Topic 10.1. Screening and management of diabetes mellitus in Friedreich ataxia
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
Topic Contents
10.1 Screening and management of diabetes mellitus in Friedreich ataxia
10.1.1 Friedreich ataxia and diabetes mellitus
10.1.2 Screening for diabetes mellitus
10.1.3 Management of diabetes mellitus
Disclaimer / Intended Use / Funding
Disclaimer
The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.
These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.
The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.
Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.
These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.
Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.
10.1 Screening and management of diabetes mellitus in Friedreich ataxia
Jaclyn Tamaroff, Andreas Eigentler, David R. Weber, Shana E. McCormack and Miriam Cnop
10.1.1 Friedreich ataxia and diabetes mellitus
It has been known for nearly a century that individuals with Friedreich ataxia (FRDA) are at risk of developing diabetes (DM) (1, 2). Reported prevalence varies between 5% and 40% (3-6). The variability in estimates can, in part, be explained by the cohort evaluated, as well as the tests and thresholds that were used to diagnose DM. Clinically, FRDA-related DM may be under-recognized using current screening practices. In addition, many individuals with FRDA may not meet diagnostic criteria for DM on initial screening, but do have evidence of abnormal glucose metabolism when evaluated with more sensitive tests. For example, in one study of 41 individuals with FRDA without known DM who underwent oral glucose tolerance testing (OGTT), 12% had DM, and 49% of participants had impaired fasting glucose and/or impaired glucose tolerance (7). Finally, DM has been reported to be a presenting feature of FRDA, though rarely (8).
Consensus diagnostic criteria for any form of DM include hemoglobin A1c (HbA1c) ≥ 6.5% (≥ 48mmol/mol), fasting plasma glucose ≥ 126mg/dL (7.0 mmol/L), two-hour glucose after an OGTT ≥ 200mg/dL (11.1 mmol/l), or a random glucose ≥ 200mg/dL (11.1 mmol/l) in a patient with symptoms of hyperglycemia (9); these criteria are also appropriate for diagnosis of FRDA-related DM.
With respect to risk factors for FRDA-related DM, some studies have found an association between longer GAA trinucleotide expansion size in the FXN gene and the odds of developing FRDA-related DM, while others have not (5, 7, 10-12). A recent large study found that individuals with FRDA-related DM were older, had longer GAA repeat lengths, and more severe FRDA (5). Having a point mutation in one allele of the FXN gene has been associated with increased risk of FRDA-related DM (3). There is evidence that GAA repeat length is most strongly associated with FRDA-related DM in those with FRDA symptom onset at age 8 to 14 years. Additionally, new data supports a relationship between the risk of FRDA-related DM and cardiac disease in FRDA (unpublished data). Though DM is related to heart failure in the general population (13), it is unknown if there is a relationship between the cardiomyopathy and DM in FRDA that is independent of overall disease severity.
In FRDA, both insulin deficiency and insulin resistance have been implicated in the development of DM. The relative contribution of each of these processes may differ across the lifespan. Typically in children, FRDA-related DM may present acutely with diabetic ketoacidosis, the hallmark of clinically relevant insulin deficiency (14), and in some cases it can be fatal (15). This insulin-dependent ketosis-prone DM may be caused by non-autoimmune loss of the insulin-producing pancreatic beta cells (16). A few reports have described a decreased number of islets and beta cells in the pancreas in individuals with FRDA (7). Other studies found no difference in glucose-stimulated insulin secretion in individuals with FRDA (17, 18), though diminished arginine-stimulated insulin release has been reported (18). The normal oscillatory insulin secretion pattern has been shown to be preserved in FRDA (19).
In addition to insulin deficiency, studies have pointed to defects in insulin action. Insulin resistance has been demonstrated at the whole body and the cellular level (in blood cells, muscle cells and liver cells) (7, 20-22). Insulin resistance may be present even in individuals with FRDA who are not obese as classified by body mass index, due to increased abdominal adiposity (7). Adults may have a more insidious onset of DM, consistent with slowly evolving insulin resistance and insulin deficiency, and may have initial abnormal glucose tolerance preceding overt DM (7). Most of the studies addressing the pathogenesis of DM in FRDA were conducted before the genetic cause of the disease was elucidated (23) and before important concepts in glucose homeostasis were established (24, 25). One of these crucial concepts is that insulin secretion is tightly regulated by insulin sensitivity (25, 26). Under physiological conditions, pancreatic beta cells increase insulin release as needed to maintain normal glucose tolerance. Thus, to interpret the insulin secretory response of the pancreatic beta cells correctly, it needs to be adjusted for insulin resistance (24, 27, 28). This approach has identified pancreatic beta cell dysfunction as central to the development of diabetes in FRDA (7).
10.1.2 Screening for diabetes mellitus
Screening tests for DM in general include measurements of fasting plasma glucose, random plasma glucose (in the setting of suggestive symptoms), HbA1c, and oral glucose tolerance testing (OGTT). Compared with fasting glucose and HbA1c, the two-hour glucose level from an OGTT will result in more diagnoses of DM in the general population as well as FRDA-related DM, and also more diagnoses of pre-DM (29), a condition characterized by abnormal glucose metabolism that may herald future development of DM (9). In FRDA, impaired glucose tolerance from an OGTT has been detected in individuals with normal fasting glucose (7). While in some other diseases with a higher risk of DM, such as cystic fibrosis, there is a recommendation for annual OGTTs (30), there is currently not enough evidence to recommend this screening strategy in FRDA.
10.1.3 Management of diabetes mellitus
Treatment of autoimmune type 1 DM in individuals without FRDA relies on insulin (type 1 DM is due to near complete insulin deficiency) and for metabolic type 2 DM (caused by relative insulin deficiency in the setting of insulin resistance), insulin, metformin, and other glucose-lowering agents are used. FRDA-related DM has features of insulin deficiency, and in some individuals, particularly adults, also insulin resistance. Therefore, for children with FRDA-related DM and for adults with evidence of decreased insulin secretion (as evidenced by low-c-peptide, presence of ketones, or acute hyperglycemia), we recommend insulin as the primary treatment. For adults with FRDA-related DM with evidence of insulin resistance we suggest individualized application of management guidelines for type 2 DM, with particular consideration of the risks and benefits related to comorbidities of FRDA (31, 32). Newer anti-diabetic agents have not been tested in FRDA and there is significant heterogeneity in FRDA-related DM; therefore, a personalized approach is warranted.
Insulin
Most individuals with FRDA-related DM are currently managed with insulin. Insulin has glucose-lowering effects in individuals with all forms of DM, and is necessary in those with minimal insulin secretion. However, side effects such as hypoglycemia may occur; hence there is interest in considering the potential utility of other agents. Additionally, for individuals with excess weight where weight loss is recommended, insulin may make weight loss more difficult. In individuals with FRDA-related DM who may have decreased dexterity, we recommend using available technologies to aid with insulin administration (e.g., pens and pumps) and blood glucose monitoring (e.g., continuous glucose monitors) (33).
Non-insulin treatments
Possible risks and benefits of non-insulin glucose-lowering agents for individuals with FRDA are described below. It is important to remember that there is currently no evidence for or against their use specifically in FRDA, nor have there been FRDA-specific safety studies for non-insulin therapies. Full review of associated risks should be undertaken prior to use of these medications. Evidence for the described therapies comes from the treatment of other forms of DM and theoretical benefits of associated mechanisms of action.
Metformin is being used in individuals with FRDA-related DM (5, 34). Metformin decreases hepatic glucose output and thereby ameliorates fasting glycemia. Lactic acidosis (35) and inhibition of complex I of the mitochondrial electron transport chain (36) are theoretical risks of metformin in all forms of mitochondrial diabetes, including FRDA-related DM. That said, there is no evidence of concern for metformin-related lactic acidosis in individuals with Maternally Inherited Diabetes and Deafness (MIDD) (37), one sub-type of mitochondrial diabetes with available data, and unlike some other disorders affecting mitochondria, FRDA does not carry a known increased risk of lactic acidosis. Therefore, metformin may be a reasonable choice of medication, though healthcare providers should discuss withholding medication during times of illness and use the lowest effective dose.
Sulfonylureas, which act on the pancreatic beta cell to cause insulin release, carry a risk of hypoglycemia but may be considered in those for whom medication costs is a substantial concern, because they are relatively inexpensive (32).
Thiazolidinediones have also been shown to inhibit complex I of the mitochondrial electron transport chain (38). Thiazolidinediones are PPAR-g agonists. Caution should be used in the context of heart failure or cardiomyopathy (39), which may pose a particular problem in FRDA. For these reasons, thiazolidinediones should not be a primary treatment for many individuals with FRDA-related DM.
Glucagon-like peptide-1 (GLP-1) agonists, which are incretin analogues, have been shown to improve glucose homeostasis in frataxin-deficient mice (40). Additionally, there are possible cardiac benefits of GLP-1 agonists, though this has not been specifically assessed in FRDA (41). A related class of medication, dipeptidyl-peptidase IV inhibitors (DPP4i) act by increasing incretins such as GLP-1. Importantly, data are mixed with respect to the effects of DPP4i in heart failure (42).
Sodium-glucose cotransport 2 (SGLT-2) inhibitors have been shown to benefit individuals with heart failure unrelated to FRDA, even in those without DM (43). It is unknown if these medications will provide a benefit to in individuals with FRDA. Because individuals with FRDA are at risk for diabetic ketoacidosis related to insulin deficiency (14), and SGLT-2 inhibitors pose a risk of ketosis (44), ketone monitoring, with serum b-hydroxybutyrate is recommended (45). Despite limited data, case reports in other types of mitochondrial DM have recommended consideration of GLP-1 agonists or SLGT-2 inhibitors due to favorable cardiac and renal profiles (46).
Screening
QUESTION: Should annual fasting glucose & HbA1c (with follow-up oral glucose tolerance testing (OGTT) for impaired fasting glucose, 100-125 mg/dL, and/or pre-diabetes by HbA1c, 5.7-6.4%) versus universal OGTT (annual vs q2-3y vs q5y) and annual fasting glucose & HbA1c be used for children (under 18y) OR adults (18y+) with Friedreich ataxia?
LEVEL OF EVIDENCE: ⨁⨁◯◯
RECOMMENDATION: We recommend at least annual screening for diabetes mellitus with HbA1c and fasting plasma glucose in children and adults with Friedreich ataxia, with consideration of an oral glucose tolerance test if impaired fasting glucose or pre-diabetes (from HbA1c) is identified, over universal screening with an oral glucose tolerance test. The decision to pursue intermittent oral glucose tolerance tests should be discussed with patients and families on an individualized basis.
JUSTIFICATION: Since individuals with Friedreich ataxia are clearly at risk for diabetes mellitus (DM) and pre-DM, annual screening with HbA1c and fasting plasma glucose is critical. Once individuals have symptoms related to hyperglycemia, they are at increased risk for acute complications and annual screening may help diagnose individuals prior to symptom onset.
SUBGROUP CONSIDERATION: This recommendation is for adults and children with Friedreich ataxia. In those with symptoms suggestive of diabetes, such as polyuria, polydipsia, or weight loss, we recommend obtaining HbA1c and random plasma glucose level to screen for diabetes. Individuals with these symptoms who are under 18 years old and/or ill-appearing should also be screened acutely for ketosis.
Evidence to Recommendation Table PDFTreatment for adults with lower-risk diabetes (HbA1c < 8.5%, no ketones, no acute hyperglycemia)
QUESTION: Should insulin alone versus metformin or novel glucose-lowering therapy (e.g., SGLT2i, GLP1RA, DPPIVi) be used for initial therapy for adults (18y+) with “lower-risk” diabetes mellitus (HbA1c <8.5%, no ketones, no acute hyperglycemia) with Friedreich ataxia?
LEVEL OF EVIDENCE: ⨁◯◯◯
RECOMMENDATION: There is insufficient evidence to favor either insulin alone or metformin or novel glucose-lowering therapies (e.g., SGLT2i, GLP1RA, DPPIVi) as initial therapy for adults with lower-risk diabetes mellitus (HbA1c < 8.5%, no ketones, no acute hyperglycemia) with Friedreich ataxia.
We suggest an individualized approach with either insulin alone, and/or a glucose-lowering agent, with the choice of medication patient dependent, particularly because of the heterogeneity in Friedreich ataxia-related diabetes mellitus.
JUSTIFICATION: While there is little data in Friedreich ataxia-related diabetes mellitus, we suggest following adult guidelines for type 2 diabetes mellitus, which indicate that first line therapy should depend on comorbidities and patient-centered treatment factors (9, 31, 32, 47, 48). Additionally, metformin is used in some individuals with Friedreich ataxia (5). There are concerns related to metformin (inhibition of complex I and risk of lactic acidosis) but one study did not find increased metformin-related cell death in Friedreich ataxia cells (36, 49). There are possible benefits, particularly cardiac benefits, from GLP-1 agonists but these have not been specifically tested in Friedreich ataxia (40, 41).
In the general population, there are benefits related to heart failure from SGLT-2 inhibitors (43), but this has not been tested in Friedreich ataxia. If one were to utilize a SGLT-2 inhibitor, ketone monitoring and close-follow up with endocrinology based on risk of euglycemic diabetic ketoacidosis (DKA) is necessary (44).
Despite limited data, in other mitochondrial disorders consideration of GLP-1 agonists or SGLT-2 inhibitors has been recommended by some clinicians, due to favorable cardiac and renal profiles (46).
SUBGROUP CONSIDERATION: This recommendation is for adults with Friedreich ataxia with lower-risk diabetes mellitus (HbA1c <8.5%, no ketones, no acute hyperglycemia).
Evidence to Recommendation Table PDFTreatment for adults with higher-risk diabetes (HbA1c >= 8.5%, ketones, or acute hyperglycemia)
QUESTION: Should insulin alone versus metformin +/- novel glucose-lowering therapy (e.g., SGLT2i, GLP1RA, DPPIVi) + insulin be used for adults (18y+) with “higher-risk” diabetes mellitus (HbA1c ≥ 8.5%, ketones, or acute hyperglycemia), once stabilized, with Friedreich ataxia?
LEVEL OF EVIDENCE: ⨁◯◯◯
RECOMMENDATION: There is insufficient evidence to favor either insulin alone or insulin in combination with metformin or novel glucose-lowering therapy (e.g., SGLT2i, GLP1RA, DPPIVi), in adults with Friedreich ataxia and higher-risk diabetes mellitus (HbA1c ≥ 8.5%, ketones, or acute hyperglycemia).
Insulin is an appropriate treatment but possible risks and benefits of adding other medications are unknown in Friedreich ataxia and treatments must be individualized.
JUSTIFICATION: Insulin is an appropriate management strategy and widely used in individuals with significant hyperglycemia and/or ketosis. Possible risks and benefits of other medications are unknown in Friedreich ataxia and therefore treatment must be individualized.
Metformin is used widely, and is used in some cases of Friedreich ataxia-related diabetes. There is a potential risk of lactic acidosis and inhibition of complex I mitochondrial respiratory chain (5, 36). If using metformin, one should consider using the lowest necessary dose, ensuring it is withheld during times of illness to avoid additional risk of lactic acidosis. While there are possible benefits with newer anti-diabetic agents such as SGLT-2 inhibitors and GLP-1 receptor agonists with respect to cardiac disease and heart failure, there is no data specifically in Friedreich ataxia (41, 43).
The use of SGLT-2 inhibitors has been associated with euglycemic diabetic ketoacidosis (DKA) (44). Since patients with Friedreich ataxia-related diabetes have decreased insulin secretion, ketone monitoring and close follow-up would be needed if starting an individual with Friedreich ataxia on this class of medication.
SUBGROUP CONSIDERATION: This recommendation is for adults with Friedreich ataxia with higher-risk diabetes mellitus (HbA1c ≥ 8.5%, ketones, or acute hyperglycemia).
Evidence to Recommendation Table PDFTreatment for children with stabilized diabetes mellitus
QUESTION: Should Insulin alone versus metformin +/- novel glucose-lowering therapy (e.g., GLP1RA) + insulin be used for children (under 18 years) with diabetes mellitus, once stabilized, with Friedreich ataxia?
LEVEL OF EVIDENCE: ⨁◯◯◯
RECOMMENDATION: We suggest using insulin alone rather than insulin and other glucose-lowering therapy as the primary treatment for most children (under 18 years old) with Friedreich ataxia-related diabetes mellitus.
JUSTIFICATION: Children with Friedreich ataxia-related diabetes tend to be more predominantly insulin deficient and therefore require insulin as treatment for diabetes mellitus. Additionally, fewer medications are approved for diabetes management in pediatrics and therefore less is known about their effects, even in “common” forms of pediatric diabetes mellitus.
SUBGROUP CONSIDERATION: This recommendation is for children with Friedreich ataxia with stabilized diabetes mellitus. In children with evidence of insulin resistance or at risk of insulin resistance (elevated fasting insulin at diagnosis of diabetes, elevated c-peptide while on insulin, elevated BMI, family history of type 2 diabetes, acanthosis nigricans on exam), additional anti-diabetic agents such as metformin or GLP-1 receptor agonists can be considered.
Evidence to Recommendation Table PDFAll individuals with Friedreich ataxia should have annual screening for diabetes mellitus and symptoms of hyperglycemia (polyuria, polydipsia, unexplained weight loss) should be reviewed with patients and families.
Management
Management of diabetes mellitus in Friedreich ataxia should involve diabetes specialists and take an individualized approach.
Lay summary of clinical recommendations for diabetes mellitus in Friedreich ataxia
Why these recommendations?
It is well known that individuals with Friedreich ataxia are at risk of developing diabetes mellitus. Studies have reported prevalence of up to 40% (4 out of 10) of individuals with Friedreich ataxia. However, diabetes may be under-recognized with current screening methods.
Screening: We recommend annual blood tests to screen for diabetes in individuals with Friedreich ataxia. It is important to diagnose diabetes early to avoid significant illness from delayed treatment.
While 2-hour oral glucose tolerance tests may be more sensitive than fasting blood tests for diagnosing diabetes related to Friedreich ataxia, there is not enough evidence at this time to suggest 2-hour oral glucose tolerance tests should be used on a routine annual basis.
Management: Insulin has been used successfully to manage high blood sugars in people with Friedreich ataxia. However, insulin also has undesirable side-effects, including low blood sugar levels.
Other anti-diabetes medications may be considered for people with Friedreich ataxia, in particular those medications that could have other health benefits. Anti-diabetes medications have been shown to be helpful for other people with diabetes, mostly adults, but have not been studied specifically in people with Friedreich ataxia and diabetes. Therefore, an individualized, patient-centered approach to diabetes management in Friedreich ataxia is recommended.
What does this mean for you as a person living with Friedreich ataxia or caring for someone living with Friedreich ataxia?
Your healthcare provider may recommend screening tests for diabetes and discuss symptoms of diabetes such as increased thirst, increased urination, or unintentional weight loss. If you have these symptoms, or questions about diabetes, you should speak to your healthcare provider.
If you are diagnosed with diabetes, your healthcare provider will help you decide on the best treatment for your particular circumstances.
Who are these recommendations specifically for?
Screening recommendations are for all individuals with Friedreich ataxia.
Management recommendations are for individuals already diagnosed with diabetes and are individualized based on age and severity of diabetes.
Professor, Universite Libre de Bruxelles, Brussels, Belgium
Email: miriam.cnop@ulb.be
Andreas Eigentler, MD, PhD
Resident of Neurology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Email: andreas.eigentler@i-med.ac.at
Shana E. McCormack, MD, MTR
Assistant Professor of Pediatrics, Attending Physician, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Email: mccormacks1@chop.edu
Jaclyn Tamaroff, MD
Instructor in Pediatrics, Division of Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nasvhille, Tennessee, USA
Email: jaclyn.tamaroff@vumc.org
David R. Weber, MD, MSCE
Assistant Professor of Pediatrics – Endocrinology, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Email: weberd@chop.edu
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These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.