ADVERTISEMENT
Potential Complications With Common Diabetes Medications: What You Should Know
Medication can play a valuable role in helping patients with diabetes manage blood glucose levels although a number of medications carry risks of causing lower extremity complications such as peripheral neuropathy and delayed wound healing. With this in mind, these authors explore possible complications with common medications including metformin and sodium-glucose co-transporter-2 (SGLT-2) inhibitors.
Researchers estimate that almost 600 million people worldwide will be diagnosed with diabetes by 2035.1
Diabetes is associated with a multitude of complications. Those affecting the lower extremity are known to increase the risk for ulceration, infection, amputation and death.2 Patients with diabetes have an estimated 25 percent lifetime risk of developing a diabetic foot ulceration (DFU).3 Infected DFUs are the primary reason for diabetes-related hospitalizations and non-traumatic lower extremity amputation in the United States.4 Tight glycemic control is paramount to minimizing these risks.5
Physicians can employ pharmacotherapy when patients cannot achieve optimal glycemic control through diet and exercise. While the primary purpose of diabetes medications is to prevent hyperglycemia through a variety of mechanisms of action, studies have also demonstrated additional health benefits such as weight loss, cardiovascular and renal benefits, and the potential to reduce the risk for certain malignancies.6-17 On the flip side, some diabetes medications have been associated with an increased risk of lower extremity complications.6-17
A Closer Look At The Risks Of Metformin
Metformin is a renally excreted principal biguanide antihyperglycemic agent that reduces blood glucose levels via multiple mechanisms including decreasing liver gluconeogenesis and intestinal glucose absorption, and increasing peripheral insulin sensitivity.18 Of note, these effects generally reach the patient with relatively low rates of hypoglycemia and weight gain.
The UK Prospective Diabetes Study was paramount in determining that metformin use reduced the risk of myocardial infarction and all-cause mortality. Further studies confirmed the anti-atherosclerotic and cardioprotective effects of metformin, leading it to become a first-line agent in the management of type 2 diabetes.2,17 This anti-atherosclerotic effect of metformin may also occur within the peripheral vasculature of the lower extremity.
The DIACART cross-sectional cohort study analyzed 198 patients with type 2 diabetes and high cardiovascular risk.6 Researchers used computed tomography (CT) scans and color duplex ultrasound to score the amount of arterial calcification present in the vasculature below the knee.6 Univariate and multivariate analysis found that metformin use was associated with a twofold reduction in mean arterial calcification scores in the below-the-knee vasculature, independent of patient age, gender, tobacco use, renal function, history of cardiovascular disease, diabetes duration, peripheral neuropathy, retinopathy, HbA1c levels and inflammation. These findings suggest that the anti-atherosclerotic effect of metformin use extends beyond its cardioprotective benefit. Further studies are needed to validate these findings.
Metformin use has also been associated with a 10 to 31 percent decrease in overall cancer incidence through a variety of mechanisms that inhibit the proliferation of malignant cells.8 It is unknown if this inhibitory effect could impact cellular proliferation necessary for wound healing.
Ochoa-Gonzalez and colleagues studied the in vivo and in vitro effects of metformin on keratinocyte proliferation and wound healing.3 The study authors found that metformin did not have a toxic effect on keratinocytes in vivo. However, the S-phase of the cell cycle, when DNA replication occurs, was prolonged, resulting in inhibition of cellular proliferation for 24 to 48 hours. This inhibitory effect on keratinocyte proliferation resulted in prolonged healing in an animal model. Significant differences in wound size at three, seven and 10 days, and continued redness and scarring were present in metformin-treated animals, suggesting that both the proliferative and remodeling phases of wound healing were affected. Reduction in DFU wound size was also prolonged in humans treated with metformin. Despite prolonged healing times, the study found metformin has a significant protective effect against amputation. The reasoning for this is unknown but may be related to metformin’s anti-atherosclerotic effect.
Can Metformin Spur The Development Of Peripheral Neuropathy?
The biggest controversy with metformin use is whether it potentiates the development of peripheral neuropathy. Peripheral neuropathy is the most common complication of diabetes and a major contributing factor to the development of DFUs and Charcot neuroarthopathy.2 Since the late 1960s, controversy has existed regarding the association of metformin use with reduced vitamin B12 levels, a known etiology of peripheral neuropathy.2,7 Metformin in theory reduces vitamin B12 levels through interference with the calcium-dependent membrane action necessary for its resorption in the terminal ileum.7
The Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS) was the largest and longest study to date on metformin treatment of those at high risk for type 2 diabetes.7 Researchers noted a 13 percent increased risk of vitamin B12 deficiency for each year of metformin use, independent of patient age, gender, baseline body mass index, diabetes status and weight change. However, the sample size of those with vitamin B12 deficiency and peripheral neuropathy was too small to determine if an association existed. The authors recommended future studies on the effects of long-term metformin use on vitamin B12 deficiency and routine monitoring of vitamin B12 levels in patients treated with metformin.
Currently, the American Diabetes Association (ADA) guidelines recommend periodic vitamin B12 measurements in metformin-treated patients, particularly if they have peripheral neuropathy.2,19 Future properly powered studies on long-term metformin use that assess for the presence of peripheral neuropathy using objective and conventional measures are required to determine the association between metformin use, vitamin B12 deficiency, and peripheral neuropathy.
Can SLGT-2 Inhibitors Increase The Risk Of Amputation?
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a novel class of drugs for glycemic management that have significant cardiovascular and renal protective benefits. The four drugs in this class are canagliflozin (Invokana, Janssen Pharmaceuticals), dapagliflozin (Farxiga, AstraZeneca), empagliflozin (Jardiance, Boehringer Ingelheim) and ertugliflozin (Steglatro, Merck). Each of these works by blocking glucose and sodium resorption within the proximal tubule of the kidneys.9,11,13,14 The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, which combined data from two trials involving over 10,000 patients with type 2 diabetes and high cardiovascular risk, was paramount in discerning the cardiovascular and renal protective benefits of canagliflozin use.9 In assessing safety in this study, the authors found that canagliflozin use was associated with an approximately twofold increase in the incidence of lower extremity amputation, leading the Food and Drug Administration (FDA) to require canagliflozin to have a black box warning of an increased risk of leg and foot amputation with its use.11
The reason for the increase in lower extremity amputations and whether this increased risk occurs with all SGLT-2 inhibitors or is specific to canagliflozin alone is unknown.10 Authors have postulated that the diuretic effect of SLGT-2 inhibitors may compromise arterial circulation in the distal vascular beds but this has yet to be proven.10,12 The results of several recently published post-market “real-life” studies report conflicting results on whether amputation rates are truly increased.12-14,16 One study found that all three SGLT-2 inhibitors had an associated increased risk of lower extremity amputation with dapagliflozin use being associated only with digital amputations although the number of amputations that occurred was small.12 Three other studies found no significant difference in lower extremity amputation rates between SLGT-2 inhibitor and conventional antihyperglycemic use.13,14,16 A closer look at these studies may provide some insight into these conflicting results.
The CANVAS program focused on patients with type 2 diabetes and high cardiovascular risk.9 Those who had high cardiovascular risk were men and women 30 years old or older who had a history of symptomatic atherosclerotic cardiovascular disease. Others at high risk were men or women 50 years old or older who had two or more of the following risk factors for cardiovascular disease: diabetes duration of 10 or more years; systolic blood pressure over 140 mmHg despite treatment with one or more antihypertensive agents; current smoking; microalbuminuria or macroalbuminuria; or high-density lipoprotein cholesterol level of greater than 1 mmol/L. Thus, these patients already had microvascular and macrovascular disease, and known risk factors for amputation.10,20 Couple this with the fact that the highest absolute risk for lower extremity amputation occurred in patients with a history of peripheral arterial disease (PAD) and prior amputation, both independent risk factors for lower extremity amputation.10,20
The relative risk for lower extremity amputation was similar between those who were and those who were not treated with canagliflozin. Analysis of various studies found that patients who did or did not take the medication are similar despite a difference in the reported amputation rates.10 However, the total number of amputations reported in these studies was small, making it difficult to definitively state that an association with the use of SLGT-2 inhibitors increases the risk for lower extremity amputation.12
In addition, below-the-knee amputation in the study was often a “catchall” term for any level of amputation that occurred below the knee, including partial foot amputations. The majority of amputations that occurred in all studies were isolated to the forefoot.9,12,13,16 One study excluded patients with a prior history of amputation to limit this potential confounding variable.13 Results of this analysis found no significant difference in amputation rates for patients who were and were not treated with an SLGT-2 inhibitor. However, the sample size was small.
Another factor to consider is that many patients in these studies had failed to obtain glycemic control with other antihyperglycemic agents, leading one to wonder if the benefit of glycemic control in the difficult to control patient and the cardiovascular and renal protective benefits outweigh the potential risk of amputation, which may be minor.
Current Insights On The Link Between SLGT-2 Inhibitors And Fractures
The FDA has also issued a warning about the potential for decreased bone mineral density and fracture risk with canagliflozin use. One study reported a 30 percent increase in fractures in those who used canagliflozin for over one year with fracture occurring as early as 12 weeks after the initiation of treatment.21 Researchers have postulated that the diuretic effect of SLGT-2 inhibitors potentiates calcium loss and phosphate retention. This imbalance can result in a loss of bone mineral density due to the loss of calcium essential for bone formation and increased parathyroid hormone secretion, which enhances bone resorption due to elevated phosphate levels.22 This reduction in bone mineral density can potentiate the risk for fractures to occur, particularly in the distal lower and upper extremities.22,23 Once again, it is not known whether this increased risk occurs with all SGLT-2 inhibitors or if it is specific to canagliflozin alone as the CANVAS program was the only study to show a positive correlation between fracture incidence and canagliflozin use.21
Two recent meta-analyses of all SLGT-2 inhibitors found significant association between the use of SLGT-2 inhibitors and increased fracture risk.22,23 Once again, though, study findings were not consistent and limited by the small number of fractures reported, the short study duration and follow-up durations as well as confounded by patients who were at risk for falls, sustained trauma, and already had other known risk factors for fracture such as old age and diabetes.21-23 Further research on SLGT-2 inhibitor use and whether they increase the potential risk for fracture is required to determine if an association exists.21-23
What Studies Say About SGLT-2 Inhibitors And Fournier’s Gangrene
On August 28, 2018, the FDA also issued a warning about the potential for Fournier’s gangrene to occur with SGLT-2 inhibitor use.24 Fournier’s gangrene, aka necrotizing fasciitis of the perineum, is a rare type of severe infection affecting approximately two out of 100,000 men annually in the United States. This condition occurs most often in men age 50 to 79 years old with diabetes being the most common risk factor for its occurrence.24,25
From March 2013 to May 2018, one study reported 12 cases of Fournier’s gangrene occurring in both men (seven) and women (five) patients on an SGLT-2 inhibitor.24 In all cases, SGLT-2 inhibitor use had begun several months prior to the infection occurring. Genital and urinary tract infections are known potential side effects of SLGT-2 inhibitor use. Researchers postulate the increased excretion of glucose in the urine is the cause of these potential side effects and may also contribute to the development of Fournier’s gangrene.9,25 The number of cases reported and the fact that almost half occurred in women while only six cases, all occurring in men, have been reported in over three decades of use of other antihyperglycemic agents, prompted the FDA to issue this warning.24 Once again, whether this potential risk factor is drug- or class-specific is unknown.
In Conclusion
Effective management of diabetes involves achieving optimal glycemic control while minimizing complications to reduce the potential morbidity and mortality associated with condition.5 As with any treatment, one should perform an individual risk/benefit assessment before initiating treatment and ongoing patient education and follow-up are vital. While early diagnosis, diet and exercise are important concepts of the overall treatment program, individualized pharmacotherapy is often required to reach treatment goals.
Metformin is an evidence-based first-line agent in the management of type 2 diabetes. SLGT-2 inhibitors have known cardiovascular and renal protective benefits.2,8,12-17 As the potential for inhibited wound healing, the development of peripheral neuropathy and the true risk of fracture, amputation and Fournier’s gangrene are currently unknown, and the fact that patients taking these medications already have other known risk factors for these complications, it is prudent that one perform an individualized risk/benefit assessment. Patients should receive education about the risks and benefits of these medications, and be made aware of the signs and symptoms of complications associated with their use.10,11,16 Discontinuation of medication use and the initiation of alternative anti-hyperglycemic medication may be warranted in patients who experience complications while taking these medications.
As members of an effective multidisciplinary team, foot and ankle specialists should be familiar with diabetes medications and maintain good communication with their patients’ primary care providers.
Dr. Marmolejo is a Clinical Wound Specialist with LifeNet Health in Renton, Wash.
Dr. Arnold is the Medical Director of Great River Wound and Hyperbaric Medicine Clinic at Great River Medical Center in West Burlington, Iowa.
References
1. Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon). 2014;42(12):698-702.
2. Ahmed MA, Muntingh GL, Rheeder P. Perspectives on peripheral neuropathy as a consequence of metformin-induced vitamin B12 deficiency in T2DM. Int J Endocrinol. 2017;2017:2452853.
3. Ochoa-Gonzalez F, Cervantes-Villagrana AR, Fernandez-Ruiz JC, Nava-Ramirez HS, Hernandez-Correa AC, Enciso-Moreno JA, Castañeda-Delgado JE. Metformin induces cell cycle arrest, reduced proliferation, wound healing impairment in vivo and is associated to clinical outcomes in diabetic foot ulcer patients. PLoS One. 2016;11(3):e0150900.
4. Hicks CW, Selvarajah S, Mathioudakis N, Sherman RE, Hines KF, Black JH 3rd, Abularrage CJ. Burden of infected diabetic foot ulcers on hospital admissions and costs. Ann Vasc Surg. 2016;33:149-58.
5. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):703-13.
6. Mary A, Hartemann A, Liabeuf S, Aubert CE, Kemel S, Salem JE, Cluzel P, Lenglet A, Massy ZA, Lalau JD, Mentaverri R, Bourron O, Kamel S. Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients. Cardiovasc Diabetol. 2017;16(1):24.
7. Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG, White NH, Crandall JP; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin b12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2016;101(4):1754-61.
8. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, SzaboE. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila). 2014;7(9):867-85.
9. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
10. Tanaka A, Node K. Increased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit? Cardiovasc Diabetol. 2017;16(1):129.
11. Aschenbrenner DS. Diabetes drug receives boxed warning for increased risk of leg and foot amputations. Am J Nurs. 2017;117(9):22-23.
12. Khouri C, Cracowski JL, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect? Diabetes Obes Metab. 2018;20(6):1531-1534.
13. Udell JA, Yuan Z, Rush T, Sicignano NM, Galitz M, Rosenthal N. Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor: results from the EASEL population-based cohort study (evidence for cardiovascular outcomes with sodium glucose cotransporter 2 inhibitors in the real world). Circulation. 2018;137(14):1450-1459.
14. Yuan Z, DeFalco FJ, Ryan PB, Schuemie MJ, Stang PE, Berlin JA, Desai M, Rosenthal N. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab. 2018;20(3):582-589.
15. Rosenthal N. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab. 2018;20(3):582-589.
16. Ryan PB, Buse JB, Schuemie MJ, DeFalco F, Yuan Z, Stang PE, Berlin JA, Rosenthal N. Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab. 2018;20(11):2585-2597.
17. Li D, Yang JY, Wang T, Shen S, Tang H. Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Metab. 2018;44(5):410-414.
18. Meštrovic, T. Metformin History. Retrieved from https://www.news-medical.net/health/Metformin-History.aspx
19. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017; 40(Suppl 1):S64–S74.
20. Sayiner ZA, Can FI, Akarsu E. Patients’ clinical characteristics and predictors for diabetic foot amputation. Prim Care Diabetes. 2018; pii: S1751-9918(18)30213-4.
21. Kalaitzoglou E, Fowlkes JL, Popescu I, Thrailkill KM. Diabetes pharmacotherapy and effects on the musculoskeletal system. Diabetes Metab Res Rev. 2018 Nov 22:e3100.
22. Tang HL, Li DD, Zhang JJ, Hsu YH, Wang TS, Zhai SD, Song YQ. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199-1206.
23. Azharuddin M, Adil M, Ghosh P, Sharma M. Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: A systematic literature review and Bayesian network meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2018;146:180-190.
24. US FDA. (2018, August 28) FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Available at https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm .
25. Kumar S, Costello AJ, Colman PG. Fournier’s gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Diabet Med. 2017;34(11):1646-1648.
