulin therapy, sulfonylureas are generally tapered and discontinued.
Thiazolidinediones (TZDs) 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 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="" a="" class="drug drug_general" href="http://www.uptodate.com/contents/pioglitazone-drug-information?source=see_link" nbsp="" percent="" style="color: #336633;">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. 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 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 (FDA), and Japanese regulators withheld action on pioglitazone pending results of ongoing review of the data.
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. DPP-4 inhibitors can be considered as add-on drug therapy for patients who are inadequately controlled on metformin, a thiazolidinedione, or a sulfonylurea. However, the modest glucose-lowering effectiveness, expense, and limited clinical experience may temper enthusiasm for these drugs.
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 many high quality head-to-head drug comparison trials. 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. Most combinations similarly reduced A1C, but there was weak 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.
EFFICACY OF COMBINATION THERAPY
Combination with metformin — Several agents can be used as add-on therapy when metformin monotherapy fails. In meta-analyses of placebo-controlled trials evaluating different drugs (sulfonylureas, thiazolidinediones [TZDs], 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. In one analysis, the reduction in A1C with sulfonylureas compared with placebo was greater than that of TZDs compared with placebo. 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 agonists, alpha-glucosidase inhibitors, and DPP-4 inhibitors were associated with weight loss or no change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than placebo.
Insulin was not included in one meta-analysis, although it is clearly the most effective and one of the least expensive of the anti-diabetic 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).
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.
Metformin plus sulfonylureas — Metformin has an additive glycemic effect when given in combination with a sulfonylurea. In the United States 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. 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 United Kingdom Prospective Diabetes Study (UKPDS) suggested that early addition of metformin to sulfonylurea therapy might increase the risk of diabetes-related death. This finding was attributed by the investigators to be due to chance. These results require further study before firm conclusions can be made.
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.
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. 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.
The early addition of a TZD to metformin to achieve glycemic goals is favored by some but not all, and is not included as a first tier option in the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus algorithm. 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.
Metformin plus meglitinides — Meglitinides may also be given in combination with
metformin, resulting in superior glycemic control than with either agent used as monotherapy. 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). Meglitinides are discussed in more detail separately.
Meglitinides were not recommended by the ADA/EASD guidelines because of higher costs (currently only available as brand name drugs) compared with 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.
Other metformin combinations — Metformin can also be given in combination with exenatide (requiring twice daily or once weekly injections), liraglutide (once daily injection), albiglutide (once weekly injection), or with DPP-4 inhibitors. 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. 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. 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). Fasting plasma glucose concentrations also decreased significantly in the patients given pioglitazone.
Combination tablets of pioglitazone and glimepiride are available in several doses. 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.
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. They act predominantly by lowering glucose concentrations after meals but may be poorly tolerated because of flatulence and other gastrointestinal (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 with the alternatives above.
INSULIN — Both patients and providers are often reluctant to initiate insulin therapy, despite its proven efficacy and cost advantage compared with 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.
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 glycated hemoglobin (A1C) >8.5 percent or with symptoms of hyperglycemia despite initial therapy with metformin and lifestyle intervention. 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 . 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 [
38]. 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 with several daily insulin injections.
While neutral protamine Hagedorn (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 fewer long-term safety data. Combination oral agent and glargine therapy does not appear to reduce or increase cardiovascular outcomes, compared with oral agent(s) only, as illustrated by the findings of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. In this trial, over 12,500 patients with cardiovascular risk factors plus type 2 diabetes or prediabetes were randomly assigned to an evening dose of glargine or to standard care. Approximately 60 percent of the patients with prior diabetes were using oral glucose-lowering agents (predominantly metformin or sulfonylurea). The glargine was titrated to achieve a fasting glucose level of <95 class="nowrap" nbsp="" span="" style="white-space: nowrap;">mg/dL
(5.3
mmol/L). After a median follow-up of six years, the achieved median fasting blood glucose levels were 94 and 123
ng/dL (5.2 and 6.8
mmol/L), respectively. The rates of incident cardiovascular outcomes were similar in the glargine and standard care groups (2.94 and 2.85 per 100 person-years). Only 11 percent of the patients in the standard therapy group received insulin. A1C values were similar at baseline (6.4) and at study end (6.2 and 6.5). Approximately 60 percent of patients in both groups were treated with statins and 75 percent with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers.
Sulfonylureas and insulin — Sulfonylureas are the oldest class of oral hypoglycemic agents. Data from the United Kingdom Prospective Diabetes Study (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. However, the combination of sulfonylurea and insulin is less efficacious and results in more weight gain than metformin and insulin. 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.
Metformin and insulin — In several trials and a meta-analysis, glycemic control was better with metformin-insulin combinations than with insulin monotherapy or with sulfonylurea-insulin combinations. In the 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. This is consistent with other observations that metformin alone does not usually produce hyperinsulinemia or weight gain. However, there are few trials with clinically important outcomes, such as cardiovascular or all cause mortality. Based upon the available evidence, we prefer combination metformin-insulin therapy to sulfonylurea-insulin therapy in individuals without contraindications to metformin.
Thiazolidinediones and insulin — The addition of a thiazolidinedione (TZD) to insulin improves glycemic control compared with insulin monotherapy. However, the combination of insulin plus either rosiglitazone orpioglitazone causes an increased incidence of heart failure and should be avoided in patients with heart failure. 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.
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. 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. 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. 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.
These findings, combined with the greater concern about adverse cardiovascular events with TZDs, particularly rosiglitazone, favor the addition of insulin glargine over rosiglitazone.
The ADA/EASD guidelines recommend rapid addition of medications and transition to new regimens to achieve target glycemic goals. 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.
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. 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. 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). In addition to the directly deleterious effects of worsening obesity, it can also lead to partial noncompliance with therapy, particularly in women.Insulin therapy is discussed in more detail elsewhere.
OTHER MEDICATIONS
GLP-1 agonists — Glucagon-like peptide-1 (GLP-1) receptor agonists affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, regulation of postprandial glucagon, and reduction of food intake. Exenatide, liraglutide, and albiglutide are GLP-1 agonists that are available in the United States, Europe, and other countries for the treatment of type 2 diabetes in patients not sufficiently controlled with diet, exercise, or oral agents. Exenatide (requires two daily injections or a once weekly injection with the long-acting release formulation), liraglutide (one daily injection), or albiglutide (once weekly injection) could be considered as add-on drugs for patients with type 2 diabetes who are poorly controlled on maximal doses of one or two oral agents. They may be most appropriate for an overweight patient who is experiencing weight gain on oral agents. However, the long-term safety and efficacy of GLP-1 agonists are not yet established. We do not recommend the use of GLP-1 agonists as monotherapy. GLP-1 agonists are reviewed in detail separately.
DPP-4 inhibitors — Dipeptidyl peptidase 4 (DPP-4) 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.
Because of high cost, relatively weak effects on glycated hemoglobin (A1C), and limited clinical data, DPP-4 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-4 inhibitors may temper enthusiasm for these drugs.
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 . 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.
SGLT2 inhibitors — Given the absence of long-term efficacy and safety data, we do not recommend sodium-glucose co-transporter 2 (SGLT2) inhibitors for routine use in patients with type 2 diabetes. SGLT2 inhibitors may play a role as a third-line agent in patients with inadequate glycemic control on two oral agents (eg, metformin and sulfonylurea) if for some reason combination metformin and insulin is not a therapeutic option.
The sodium-glucose co-transporter 2 (SGLT2) is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. The ability to lower blood glucose and A1C levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. The glucose-lowering effect is independent of insulin (beta cell function and insulin sensitivity).
SGLT2 inhibitors have been studied as monotherapy and in combination with metformin, sulfonylureas,pioglitazone, sitagliptin, and insulin . Dapagliflozin and canagliflozin are available in Europe and the United States, and other SGLT2 inhibitors are in development. In meta-analyses of clinical trials comparing SGLT2 inhibitors with placebo or active comparators (metformin, sulfonylurea, DPP-4 inhibitor, insulin), SGLT2 inhibitors reduced A1C by approximately 0.5 to 0.7 percentage points (mean difference versus active comparators -0.06 percent), making them relatively weak glucose-lowering agents, similar in potency to the DPP-4 inhibitors.
As examples:
●In a 24-week double blind trial, 597 patients with type 2 diabetes inadequately controlled with sulfonylureas (A1C 7 to 10 percent) were randomly assigned to dapagliflozin (2.5, 5, or 10 mg) or placebo once daily. The mean change in A1C from baseline was greater with dapagliflozin (-0.58, -0.63, and -0.82 percentage points for the three doses of dapagliflozin, respectively, versus -0.13 percentage points with placebo). Dapagliflozin reduced weight (-1.18 to -2.26 kg compared with -0.72 kg in the placebo group).
●In a 52-week double blind trial, 814 patients with type 2 diabetes inadequately controlled with metformin(mean A1C 7.7 percent) were randomly assigned to dapagliflozin or glipizide . The mean reduction in A1C was similar in both groups (-0.52 percentage points). Dapagliflozin reduced weight (-3.2 versus +1.2 kg with glipizide) and produced less hypoglycemia (3.5 versus 40.8 percent with glipizide).
●In another trial, 808 patients with type 2 diabetes mellitus inadequately controlled with insulin and up to two oral agents were randomly assigned to dapagliflozin (2.5, 5, or 10 mg once daily) or placebo. After 24 weeks, A1C decreased by 0.79 to 0.96 percentage points with dapagliflozin compared with 0.39 percentage points with placebo (mean difference -0.40 to -0.57 percent in the 2.5 to 10 mg groups). Daily insulin dose decreased by 0.63 to 1.95 units with dapagliflozin and increased by 5.65 units with placebo. Dapagliflozin reduced weight (-0.92 to 1.61 versus + 0.43 kg with placebo). The rate of hypoglycemic episodes was higher in the dapagliflozin group (56.6 versus 51.8 percent).
●In a double blind trial, 451 patients with type 2 diabetes were randomly assigned to canagliflozin (several doses), sitagliptin 100 mg daily, or placebo . After 12 weeks, the reduction in A1C from baseline ranged from -0.7 to -0.95 percentage points in the canagliflozin group versus -0.74 and -0.22 percentage points for sitagliptin and placebo, respectively. In another double blind trial, 755 patients with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea (mean A1C 8.1 percent) were randomly assigned to canagliflozin (300 mg daily) or sitagliptin (100 mg daily). Using this dose of canagliflozin, the mean reduction in A1C from baseline was significantly better with canagliflozin than sitagliptin (least squares mean change -1.03 and -0.66 percent, respectively). Canagliflozin reduced weight (-2.5 versus 0.3 percent change from baseline) and systolic blood pressure (-5.1 versus 0.99 mmHg, respectively) compared with sitagliptin. Although the overall incidence of adverse events was similar for the two drugs, the frequency of genital fungal infections was almost sixfold higher with canagliflozin. The overall results of this study must be viewed cautiously as almost 40 percent of the subjects did not complete the year-long study.
●In a 52-week double blind trial, 1452 patients with type 2 diabetes inadequately controlled with metformin(mean A1C 7.8 percent) were randomly assigned to glimepiride (titrated based upon blood glucose, median dose 5.6 mg daily) or canagliflozin (100 or 300 mg daily). The mean reduction in A1C from baseline was similar in the glimepiride and lower dose canagliflozin groups (-0.81 and -0.82 percentage points, respectively) and better in the higher dose canagliflozin group (-0.93 percentage points). The proportion of patients achieving an A1C <7 11="" 14="" 2="" 31="" 3="" 4.4="" 56="" among="" and="" approximately="" associated="" but="" canagliflozin="" compared="" frequent="" genital="" glimepiride="" groups="" had="" hypoglycemia="" infections="" kg="" less="" more="" of="" or="" p="" patients="" percent="" reduced="" respectively="" severe="" similar="" to="" versus="" was="" weight="" with="" women:="" yeast="">
The overall benefits of SGLT2 inhibitors include a decrease in blood pressure and weight, and a low incidence of hypoglycemia when used as monotherapy or in combination with metformin. In a systematic review ofdapagliflozin trials, there was a reduction in systolic blood pressure at all doses (-1.3 to -7.3 mmHg compared with +0.2 to -0.11 mmHg in the control groups). In 12-week trials of dapagliflozin,
canagliflozin, and empagliflozin, weight loss of 2 to 3 kg was reported . The weight loss appears to be sustained over time. In a meta-analysis of three longer-term trials (48 to 52 weeks) comparing dapagliflozin (10 mg daily) versus placebo, there was a significant reduction in weight in the dapagliflozin group (mean difference -2.36 kg, 95% CI -2.85 to -1.88).
In clinical trials, side effects of SGLT2 inhibitors include an increased incidence of vulvovaginal candidiasis, reported in 10 to 15 percent of women. Similarly, in meta-analyses of dapagliflozin trials (10 mg), there was a higher rate of vulvovaginal candidal infections (9.5 versus 2.6 percent in the control groups). In addition, there was a small but significant increase in the rate of urinary tract infections (8.8 versus 6.1 percent). There were 10 cases of bladder cancers diagnosed among dapagliflozin users in clinical trials, five of which occurred in the first six months of dapagliflozin, a much shorter time interval than would be expected if dapagliflozin promoted tumorigenesis. However, these findings have prompted the US Food and Drug Administration to recommend postmarketing surveillance studies. There are no long-term safety data with regard to the effects of chronic glucosuria on the urinary tract. In addition, there are no data on microvascular or cardiovascular outcomes.
Canagliflozin is taken orally before the first meal of the day. The initial dose is 100 mg once daily, and it can be increased to 300 mg daily to achieve glycemic goals. In patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 45 to 59 mL/min), the dose should not exceed 100 mg daily. Canagliflozin should not be given to patients with eGFR <45 class="nowrap" nbsp="" span="" style="white-space: nowrap;">mL/min
or in patients with severe hepatic impairment. No dose adjustment is needed in patients with mild or moderate hepatic impairment .Dapagliflozin (10 mg once daily) can be taken any time of day, with or without food. It is not recommended for use in patients with eGFR <60 class="nowrap" nbsp="" span="" style="white-space: nowrap;">mL/min or in patients with active bladder cancer. For patients with severely reduced liver function, a starting dose of 5 mg is recommended. There is limited experience with either drug in patients with severe hepatic impairment.
Colesevelam is a bile acid sequestrant that lowers low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia . 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.
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). 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. The clinical implications of this increase are unknown.
Bromocriptine is an ergot-derived dopamine agonist that has been used for over two decades for the treatment of hyperprolactinemia and Parkinson disease.
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. 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) . Common side effects include nausea, vomiting, dizziness, and headache. The mechanism of action in reducing blood sugar is unknown.
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Despite these impressive metabolic results, concerns remain about acute post-operative complications including need for re-operations and re-hospitalizations and rare, but potentially severe adverse events, and the long-term success rates in maintaining weight loss and reproducibility of the results in patients with an extensive history of diabetes or with a different surgical team . 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.
