REVIEW ARTICLE

Achieving Glycemic Goals With Addition of Incretin-based Therapies to Insulin in Patients With Type 2 Diabetes Mellitus Joseph Tibaldi, MD

Abstract: As type 2 diabetes mellitus progresses, multiple antihyperglycemic agents are needed to maintain adequate glycemic control. Consensus guidelines recommend combining agents with complementary mechanisms of action. Given that hypoglycemic events increase the risk of cardiovascular disease and that weight gain affects mortality in obese individuals, it is important to control hyperglycemia without inducing hypoglycemia or weight gain. Peer-reviewed clinical trial data from patients requiring insulin-containing combination therapy suggest that insulin may be more effective at controlling hyperglycemia when given with appropriate combination therapy, but insulin is associated with weight gain and hypoglycemia. Some agents should not be combined with insulin because of associated weight gain and edema (ie, thiazolidinediones) or hypoglycemia (ie, sulfonylureas). Conversely, the lack of weight gain and hypoglycemia associated with metformin, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors and suppression of glucagon secretion by both classes of incretin-based therapies suggest that these agents are well suited to combination therapy with insulin. Key Indexing Terms: Hypoglycemia; Incretin; Insulin; Type 2 diabetes mellitus; Weight. [Am J Med Sci 2014;347(6):491–501.]

I

n patients with type 2 diabetes mellitus (T2DM), intensive glycemic control is associated with reductions in the longterm complication of microvascular disease1,2 and possibly macrovascular disease, although that evidence is less well established.2,3 Long-term data indicate that even if hemoglobin A1C (A1C) increases over time, early intensive glycemic control benefits patients in later years with regard to these outcomes,2 a concept known as metabolic memory or the legacy effect.4 Some antihyperglycemic agents have adverse effects of hypoglycemia and weight gain, which add to the already increased risk of cardiovascular disease.5,6 Thus, an important goal in T2DM management is to achieve glycemic control without increasing the risk of hypoglycemia or weight gain.7 The complex pathophysiology of T2DM and the characteristic progressive loss of b-cell function ultimately require most patients to initiate combination therapy.3,7 Because the core defects in T2DM are insulin resistance and impaired pancreatic insulin secretion, exogenous insulin is often administered to achieve glycemic control. However, as the physiologic effects of insulin are to promote glucose uptake and fat storage, this approach is associated with substantial risks of hypoglycemia From Queens Diabetes & Endocrinology Associates, Flushing, NY. Submitted February 14, 2013; accepted in revised form September 4, 2013. J. Tibaldi reports serving on the speaker’s bureau for Daiichi-Sankyo Co, Ltd, Merck, Janssen and Novo Nordisk and on an advisory board for Novo Nordisk. This study was supported by funds from Bristol-Myers Squibb and AstraZeneca. The author has no other conflicts of interest to disclose. Correspondence: Joseph Tibaldi, MD, Queens Diabetes & Endocrinology Associates, 59-45 161st St, Flushing, NY 11365 (E-mail: [email protected]).

The American Journal of the Medical Sciences



and weight gain.8 Furthermore, injection of exogenous insulin leads to nonphysiologic systemic absorption; high peripheral levels of insulin may stimulate fat storage and result in low hepatic/ portal levels. In addition, some insulin regimens fail to provide adequate postprandial glucose control. This is important because A1C integrates both fasting and postprandial glucose levels, with data suggesting that postprandial glucose is the major contributor in achieving A1C levels ,7.3% and therefore is a crucial target for achieving glycemic goals.9 Consequently, insulin-containing combination therapy should include agents that improve postprandial glycemic control without increasing the risk of hypoglycemia or weight gain. The objective of this review is to summarize the clinical considerations regarding the use of insulin-containing combination therapy in patients with T2DM who are inadequately controlled on their current insulin therapy. Although clinicians may be more likely to adjust the dose of insulin than to add on another medication in clinical practice, the studies reviewed herein demonstrate the rationale, efficacy and safety of combining incretin-based therapies (ie, glucagon-like peptide-1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) with insulin in patients with T2DM.

CLINICAL CONSIDERATIONS REGARDING THE USE OF INSULIN The American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology guidelines recommend basal insulin therapy, basal-bolus therapy and therapy with premixed insulins; the final selection is left to the patient and clinician. Regular human insulin and neutral protamine Hagedorn insulin are less desirable because they do not adequately mimic the physiologic time course of insulin, increasing the risk of hypoglycemia.7 The recently published AACE algorithm recommends that basal insulin be used with caution in dual therapy regimens with metformin and in triple therapy regimens with metformin and a second-line agent for patients with A1C level $7.5%. It also recommends insulin with or without other agents for patients with A1C level .9.0%.10 The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement recommends the addition of basal insulin to metformin monotherapy. For patients who do not achieve glycemic goals on combination regimens, intensive insulin therapy is recommended by both the ADA/EASD and the AACE.3,10 Insulin therapy is usually initiated with a once-daily dose of long-acting insulin added to oral agents. The dose must be optimized to reduce fasting plasma glucose to the established goal without causing hypoglycemia. Basal regimens can normalize fasting plasma glucose but typically do not provide adequate postprandial glucose control.11,12 If A1C level remains .7%, therapy must be intensified to lower the postprandial glucose values.9 At this point, therapy must address the lack of adequate prandial insulin. Options include switching to twice-daily injections of premixed insulin or administering

Volume 347, Number 6, June 2014

491

Tibaldi

basal insulin with additional injections of prandial insulin (basal-bolus approach). Limitations of the former approach include (1) a fixed amount of prandial insulin and lack of lunchtime coverage and (2) the inability to compensate when meals and patient activity are variable. The limitation of the latter approach is the need to choose the correct amount of prandial insulin for the amount of carbohydrate consumed in the setting of the patient’s activity and exercise levels, which is a daunting task. Premixed insulins can control both fasting plasma glucose and postprandial glucose but may cause more weight gain and hypoglycemia than basal regimens.11 A critical review of the published clinical trial literature from January 1990 to June 2010 on the initiation of insulin treatment with basal insulin and premixed insulin found that twice-daily premixed regimens reduced A1C level by approximately 0.5% more than once-daily basal regimens. The premixed regimens were also associated with a greater amount of weight gain, but the difference in weight gain between regimen types was not statistically significant.13 Recent head-to-head clinical trial comparisons of basal-bolus and premixed insulin regimens favor basal-bolus regimens in terms of glycemic control, patient satisfaction and cost. The Glulisine in Combination with Insulin Glargine in an Intensified Insulin Regimen (GINGER) study, a 52-week, open-label, randomized study of 310 patients with poorly controlled T2DM on premixed insulin therapy 6 metformin found that a regimen of once-daily insulin glargine and mealtime glulisine produced significantly greater reductions in A1C level and daytime and postprandial blood glucose than did a regimen of twice-daily premixed insulin after 52 weeks (P , 0.01), with no significant difference between the groups in the incidence of hypoglycemia or daily insulin doses. However, the basal-bolus regimen was associated with significantly greater mean weight gain (3.6 6 4.0 kg versus 2.2 6 4.5 kg; P 5 0.0073).14 Patients with T2DM (n 5 306) and type 1 diabetes mellitus (n 5 82) participating in a 24-week crossover trial of 12 weeks of insulin glargine plus premeal glulisine versus 12 weeks of twice-daily premixed analog insulin reported significantly improved quality of life (P , 0.001), less glucose variability (P , 0.0001) and greater reductions in A1C level (P , 0.0001) with insulin glargine/glulisine, with comparable rates of symptomatic hypoglycemia with both treatments.15 A randomized study with a pragmatic design that compared clinical practice outcomes with insulin glargine/glulisine and premixed insulin regimens in 197 patients with T2DM also demonstrated significantly greater A1C reductions with insulin glargine/glulisine versus premixed insulin (P , 0.01). The insulin glargine/glulisine was associated with lower medication costs and greater weight gain compared with premixed regimens; no significant differences in quality of life were noted between the groups.16 Patients and their physicians are often reluctant to initiate insulin therapy. Common patient concerns include weight gain, social embarrassment and stigma, fear of hypoglycemia, lifestyle changes and restrictions, injection pain, feelings of failure and guilt and worsening disease. Clinician concerns include patient anger, patient compliance, resentment of the extra burden of patient crises during insulin initiation, anger at oral antidiabetic drug failure, losing or alienating the patient, inadequate patient education resources and fear of patient hypoglycemia and weight gain.17 Additional insight into barriers to insulin therapy was obtained from an analysis of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study, which was conducted via structured interviews to investigate self-reported patient and provider attitudes regarding insulin therapy and their correlates. Among U.S. physicians and nurses, a strong belief existed that insulin therapy should

492

be delayed until absolutely necessary; interestingly, the perception of clinical efficacy was strongly associated with this delay, as only slightly more than half of the physicians and nurses agreed that insulin had a positive impact on patient care. Patients in the United States reported a low level of perceived insulin efficacy and a high level of self-blame for needing insulin.18 Structured interviews of primary care providers who participated in the Translating Research Into Action for Diabetes (TRIAD) study were conducted to determine their views on insulin initiation and what factors affect their decision. Most felt that failure to reach glycemic targets with other therapies would prompt them to initiate insulin therapy in their patients. However, patient refusal/resistance and poor patient self-management skills were commonly reported as barriers to insulin initiation. Primary care providers cited fear of injections, patients’ beliefs that using insulin means they will get sicker and inconvenience associated with injections and self-monitoring of glucose as the main reasons for patients to refuse therapy.19 The ADA/EASD position statement advises educating patients at diagnosis that T2DM is a progressive disease and that over time, they will require more medications to control their hyperglycemia.3 Patients should understand that the need for insulin reflects the progressive nature of the disease and not their own failure. In addition, they must be aware that after an insulin regimen has been started, it will require intensification.11 In the Treating to Target in Type 2 Diabetes (4-T) study, which compared biphasic, prandial and basal insulin added to metformin and sulfonylurea in 708 insulin-naive patients, 17.0%, 23.9% and 8.1% of patients in the biphasic, prandial and basal insulin groups, respectively, achieved A1C level #6.5% after 1 year, demonstrating that most patients on insulin had inadequate glycemic control.20 After 3 years, when 67.7%, 73.6% and 81.6% of the patients in the biphasic, prandial and basal insulin groups, respectively, were on 2 types of insulin, less than half of the patients in each group achieved A1C level #6.5% (31.9%, 44.8% and 43.2%, respectively).21

INSULIN IN COMBINATION WITH OTHER ANTIHYPERGLYCEMIC AGENTS FOR GLYCEMIC CONTROL Selection of agents to use with insulin is based on complementary mechanisms of action to address multiple disease mechanisms without the need for maximal dosing of individual agents. A review of available antihyperglycemic agents and their associated adverse effects enables the identification of potentially favorable and unfavorable combinations with insulin (Table 1). Figure 1 illustrates the mechanisms of action of common classes of antihyperglycemic agents. Metformin is an orally administered biguanide that acts on the liver to reduce hepatic glucose production and improve insulin sensitivity; it also weakly sensitizes muscle to insulin. Use of metformin as monotherapy is not associated with hypoglycemia, but it is associated with modest weight loss.3,8,10 Thus, the use of metformin in combination with insulin should not exacerbate insulin-associated hypoglycemia and may help ameliorate insulin-associated weight gain. Moreover, addition of metformin to insulin therapy may allow for a decrease in insulin dosage depending on the level of glycemic control. Thiazolidinediones (TZDs) are orally administered modulators of peroxisome proliferator-activated receptor g that preserve b-cell function in animal studies and provide a durable effect on glycemic control; they are also strong insulin sensitizers in liver, muscle and adipose tissue. Hypoglycemia is uncommon with TZDs, but they are associated with edema and weight gain, Volume 347, Number 6, June 2014

Ó 2014 Lippincott Williams & Wilkins

TABLE 1. Available antihyperglycemic agents and advantages/disadvantages of combination therapy with insulin Advantages/ disadvantages to Route of combination therapy Hypoglycemia Weight effect Agent or class Description/effect3,7,8,22 administration with insulin (monotherapy) (monotherapy) Metformin

Biguanide

Reduces hepatic glucose production Improves insulin sensitivity Weakly sensitizes muscle to insulin Reduces absorption of glucose from the gut Thiazolidinediones Modulate peroxisome proliferatoractivated receptor g Strong insulin sensitizers in liver, muscle and adipose tissue Sulfonylureas and Insulin secretagogues that interact with glinides adenosine triphosphate-sensitive potassium channels on b cells. a-Glucosidase Decrease the amount of glucose absorbed inhibitors from the small intestine

Oral

No

Loss

Warnings/side effects Black box warning: rare metabolic complication of lactic acidosis, which is fatal in .40% of cases23 Vitamin B12 levels must be measured periodically GI side effects3

Oral

Weight gain and risk of heart failure are disadvantages

Oral

Oral

Pramlintide

Synthetic amylin analog Slows gastric emptying and inhibits glucagon production

Injectable

GLP-1 receptor agonists

Incretin-based agents

Subcutaneous injection

Uncommon

Gain

Black box warning: risk of development or exacerbation of congestive heart failure Associated with edema, fractures, and bladder tumors3,7,8,24 Major side effect of sulfonylureas is hypoglycemia3,7

Exacerbate risk of hypoglycemia

Yes

Gain

Not associated with hypoglycemia or weight gain Not associated with hypoglycemia or weight gain; adjustments in insulin dose may be needed to avoid hypoglycemia Not associated with hypoglycemia; typically result in weight loss

No

Neutral

Commonly associated with GI AEs22

No

Loss

Black box warning: potential for insulininduced severe hypoglycemia25

No

Loss

Victoza and Bydureon prescribing information contain a black box warning regarding the possible risk of thyroid C-cell tumors; this was noted in rodents and thus far has not been seen in humans26,27 Warning regarding risk of pancreatitis28

Nausea or vomiting27,29

493

(Continued)

Insulin + Incretin-Based Agents in T2DM

Resistant to inactivation by DPP-4 Mimic the actions of endogenous GLP-1 to stimulate insulin secretion Exenatide is available in a short-acting and long-acting formulation. The shortacting formulation of exenatide is primarily a postprandial glucose modulator; the long-acting exenatide formulation and liraglutide lower fasting blood glucose and postprandial glucose levels30

Not associated with hypoglycemia or weight gain; may produce weight loss

494

SGLT2 inhibitors

AE, adverse event; DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2; T2DM, type 2 diabetes mellitus.

Associated with genital mycotic infection and urinary tract infection Risk of hypotension31,32 Loss No Not associated with hypoglycemia but may require lowering the insulin dose; typically result in weight loss

Risk of serious hypersensitivity reactions3

Warning regarding risk of pancreatitis28 Neutral No Not associated with hypoglycemia; weight neutral

Incretin-based agents Oral Inhibit DPP-4, the enzyme responsible for incretin degradation Increase the levels of endogenous GLP-1 and gastric inhibitory polypeptide to enhance b-cell function Stimulate insulin secretion Decrease glucagon secretion Effects on glucose are mostly postprandial Inhibit renal glucose reabsorption Oral DPP-4 inhibitors

Agent or class

TABLE 1.

(Continued )

Description/effect3,7,8,22

Route of administration

Advantages/ disadvantages to combination therapy with insulin

Hypoglycemia Weight effect (monotherapy) (monotherapy)

Warnings/side effects

Tibaldi

which is even more prominent when used with insulin.3,8,10 Thus, recommendations are to use reduced doses of TZDs or to not use them in combination with insulin unless required to minimize the insulin dose.3 Sulfonylureas and glinides are orally administered insulin secretagogues; they augment second-phase insulin secretion and hasten b-cell decline, and their glycemic effects are not durable. In addition, their use is associated with hypoglycemia because of nonphysiologic insulin secretion and secondary weight gain.3,8,10 Consequently, they are not good candidates for combination therapy with insulin. a-Glucosidase inhibitors are orally administered agents that act by delaying glucose absorption in the small intestine. They are not associated with hypoglycemia and are weight neutral. They are poorly tolerated owing to gastrointestinal side effects and seldom used in the United States and Europe. Pramlintide is an injectable synthetic amylin analog that slows gastric emptying, promotes satiety and inhibits glucagon production. It is indicated as an adjunct therapy to insulin,3 is not associated with hypoglycemia and produces weight loss.3,7,8,10 The sodium glucose cotransporter 2 inhibitors are the newest class of oral antidiabetes drugs. These agents lower blood glucose by inhibiting glucose reuptake in the kidney and are associated with modest weight loss.33,34 Sodium glucose cotransporter 2 inhibitors are not associated with hypoglycemia as monotherapy, but they may increase the risk of hypoglycemia when combined with insulin or insulin secretagogues and may require lowering the insulin dose.31–35 The incretin-based agents include the injectable GLP-1 receptor agonists and the orally administered DPP-4 inhibitors. GLP-1 receptor agonists are resistant to inactivation by DPP-4 and mimic the actions of endogenous GLP-1 to stimulate insulin secretion. These agents also inhibit glucagon secretion, delay gastric emptying, promote satiety and preserve b-cell function. They are not associated with hypoglycemia, and they are associated with weight loss.3,10,36 DPP-4 inhibitors act by inhibiting the enzyme that degrades endogenous incretins. This inhibition increases the levels of endogenous GLP-1 and gastric inhibitory polypeptide to enhance b-cell function. DPP-4 inhibitors stimulate both first- and second-phase insulin secretion and decrease glucagon secretion and thus target postprandial glucose levels. Because the actions of DPP-4 inhibitors are glucose dependent, they are not associated with hypoglycemia; these agents are weight neutral.3,10,36 These features make incretin-based agents feasible for combination therapy with insulin (see below). Addition of insulin may require modifications to existing therapy. Although metformin can be and usually is continued in combination with insulin unless contraindicated, sulfonylureas and glinides should be discontinued, as adding insulin to insulin secretagogues further increases the risk of hypoglycemia.3,7 Caution must be exercised when using TZDs with insulin, as the increased incidence of fluid retention can lead to congestive heart failure.7,24

INCRETIN-BASED AGENTS IN COMBINATION WITH INSULIN Endogenous incretins stimulate insulin release prandially in a glucose-dependent manner and suppress glucagon secretion. The incretin-based agents directly address incretin deficiency or resistance and the resultant decrease in insulin as part of T2DM pathology.8 Incretin-based agents have several advantages. Their activity is glucose dependent, which means that their effects diminish as glucose levels return toward normal. Therefore, the risk of hypoglycemia is minimal when they are Volume 347, Number 6, June 2014

Insulin + Incretin-Based Agents in T2DM

FIGURE 1. Mechanisms of action of common antihyperglycemic agents indicated for the treatment of T2DM. Available antihyperglycemic agents may act on 1 or more of the altered pathways in T2DM. Impaired pancreatic insulin secretion can be addressed by TZDs, GLP-1 RAs, DPP-4 inhibitors or sulfonylureas. TZDs also sensitize muscle cells to insulin and inhibit hepatic gluconeogenesis and lipolysis. Metformin, GLP-1 RAs and DPP-4 inhibitors inhibit hepatic gluconeogenesis, and metformin weakly sensitizes muscle cells to insulin and reduces intestinal absorption of glucose. GLP-1 RAs and DPP-4 inhibitors stimulate insulin secretion and decrease glucagon secretion, and GLP-1 RAs additionally promote satiety. Pramlintide acts to both decrease glucagon secretion and promote satiety. The SGLT2 inhibitors reduce reabsorption of filtered glucose and lower the renal threshold for glucose, resulting in an increased urinary glucose excretion. DPP-4, dipeptidyl peptidase-4; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; HGP, hepatic glucose production; SGLT2, sodium-glucose cotransporter 2; T2DM, type 2 diabetes mellitus; TZD, thiazolidinediones. Adapted with permission from DeFronzo.8

used as monotherapy.36 Furthermore, the suppression of glucagon secretion by these agents is a complementary mechanism to insulin therapy. Although clinicians may be more apt to adjust the insulin dose than to add on another medication, incretinbased agents have the potential to spare prandial injections. In the author’s experience, the incidence of hypoglycemia is minimal when DPP-4 inhibitors are added to insulin therapy, so no change in insulin dose is necessary. If A1C level is ,7.5% with basal insulin therapy, a DPP-4 inhibitor can be added, and if A1C level is ,8.5%, a long-acting GLP-1 receptor agonist can be added. If weight loss is desired, a GLP-1 receptor agonist can be selected. Because of the potential for anorexia, if adding a GLP-1 receptor agonist to insulin therapy, the experience of the author suggests that one may consider lowering the insulin dose by 20% and evaluating the patient’s response over time to determine whether an increase is needed. Ó 2014 Lippincott Williams & Wilkins

In addition, the weight neutrality associated with DPP-4 inhibitors and weight loss seen with GLP-1 receptor agonists are particularly attractive, given the weight gain associated with insulin. The absence of weight gain may relate to the fact that incretin-stimulated insulin secretion is more physiologic than exogenous insulin administration, with insulin secreted via the portal system. Consequently, combination therapy with these agents should not worsen and may lessen insulin therapy– associated weight gain. By the time most individuals initiate insulin therapy, they have significant loss of b-cell function. Although this should limit their body’s ability to produce insulin, the incretin-based agents can still augment the effects of endogenous and exogenous insulin in these individuals. Both GLP-1 receptor agonists and DPP-4 inhibitors modulate postprandial glucose excursions that may reduce the need for prandial insulin. Thus, if a DPP-4

495

Tibaldi

inhibitor is used for intensification instead of additional insulin injections, the dosage of insulin and the number of injections per day could decrease. Adding incretin-based therapy to insulin may also overcome obstacles of insulin therapy, such as fluctuations in glucose levels with meals, by enhancing the secretion of endogenous mealtime insulin to help control prandial glucose spikes. One potential disadvantage to the use of GLP-1 receptor agonists in combination with insulin is patient acceptability of additional daily injections of these incretinbased drugs; however, this may not be a problem in patients already receiving insulin therapy. It should be noted that the U.S. Food and Drug Administration (U.S. FDA) mandated a warning on the prescribing information for GLP-1 receptor agonists and DPP-4 inhibitors regarding the risk of pancreatitis. Although acute pancreatitis may develop in certain patients and can be severe or fatal, a recent database study of almost 800,000 patients compared the risk of acute pancreatitis between patients with and without diabetes and among users of a GLP-1 receptor agonist, a DPP-4 inhibitor and control diabetes medications (sulfonylureas, biguanides, or TZD) and found that the use of incretin-based therapies had no correlation with the incidence of acute pancreatitis. An increased incidence of pancreatitis was observed in patients with diabetes versus those without diabetes but not in GLP-1 receptor agonist or DPP-4 inhibitor users versus control diabetes medication users.28 The U.S. FDA is investigating reports of possible increased risk of pancreatitis and precancerous cellular changes of the pancreas in patients with T2DM receiving incretin-based tharapies.37 Incretin-based agents approved in the United States include the GLP-1 receptor agonists exenatide (immediaterelease [Byetta; Amylin Pharmaceuticals, Inc, San Diego, CA] and extended-release [Bydureon; Amylin Pharmaceuticals, Inc, San Diego, CA] forms) and liraglutide (Victoza; Novo Nordisk A/S, Bagsvaerd, Denmark), and the DPP-4 inhibitors sitagliptin (Januvia; Merck Sharp & Dohme (Italia) S.p.A., Pavia, Italy), saxagliptin (Onglyza; Bristol-Myers Squibb Company, Princeton, NJ), linagliptin (Tradjenta; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) and alogliptin (Nesina; Takeda Pharmaceuticals America, Inc, Deerfield, IL). The DPP-4 inhibitor vildagliptin is approved only in Europe. The effects of exenatide (5 mg twice daily for 2 weeks followed by 10 mg twice daily for 2 weeks) and sitagliptin (100 mg once daily) as add-on therapy to basal insulin (insulin glargine, titrated to a fasting blood glucose target of #100 mg/dL) and preexisting treatment with metformin were investigated in a 4-week, proofof-concept study.38 At the end of treatment, the unadjusted 6-hour postprandial blood glucose excursion after a standardized breakfast was compared among the patients who received exenatide add-on therapy, sitagliptin add-on therapy and no add-on therapy (control). Postprandial glucose excursions in the exenatide and sitagliptin groups were significantly reduced versus those in the control group (17% reduction with add-on exenatide [P 5 0.0036]; 20% reduction with add-on sitagliptin [P 5 0.0008]; no difference between add-on therapies). Significant improvements from baseline with incretin-based add-on therapy versus control were also seen in A1C, 7-point 24-hour glucose profiles, fasting blood glucose and lipids. No major hypoglycemic episodes (episodes that patients were not able to self-treat) were noted in any group; minor hypoglycemia (blood glucose ,50 mg/dL) occurred in 2 patients treated with exenatide, 3 treated with sitagliptin and 2 in the control group. Body weight decreased slightly in the exenatide group compared with that in the control group (P 5 0.0377) and remained

496

stable in the sitagliptin and control groups. The mean dose of insulin remained relatively stable in the exenatide and sitagliptin groups but increased by 5.6 IU in the control group.38 Incretin-based add-on therapy in patients inadequately controlled on insulin 6 metformin was assessed in longer-term (range, 24–30 weeks) randomized controlled trials with exenatide,39 sitagliptin40 and saxagliptin.41 In an exenatide trial, patients received add-on therapy with exenatide 10 mg twice daily (n 5 138) or placebo (n 5 123). After 30 weeks, mean baseline A1C level (8.3% in the exenatide group and 8.5% in the placebo group) decreased by 1.74% with exenatide versus 1.04% with placebo (P , 0.001). Rates of hypoglycemia did not differ between the groups. Minor hypoglycemia occurred in 25% of exenatide patients and 29% of placebo patients. Major hypoglycemia occurred in 1 placebo patient. Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo. The mean dose of insulin increased by 13 U/d with exenatide and 20 U/d with placebo.39 Based on these results, in October 2011, the U.S. FDA approved exenatide as an add-on therapy to insulin glargine, with or without metformin and/or a TZD, in conjunction with diet and exercise for adults with T2DM for whom adequate glycemic control has not been achieved with insulin glargine alone. Although phase III clinical trial data are not yet published, liraglutide add-on therapy to insulin detemir is also approved by the U.S. FDA.26 An exploratory post hoc analysis of the pivotal clinical trial of exenatide and insulin glargine described above39 found that improvements in A1C level and decreases in weight occurred regardless of baseline A1C, diabetes duration, and body mass index.42 A retrospective analysis of data from a U.S. insurance claims database found that clinical outcomes with exenatide in combination with insulin glargine (both given at the same time or one given as add-on therapy to the other) after 1 year included significant reductions from baseline in A1C level (range, 20.4% to 21.2%) and a similar incidence of hypoglycemia among groups.43 Real-world use of exenatide in combination with insulin glargine was also examined in a retrospective chart review of patients in 26 large practices throughout the United States. Regardless of the order of treatment (exenatide added on to insulin glargine or insulin glargine added on to exenatide), A1C level decreased significantly from baseline through 24 months (20.7% for both groups pooled). Body weight was unchanged with insulin glargine added on to exenatide and decreased with exenatide added on to insulin glargine. The incidence of hypoglycemia did not differ between the groups.44 In a preliminary report in patients with T2DM, addition of liraglutide to insulin degludec + metformin reduced A1C level to a greater extent (20.74% versus 20.39%) with weight loss (22.8 kg) and less hypoglycemia, compared with those receiving insulin aspart added to insulin degludec + metformin, who experienced weight gain (+0.9 kg).45 In the sitagliptin trial,40 641 patients received 100 mg of sitagliptin (n 5 322) or placebo (n 5 319) once daily as add-on therapy to insulin (premixed, long acting or intermediate acting) 6 metformin. After 24 weeks, the mean change from baseline A1C (8.7% in the sitagliptin group; 8.6% in the placebo group) was significantly greater with sitagliptin versus placebo add-on therapy (20.6% versus 0, respectively; P , 0.001), and the mean change from baseline in 120-minute postprandial glucose was significantly greater with sitagliptin versus placebo add-on therapy (230.9 mg/dL versus 5.2 mg/dL, respectively; P # 0.001). The incidence of symptomatic hypoglycemia was significantly higher with sitagliptin versus placebo add-on therapy (16% versus 8%, respectively; P 5 0.003); there were 155 hypoglycemic episodes in the sitagliptin group (52 of the 138 episodes with Volume 347, Number 6, June 2014

Ó 2014 Lippincott Williams & Wilkins

TABLE 2. Planned and ongoing clinical trials of incretin-based add-on therapy to insulin as of June 2013

Agent GLP-1 receptor agonists Exenatide

Liraglutide

Phase

FLAT-SUGAR: FLuctuATion reduction with inSUlin and GLP-1 Added togetheR (NCT01524705)

IV

The effect of liraglutide on insulinassociated weight gain in patients with T2DM (NCT01392898)

NR

Phase 3 study of liraglutide in individuals with type 2 diabetes using insulin (NCT01628445)

III

Liraglutide and insulin-001, a randomized prospective trial of liraglutide added to high-dose insulin therapy vs. high-dose insulin therapy alone in insulin-resistant patients with type 2 diabetes (NCT01654120) Adding liraglutide to high-dose insulin: breaking the cycle (NCT01505673)

IV

The effect of liraglutide vs. placebo when added to basal insulin analogues with or without metformin in subjects with type 2 diabetes (NCT01617434)

IV

III

Treatment arms

Exenatide 5 mg BID for 6 Change in mo, metformin #1000 coefficient of mg BID for 6 mo, insulin variation of glargine QD for 6 mo continuous glucose Metformin #1000 mg BID readings for 6 mo/ insulin glargine QD 6 mo/prandial insulin (aspart, glulisine, or lispro) for 6 mo Liraglutide 1.8 mg QD Change in body weight from Insulin dosed according to baseline to titration scheme week 26 Liraglutide 1.8 mg SC Change from baseline in Placebo A1C at week 24 Liraglutide 1.8 mg QD + Change from insulin SC 4 times a day, baseline in titrated during the study A1C at 6 mo Insulin SC 4 times a day, titrated during the study

Status

Estimated study completion date

Sponsor

Recruiting

July 2014

Recruiting

September 2013 Radboud University

Recruiting

NR

University of Manitoba

Recruiting

June 2013

Mountain Diabetes and Endocrine Center

June 2013

Ildiko Lingvay

Liraglutide 1.8 mg QD + Glycemic control Recruiting insulin .1.8 U/kg/d (A1C) at 2 and 6 mo Placebo + insulin .1.8 U/kg/d Liraglutide (max 1.8 mg SC Change in A1C Active, not daily) + pretrial basal from baseline recruiting insulin 6 metformin to week 126 Placebo + pretrial basal insulin 6 metformin

University of Washington

September 2013 Novo Nordisk

(Continued)

497

Insulin + Incretin-Based Agents in T2DM

Official title (trial number)

Primary end point

Tibaldi

498 TABLE 2.

(Continued )

Agent DPP-4 inhibitors Sitagliptin

Estimated study completion date

Official title (trial number)

Phase

Treatment arms

Primary end point

Comparison between sitagliptin add-on therapy and insulin dose increase therapy for uncontrolled type 2 diabetes on insulin therapy (NCT01100125) Open-label, randomized, activecontrolled, parallel-arm, single-center study on effect of sitagliptin on T2DM patients on treatment with metformin and insulin (NCT01341717)

IV

Sitagliptin 100 mg QD Insulin dose increase (Lantus)

Change in A1C from baseline to week 24

Recruiting

November 2011 Seoul National University Bundang Hospital

IV

Sitagliptin 100 mg QD + Change in A1C metformin $1000 mg from baseline BID + insulin TDD to month 6 .10 IU QD/BID Glimepiride 1 mg/2 mg/3 mg QD + metformin $1000 mg BID + insulin TDD .10 IU QD/BID Sitagliptin 100 mg QD + Change from metformin $1500 mg/d + baseline in insulin glargine daily insulin dose at Placebo QD + metformin week 24 $1500 mg/d + insulin glargine

Recruiting

September 2013 Jothydev’s Diabetes and Research Centre

Active, not recruiting

June 2013

Merck

Sitagliptin 100 mg QD + stable dose of insulin 6 metformin Placebo + stable dose of insulin 6 metformin

Recruiting

January 2014

Merck

Volume 347, Number 6, June 2014

A phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial to study the safety and insulin-sparing efficacy of the addition of sitagliptin in T2DM patients who have inadequate glycemic control (NCT01462266) A phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial in China to study the safety and efficacy of the addition of sitagliptin in T2DM patients who have inadequate glycemic control on insulin therapy, alone or in combination with metformin (NCT01590797)

III

III

Change from baseline in A1C at week 24

Status

Sponsor

(Continued)

Ó 2014 Lippincott Williams & Wilkins

TABLE 2.

(Continued )

Agent Vildagliptin

Alogliptin

Treatment arms

Primary end point

Official title (trial number)

Phase

A 24-wk, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to assess the efficacy and safety of vildagliptin 50 mg BID as an add-on therapy to insulin, with or without metformin, in T2DM patients (NCT01582230)

III

Multicenter crossover trial to assess the glycemic profiles on 8 wk of vildagliptin and sitagliptin treatment, each in T2DM patients with preexisting cardiovascular disease pretreated with insulin, using a PROBE design (NCT01686932) A multicenter, double-blind, randomized, parallel-group, placebocontrolled study to compare the effect of 13-wk treatment with vildagliptin as add-on therapy to improve glucose variability in T2DM patients inadequately controlled with insulin (NCT01862263) A phase III study to investigate the efficacy and safety of SYR-322 when used in combination with insulin preparation in T2DM patients in Japan (NCT01521962)

IV

8 wk vildagliptin followed by 8 wk sitagliptin 8 wk sitagliptin followed by 8 wk vildagliptin

IV

Vildagliptin 50 mg BID + Percentage of insulin 20 to 40 IU/d patients with hypoglycemic Placebo BID + insulin 20 to events 40 IU/d

Not yet recruiting October 2014

III

Alogliptin 25 mg Insulin

Recruiting

Vildagliptin 50 mg BID

Placebo

Status

Estimated study completion date

Change in A1C Active, not from baseline recruiting to study end point in overall study population Change in A1C from baseline to study end point in Chinese study population Hypoglycemic Recruiting profile

Change in A1C from baseline to week 12

May 2013

Sponsor Novartis

November 2013 Novartis

Novartis

Data obtained from www.ClinicalTrials.gov. Accessed June 3, 2013. BID, twice daily; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; NR, not reported; QD, once daily; SC, subcutaneous; T2DM, type 2 diabetes mellitus; TDD, total daily dose.

499

Insulin + Incretin-Based Agents in T2DM

NR: data Takeda collection date Pharmaceutical for primary Company Limited outcome measure is November 2013

Tibaldi

a concurrent fingerstick glucose value were #50 mg/dL) and 76 in the placebo group (20 of the 73 episodes with a concurrent fingerstick glucose value were #50 mg/dL). Severe hypoglycemia was experienced by 2 patients receiving sitagliptin and 1 patient receiving placebo. Body weight did not change significantly from baseline in either group. The mean daily dose of insulin did not change from baseline in the sitagliptin group and increased by 1.6 U in the placebo group.40 Sitagliptin was approved by the U.S. FDA in February 2010 as add-on therapy to insulin with or without metformin. In the saxagliptin trial,41 455 patients received 5 mg of saxagliptin (n 5 304) or placebo (n 5 151) once daily as addon therapy to insulin (premixed, long acting or intermediate acting) 6 metformin. After 24 weeks, the mean change from baseline A1C (8.7% with saxagliptin; 8.6% with placebo) was significantly greater with saxagliptin versus placebo (20.73% versus 20.32%, respectively; P , 0.0001), as was the mean change from baseline in 120-minute postprandial glucose (227.2 mg/dL versus 24.2 mg/dL, respectively; P # 0.0016). The magnitude of reductions in A1C from baseline to week 24 with saxagliptin add-on therapy was similar with or without metformin use. There was a similar incidence of reported hypoglycemia between the treatment groups (saxagliptin, 18.4%; placebo, 19.9%), whereas the incidence of confirmed hypoglycemia with associated symptoms (with fingerstick glucose measurement of #50 mg/dL) was higher with saxagliptin versus placebo (5.3% versus 3.3%). Major hypoglycemic events were experienced by 3 patients receiving saxagliptin and 2 patients receiving placebo. Changes from baseline in body weight at week 24 were similar in both groups and not clinically significant. The adjusted mean increase from baseline in insulin dose at week 24 was 1.7 U/d in the saxagliptin group and 5.0 U/d in the placebo group. Saxagliptin was approved by the U.S. FDA in December 2011 as add-on therapy to insulin with or without metformin. Add-on therapy with incretin-based agents in patients inadequately controlled with insulin-based regimens continues to be an area of active research. Information available on www.clinicaltrials.gov regarding studies of incretin-based add-on therapy to insulin therapy indicates that as of June 2013, 13 additional trials are ongoing, and 1 trial is planned but not yet open for recruitment. A summary of these trials is provided in Table 2.

CONCLUSIONS Most patients with T2DM will eventually require insulin, and most barriers to insulin initiation for patients and health care providers can be overcome with appropriate education and collaboration with diabetes educators. Insulin combinations should include agents that improve glycemic control without increasing the risk of hypoglycemia or weight gain. The incretinbased agents meet these criteria and, in addition to their efficacy alone and in combinations with other agents, are effective and tolerable in combination with insulin. Current data suggest that add-on therapy with incretin-based agents benefits patients inadequately controlled on insulin therapy without the propensity for hypoglycemia and weight gain, and at potentially lower doses of insulin, which should ultimately improve outcomes. ACKNOWLEDGMENTS The author thanks Stephanie Leinbach, PhD, and Erica S. Wehner, RPh, CMPP, from Complete Healthcare Communications, Inc (Chadds Ford, PA) for providing medical writing support for the preparation of this manuscript, with funding from Bristol-Myers Squibb and AstraZeneca.

500

REFERENCES 1. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837–53. 2. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89. 3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35: 1364–79. 4. Ranjit Unnikrishnan I, Anjana RM, Mohan V. Importance of controlling diabetes early—the concept of metabolic memory, legacy effect and the case for early insulinisation. J Assoc Physicians India 2011;59:8–12. 5. Johnston SS, Conner C, Aagren M, et al. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care 2011;34:1164–70. 6. Fox CS, Pencina MJ, Wilson PW, et al. Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham Heart Study. Diabetes Care 2008;31: 1582–4. 7. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract 2009;15:540–59. 8. DeFronzo R. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773–95. 9. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA (1c). Diabetes Care 2003;26:881–5. 10. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013;19:327–36. 11. Triplitt C. How to initiate, titrate, and intensify insulin treatment in type 2 diabetes. US Pharm 2007;32:10–6. 12. Hamaty M. Insulin treatment for type 2 diabetes: when to start, which to use. Cleve Clin J Med 2011;78:332–42. 13. Vaag A, Lund SS. Insulin initiation in patients with type 2 diabetes mellitus: treatment guidelines, clinical evidence and patterns of use of basal versus premixed insulin analogues. Eur J Endocrinol 2012;166: 159–70. 14. Fritsche A, Larbig M, Owens D, et al. Comparison between a basalbolus and a premixed insulin regimen in individuals with type 2 diabetesresults of the GINGER study. Diabetes Obes Metab 2010;12:115–23. 15. Testa MA, Gill J, Su M, et al. Comparative effectiveness of basalbolus versus premix analog insulin on glycemic variability and patientcentered outcomes during insulin intensification in type 1 and type 2 diabetes: a randomized, controlled, crossover trial. J Clin Endocrinol Metab 2012;97:3504–14. 16. Levin PA, Zhang Q, Mersey JH, et al. Glycemic control with insulin glargine plus insulin glulisine versus premixed insulin analogues in realworld practices: a cost-effectiveness study with a randomized pragmatic trial design. Clin Ther 2011;33:841–50. 17. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord 2002;26:S18–24. 18. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28: 2673–9.

Volume 347, Number 6, June 2014

Insulin + Incretin-Based Agents in T2DM

19. Ratanawongsa N, Crosson JC, Schillinger D, et al. Getting under the skin of clinical inertia in insulin initiation: the Translating Research into Action for Diabetes (TRIAD) Insulin Starts Project. Diabetes Educ 2012;38:94–100. 20. Holman RR, Thorne KI, Farmer AJ, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007;357:1716–30. 21. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009;361: 1736–47. 22. American Diabetes Association. Standards of medical care in diabetes–2012. Diabetes Care 2012;35(suppl 1):S11–63. 23. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27:1791–3. 24. ACTOS (pioglitazone hydrochloride) [full Prescribing Information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2011. 25. SymlinÒ (pramlintide acetate) [full prescribing information]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2008.

inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372–82. 35. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928–38. 36. Drucker DJ, Sherman SI, Gorelick FS, et al. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 2010;33:428–33. 37. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm. Accessed July 11, 2013. 38. Arnolds S, Dellweg S, Clair J, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-ofconcept study. Diabetes Care 2010;33:1509–15.

26. VictozaÒ (liraglutide [rDNA origin]) [full prescribing information]. Princeton, NJ: Novo Nordisk, Inc.; 2011.

39. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011;154:103–12.

27. Bydureon™ (exenatide extended-release for injectable suspension) [full prescribing information]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2012.

40. Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010;12:167–77.

28. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care 2010;33:2349–54.

41. Barnett AH, Charbonnel B, Donovan M, et al. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin 2012;28:513–23.

29. Byetta (exenatide) [full prescribing information]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2011. 30. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, openlabel, non-inferiority study. Lancet 2008;372:1240–50. 31. Invokana™ (canagliflozin) [full Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 32. Forxiga™ (dapagliflozin) [summary of product characteristics]. Anagni, Italy: Bristol-Myers Squibb Company; 2012. 33. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217–24. 34. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus

Ó 2014 Lippincott Williams & Wilkins

42. Rosenstock J, Shenouda SK, Bergenstal RM, et al. Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes. Diabetes Care 2012;35:955–8. 43. Levin P, Wei W, Wang L, et al. Combination therapy with insulin glargine and exenatide: real-world outcomes in patients with type 2 diabetes. Curr Med Res Opin 2012;28:439–46. 44. Levin PA, Mersey JH, Zhou S, et al. Clinical outcomes using longterm combination therapy with insulin glargine and exenatide in patients with type 2 diabetes mellitus. Endocr Pract 2012;18:17–25. 45. Mathieu C, Rodbard HW, Cariou B, et al. Comparison of addition of liraglutide to insulin degludec plus metformin vs. addition of a single dose of rapid-acting insulin analog to largest meal in type 2 diabetes. Presented at: American Diabetes Association 73rd Scientific Sessions; June 21-25, 2013; Chicago IL. Poster 911-P.

501