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Lung cancer is the most common form of cancer worldwide and is, by far, the leading cause of cancer deaths. Non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases in the U.S. and, when first diagnosed at a metastatic stage, has a horrific survival of less than a year for 26% of patients. Identifying treatments that can increase survival for this menacing disease is thus of the utmost importance, and one potential avenue toward this goal has been identified from among existing treatments for another deadly disease, type 2 diabetes (T2D). In particular, the class of anti-diabetic drugs known as sodium-glucose cotransporter 2 (SGLT2) inhibitors may show promise for its ability to reduce mortality rates for NSCLC, as indicated by a recent observational study by Luo et al.
Links Between Diabetes, SGLT2, and Cancer
Glucose metabolism is known to affect the development of cancer, and the preexisting dysfunction of glucose metabolism is one of the proposed mechanisms for the increased incidence of certain types of cancer – including pancreatic, liver, colon, breast, and endometrial cancers – among patients with T2D. Evidence of increased incidence of lung cancer among patients with T2D is more controversial, but recent studies and meta-analyses have been fairly consistent in showing that preexisting T2D negatively impacts NSCLC prognosis. In patients with either stage IIIB or stage IV NSCLC, patients with coexisting diabetes had an average survival 5 months shorter than non-diabetic patients (15 months vs. 20 months, a 25% reduction in total survival time).
Various classes of anti-diabetic drugs have been tested on cancers to improve patient care and mortality rates. These drugs all achieve the common goal of reducing elevations in systemic glucose levels, but their distinct mechanisms of action can result in unique effects on glucose metabolism at the level of specific tissues and cancer types. Data to date from in vitro, animal, and early clinical studies have suggested that SGLT2 inhibitors in particular may show unique promise for slowing the progression of NSCLC.
The cotransporter protein SGLT2 is responsible for 80-90% of glucose reabsorption in the kidney, so inhibition of SGLT2 promotes renal excretion of glucose, a means of controlling blood glucose independently of insulin levels. This systemic effect of lowering glucose, and increasing insulin sensitivity, likely underlies part of the apparent anti-tumor effects of SGLT2 inhibitors, as other glucose-lowering drugs also appear to have some benefits. (For instance, administration of metformin was associated with increased median survival by 2 months in metastatic lung cancer patients.) Since cancer cells are known for their high glucose consumption rates, restricting local glucose metabolism through the effects of anti-diabetic drug classes may at least partially explain the increase in efficacy of certain drug classes more than others in combating certain tumors, though it remains unclear if glucose levels would ever fall low enough to actually become rate-limiting in this process. A more plausible explanation, I believe, is that the anti-cancer effects of these drugs are from their effect on reducing insulin and restricting cancer growth by inhibiting the PI3K pathway. (An interesting in vitro or animal experiment would be to compare the use of exogenous insulin with these anti-diabetic drugs to differentiate the effects of lowering blood glucose from the effects of reducing insulin.)
Regardless of the mechanism, SGLT2 inhibitors may have an extra advantage over other anti-diabetic drug classes for preventing the progression of lung cancer. SGLT2 is expressed in lung tumor development, and lung tumor cells use this transporter as their primary means of importing glucose. These findings suggest that SGLT2 inhibitors may therefore have life-extending effects beyond their impact on systemic glucose regulation in the particular case of NSCLC cancer, as blocking SGLT2 may essentially starve the developing cancer cells. However, large-scale evidence that SGLT2 inhibitors offer additional protection has been absent, leading Luo and colleagues to conduct their investigation.
Lung cancer survival with SGLT2 inhibitors
In their observational study, Luo and colleagues used the linked SEER-Medicare database to investigate the effects of SGLT2 inhibitors on NSCLC survival. The analysis included 24,915 patients aged ≥66 years who were diagnosed with NSCLC between 2014 and 2017 and had a preexisting diagnosis of T2D. Over a mean follow-up period of 21.2 months, the authors found that NSCLC patients using SGLT2 inhibitors had a significant 32% relative reduction in all-cause mortality compared to non-users (i.e., patients with uncontrolled diabetes and those taking metformin and other anti-diabetic medications), even after adjusting for confounding factors such as age, gender, race, comorbidities, tumor stage, and cancer treatment (HR: 0.68; 95% CI: 0.60-0.77). Among patients who had used an SGLT2 inhibitor for ≥12 months, the effect was even stronger, with a 46% relative reduction in all-cause mortality compared to non-users (HR: 0.54; 95% CI: 0.44-0.68).
Normally, reporting relative risk reductions overinflates the significance of effects, but in this case, because NSCLC survival is so low, there is much less discrepancy between the absolute and relative risk reductions. NSCLC patients using SGLT2 inhibitors had a crude mortality rate of 49%, a stark 25.5% lower than the crude mortality rate of 74.5% in all other included patients. Similar to previous research, in the subpopulation that used metformin alone, there was a slight increase in survival (70% crude mortality rate), but metformin combined with an SGLT2 inhibitor had the lowest crude mortality rate – 47%. Even with a heterogeneous reference group of non-SGLT2 inhibitor users, the directionality and magnitude of the effects are strong enough to warrant further investigation. These results are especially surprising when we consider that metformin is a first-line therapy for T2D and other drug classes are typically added as the disease becomes more advanced. So we would expect that SGLT2 inhibitor users had more severe diabetes and theoretically should have shorter overall survival.
This study observed that patients using SGLT2 inhibitors were less likely to have metastatic lung cancer. Both lymph nodes and metastatic lesions can have high expression of SGLT2. One possible explanation for the increased survival of these patients is that SGLT2 inhibitors limit disease progression by impeding the survival of metastatic cancer cells, which would support the 31% relative reduction in lung cancer mortality in the population taking SGLT2 inhibitors compared to all other diabetic lung cancer patients.
Limitations of extrapolating the data
Although the improved survival may seem drastic, the relatively short follow-up wasn’t long enough to determine the average duration of the survival benefits associated with SGLT2 inhibitors or the overall survival. The five-year overall survival for NSCLC in T2D patients is about 20%, and it’s unclear if the 52% survival rate at 21 months with SGLT2 inhibitor use translates to a higher 5-year survival rate. Still, to those with such a rapidly deadly disease, prolonging life for even just a few months is substantial.
However, in addition to longer follow-up, these findings need to be replicated in a larger population to better assess whether the association between SGLT2 inhibitor use and increased survival is real. In the study by Luo et al., the number of total SGLT2 inhibitor users as a whole class was a very small percentage of the entire population (only 531 people, or 2.1% of the population). This is likely due to the relatively recent development and approval of SGLT2 inhibitor drugs, with canagliflozin, the first FDA-approved SGLT2 inhibitor, cleared for use only nine months before the study period and other SGLT2 inhibitors approved in later years. Any lag in the adoption of SGLT inhibitors as an anti-diabetic treatment would thus limit qualifying patients for this study. Additionally, the type of SGLT2 inhibitor used was non-uniform even among this small sub-population.
But there are other, perhaps more important, considerations that impact the replicability of the findings. The population prescribed SGLT2 inhibitors had different clinical characteristics from other groups – they were on average 3.5 years younger, more likely to have chronic kidney disease, and less likely to have cardiovascular disease. In such a small population, differences in clinical characteristics, especially age, may have a more considerable impact than the anti-diabetic drug prescribed, which may explain why this population was seen to live longer despite likely having more advanced diabetes. Furthermore, the differences listed here only represent those that we know based on information available from the source database. Other relevant information such as measures of glycemic control, BMI, or other health-related behaviors such as smoking and physical activity were not available but may have impacted study results.
Additionally, although the analysis includes the number of patients prescribed metformin, an SGLT2 inhibitor, or both, 16,688 included patients were classified as “neither,” with a complete lack of information if those patients were on another type of anti-diabetic medication (e.g., DPP-4 inhibitors, GLP-1 agonists, sulfonylureas) or if their diabetes was uncontrolled. Glycemic control (even if not the mechanism of control) via hemoglobin A1c measurements is an important missing piece of information, since other studies have shown that NSCLC patients with poor glycemic control (hemoglobin A1c level ≥8.0%) have poorer survival rates than those with lower HbA1c.
Indirect effects on cancer patient health
In addition to glycemic control and any effects on metastatic cancer, there are indications that SGLT2 inhibitors are cardioprotective in patients with T2D. As the name suggests, SGLT2 inhibitors facilitate the reabsorption of both glucose and sodium, and the inhibition of SGLT2 has a diuretic effect from the reduction of circulating levels of both of these molecules. This in turn reduces high blood pressure – another common comorbidity of T2D.
Diuretic effects are one explanation for observed improvements in heart failure outcomes, since other diuretic therapies are used to manage the symptoms of congestion, such as edema. SGLT2 inhibitors, versus other glucose-lowering drugs, have been associated with a 39% reduction in hospitalization for heart failure and a 51% reduction in all-cause mortality. As a class of drugs, SGLT2 inhibitors have also demonstrated renal protective attributes, including the reduction of albuminuria, and slowing glomerular filtration loss and progression to end-stage kidney disease. These more widespread effects and the ITP experimental success in extending the lifespan of male mice with the SGLT2 inhibitor canagliflozin have increased interest in investigating if SGLT2 inhibitors have other protective effects against chronic disease. Further studies are needed to elucidate if SGLT2 inhibitors extend lifespan due to their direct effects on cancer itself or by the indirect effects of improving cardiovascular and renal health in cancer patients.
The bottom line
A diagnosis of T2D increases the risk of both getting and dying from cancer, which likely relates at least in part to cancer cells’ demand for glucose and the activation of PI3K by the accompanying levels of elevated insulin. But targeting systemic glucose reduction may not be the only way – or even the most effective way – to deprive malignant cells of the nutrients they require. With an increasing number of pharmacological options for glycemic control, a detailed understanding of their respective effects on different types of tissues and cancers could open the door for more tailored treatments to optimize both glycemic control and combating specific forms of cancer in patients comorbid for both diseases. For instance, if a diabetic patient well-maintained on metformin and a sulfonylurea develops NSCLC, modifying the anti-diabetic therapeutic strategy to metformin and an SGLT2 inhibitor might provide the same benefit to glycemic control while offering the added advantage of more targeted treatment of the cancer.
Of course, the data presented by Luo et al. only represent an association between SGLT2 inhibitor use and increased NSCLC survival. Truly determining whether SGLT2 inhibition has a causal role in protecting against lung cancer progression is extremely challenging without randomized trials, but because SGLT2 inhibitors appear to offer the greatest life-extension benefits when used for over one year prior to a lung cancer diagnosis, there are no easy ways to conduct randomized trials to capture this possible effect. Starting with lung cancer patients and randomizing to an SGLT2 inhibitor or placebo would miss the one-year lead-up window, while starting with healthy or diabetic patients and randomizing to an SGLT2 inhibitor or placebo would likely require a prohibitively long study duration to achieve lung cancer incidence rates that would be amenable to statistics. (Even among diabetics who go on to develop lung cancer, the average time between diabetes diagnosis and lung cancer diagnosis is nearly eight years.)
However, further prospective trials and animal studies can be conducted to confirm the promising initial results of Luo et al. on SGLT2 inhibitor use and lung cancer survival. This offers some hope for an otherwise terrible prognosis and may continue to change the landscape of T2D management as well.
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