Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor
The incretin effect was discovered after experiments found that administration of oral glucose resulted in an increased insulin secretion compared to the same amount of intravenous glucose in healthy controls.42 This effect was eventually ascribed to two hormones produced in the gut, glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both hormones have roles in controlling glucose appearance similar to that of amylin. GLP-1 has been shown to suppress glucagon production, augment glucose-dependent insulin secretion, promote early satiety, and delay gastric emptying.43 Given this physiological abnormality and the beneficial clinical effects, the first GLP-1 analog, exenatide, was approved by the FDA in 2005 for use in T2D….
The incretin effect is somewhat different in T1D patients when compared to T2D. The incretin effect was originally measured by noting the increased release of insulin from an oral glucose load as compared to an IV load. As T1D patients typically do not make insulin, this same effect cannot be demonstrated. However, studies have been done in T1D patients in which levels of GIP and GLP-1 were directly measured after an oral glucose load. These studies have shown that T1D patients seem to make a normal amount of the incretin hormones when compared to controls. However, it was shown that T1D patients had an increased glucagon response to an oral compared to IV load.44 Taken together, these findings make the argument that while T1D patients produce a normal amount of these gut hormones, there still appears to be a dysregulation between the gut and pancreas in which glucagon is not effectively suppressed (see Figure 13.7). This phenomenon raises the possibility that therapeutic intervention with GLP-1 agonists may have beneficial effects in T1D.
Several studies have begun to look specifically at the clinical benefits of GLP-1 agonists in T1D. One such study took 30 patients with T1D and gave them liraglutide once daily over a 4-week period.45 This study broke patients into C-peptide–positive and C-peptide–negative subgroups and compared the effect of the liraglutide with insulin vs. insulin therapy alone. In both C-peptide negative (<0.03 nmol/l) and C-peptide–positive groups (>0.06 nmol/l), the addition of once daily liraglutide showed a trend toward lowered A1C (–0.2% and –0.5%, respectively) at 4 weeks but was not statistically significant. Liraglutide did lead to significantly lower total insulin dose (approximately –0.2 U/kg) and weight loss (–2.3 kg).
Figure 13.7 (a) Levels of GLP-1 are not diminished in T1D. (b) Paradoxical increased glucagon levels in response to oral glucose load compared to IV load in T1D. Source: Hare KJ, Vilsbøll T, Holst JJ, Knop FK: Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab 298:E832–E837, 2010. Reprinted with permission from the publisher.
Hypoglycemia was not increased with liraglutide but mild and transient nausea was noted at initiation. The degree of insulin dose reduction was found to correlate with underlying β-cell function in that the C-peptide– positive group was able to reduce insulin usage more than the C-peptide–negative group. This study highlights that the clinical benefits of GLP-1 agonists may go beyond glucose dependent insulin secretion as both C-peptide–positive and C-peptide–negative patients trended toward improved glycemic control (see Figure 13.8).45
Figure 13.9 Six months of liraglutide lowered A1C and fasting blood glucose while reducing weight, insulin dose, duration of hyperglycemia, and glucose variability. Source: Varanasi A, Bellini N, Rawal D, Vora M, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P: Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 165:77–84, 2011. Reprinted with permission from the publisher.
In summary, GLP-1 agonists have a potential therapeutic role in T1D both in long-standing and new-onset disease. In general, the medication has similar effects as pramlintide by reducing postprandial hyperglycemia while reducing insulin usage and promoting weight loss. An additional advantage of the GLP-1 agonists is the longer dosing intervals. Once-weekly exenatide has been FDA approved for use in T2D patients and even longer formulation including once-monthly and even once/year-infusion devices are being studied. If such formulations could be approved for T1D, the fear of multiple injections would be somewhat alleviated. In the adult patients, longer duration trials and head-to-head comparisons with pramlintide are in process.
Both GLP-1 and GIP are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) with circulating half-lives of only several minutes. Therefore, effectively inhibiting this enzyme results in prolonged duration of endogenous GLP-1. Sitagliptin, the first DPP-4 inhibitor, was approved for use in T2D in 2006 and has proven to be a valuable addition in the armamentarium of treating T2D. Like GLP-1 agonists, DPP-4 inhibitors have shown to reduce postprandial hyperglycemia without increased incidence of hypoglycemia.47 They do not show the weight loss that GLP-1 agonists do but carry the benefit of being an oral medication while GLP-1 agonists are exclusively injectables.
One randomized, double-blind trial evaluated the effect of sitagliptin 100 mg/day in 20 patients with T1D. Patients were given sitagliptin 100 mg/day or placebo for 4 weeks and then crossed over. Compared to placebo, sitagliptin was shown to reduce A1C at 4 weeks (–0.27%), reduce postprandial hyperglycemia, and reduce total insulin dose (–0.051 U/kg). No change in weight or hypoglycemic episodes was observed. Limitations were a small sample size, a short trial interval of only 4 weeks, and large placebo effect (see Figure 13.10).48
As with the GLP-1 agonists, larger studies are needed to define the clinical effect of DPP-4 inhibitors in T1D. Additionally, as this class of medication has shown immune modulatory effects, its role in early onset disease is being evaluated. A study funded by the JDRF is underway in which new-onset T1D with disease duration of less than 6 months will be randomized to sitagliptin and lansoprazole (thought to aid β-cell survival by increasing endogenous gastrin levels) vs. placebo with a primary outcome of C-peptide response to a mixed meal tolerance test at baseline compared to at 1 year.
Metformin is an established oral agent that is widely used as a first line agent in the treatment of T2D.49 Its mechanism of action centers around decreasing hepatic glucose production and improving insulin sensitivity. Administration is associated with A1C reduction, weight loss, an improved lipid profile, and decreased levels of inflammation represented by C-reactive protein in T2D. These beneficial effects have led to multiple trials evaluating its use in T1D. Two large reviews have compiled the clinical evidence to date.
Figure 13.10 Sitagliptin reduced mean glucose, A1C, and insulin dose while increasing time spent in euglycemia. Source: Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK: Effect of sitagliptin on glucose control in adult patients with type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med 28:1176–1181, 2011. Reprinted with permission from the publisher.
In 2009, a Cochrane review was published on the addition of metformin to insulin in adolescents with T1D.50 After searching for any randomized control trial of at least 3-months duration, only two studies could be included. Both trials were 3 months in length and included 30 poorly controlled adolescents (average baseline A1C of around 9%) randomized to placebo vs. metformin up to 2 g/day in addition to insulin. Both studies suggested that metformin therapy led to a reduction in A1C values. There were no comments about lipid profiles or insulin sensitivity although one study noted a 10% reduction in total insulin dosage. Given these findings, the authors conclude that there is some evidence that metformin can improve glycemic control in adolescents but larger studies of longer duration are needed.
A second review was published in 2010 that evaluated the effect of adding metformin to insulin therapy in any patient with T1D.51 The authors ultimately found nine studies that met their search criteria, two of which were also in the Cochrane review noted above. Due to heterogeneity between studies, only five could be included into a formal meta-analysis. In these five studies, metformin had no statistically significant change in A1C but was found to lower insulin dosage by 6.6 U/day. Of note, the largest and longest trial included was of 100 patients randomized to metformin 1g BID vs. placebo and followed for 1 year. In this study, there again was no statistically significant change in A1C, however total daily insulin dose was reduced (–5.7 U/day) and weight loss was observed (–1.74 kg).52
Taking all the data together, metformin appears to have a beneficial effect on insulin sensitivity with reduction in overall insulin requirements and weight. The effect on overall glycemic control is somewhat less clear. As a result, metformin is not currently advocated as an adjunctive therapy for any subgroup of patients with T1D. Clinical data makes it difficult to firmly recommend or refute the use of metformin in an off-label fashion as some patients may benefit from the medication. The group of patients that would theoretically show the most benefit would be poorly controlled diabetics who are overweight and requiring large amounts of insulin.
A large trial entitled “REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)” is currently underway to evaluate the effects of metformin on cardiovascular and metabolic outcomes in T1D. The trial will enroll 500 patients, randomize them to 1g BID of metformin vs. placebo and then follow them for 3 years. The primary outcome will be change in averaged mean common carotid artery intima-media thickness. Multiple other secondary outcomes including A1C and lipid profiles will be evaluated. This study will be the largest and longest running study to date and will hopefully provide a clear answer to the role of metformin in T1D. It is estimated to reach completion in 2016.
Leptin is a 167 amino acid neurohormone produced by adipocytes that plays a key role in the central regulation of appetite, fat and glucose metabolism, and weight. Recombinant leptin (metreleptin) therapy has been shown to have beneficial metabolic effects in patients with lipodystrophy.53 In T1D, mouse studies have shown that administration of leptin alone can restore the health of insulin-deficient animals by eliminating ketoacidosis, effectively making it the only hormone other than insulin with this ability.54,55 Leptin inhibits glucagon production and serves to offset the anabolic effects of insulin on lipids by inhibiting lipo-genesis and cholesterol biosynthesis. A pilot study is underway evaluating the use of adjunctive leptin therapy in T1D. Fifteen patients will be treated with recombinant human leptin and will serve as their own controls. The endpoints will include A1C, energy intake, glucose variability, insulin dose, and others. The study is expected to reach completion in early 2013.
Following cleavage of proinsulin in the islet cells, C-peptide is released along with insulin in equimolar amounts into the portal circulation. C-peptide has long been viewed as an inert byproduct of insulin production, but a recent surge in research has revealed that the peptide has biological activity as its own hormone. Research involving the therapeutic replacement of C-peptide has revealed conflicting results in the T1D and T2D populations. In T2D patients, C-peptide was found to accumulate in carotid artery walls and may promote athrogenic lesions.56 T1D studies, however, have shown more promising results.
A growing amount of evidence in the T1D population has shown that C-peptide replacement can prevent or even reverse diabetic complications in rats, namely neuropathy and nephropathy.57–60 Several human trials have gone on to demonstrate that therapeutic administration has positive effects on diabetic neuropathy as evidenced by improving nerve conduction velocities.61,62 These findings represent a paradigm shift in how we view C-peptide. The protein has long been useful as a surrogate marker for insulin production, and it is well known that preservation of C-peptide status leads to a lower incidence of diabetic complications.32 With evidence of its utility as a therapeutic, it may be the peptide itself that is leading to favorable outcomes. Development of a longer acting subcutaneous injection of C-peptide is underway, which will assist in furthering clinical trials.63
In addition to the therapeutic agents described above, studies have looked into α-glucosidase inhibitors, colesevelam, thiazolidinediones (TZDs), and others.64–66 In general, these studies enrolled very few patients and showed, at best, mild clinical benefits. Therefore, the benefit of these medications is unknown and thus they are not recommended at this time.
Since the discovery of insulin, therapies for T1D have focused on different insulin formulations, meal planning around dosing, correction doses, and other interventions that could be described as insulincentric. However, with the relatively recent discovery of amylin deficiency in T1D, a newfound interest in investigating other potential pathways to treat this patient population has emerged. Furthermore, the proven clinical benefits and FDA approval of pramlintide has shown that adjunctive therapies in T1D can be effectively implemented into clinical practice. This fact has opened the door for an expanded investigation into other therapies. Currently, the incretin-based therapies may have the most promise, as more evidence is accumulating regarding their clinical benefits. Furthermore, with oral administration of the DPP-4 inhibitors and longer acting GLP-1 agonists, patient compliance may increase. Going forward, more clinical trials with larger patient numbers and study durations will need to be done. With some of these already underway, practitioners can expect that the repertoire of medications used to treat patients with T1D will expand in the near future.
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Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.
Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.