INSULIN SENSITIZERS
There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.34
Metformin, a biguanide, is the oral drug of choice
Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.1
Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.35 It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.36 Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).35
Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.34 Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,21,23,25,38–40 while others have shown no effect.41 Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.42 Further, metformin users have a lower cancer mortality rate than nonusers.24,43
Thiazolidinediones
TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.44 They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.44
Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.44 The risk appears to rise with cumulative dose.45,46
Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).49
On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.47 In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.50–53
Home et al54 compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).
Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.54
Colmers et al47 pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:
- Colorectal cancer RR 0.93, 95% CI 0.87–1.00
- Lung cancer RR 0.91, 95% CI 0.84–0.98
- Breast cancer RR 0.89, 95% CI 0.81–0.98.
INCRETIN-BASED THERAPIES
Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.55
There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).55 Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.
When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.55 GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.
GLP-1 receptor agonists
Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.
Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.56
Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.
DPP-IV inhibitors
Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.
Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).
Concerns about thyroid cancer with incretin drugs
Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.
Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.26 This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.26
Gier et al27 assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.
Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.57
A meta-analysis by Alves et al58 of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.
MacConell et al59 pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.
Concerns about pancreatic cancer with incretin drugs
Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.
In a point-counterpoint debate, Butler et al28 argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck60 argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.
Bailey61 outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.
Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).62
The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.63