OBJECTIVETo evaluate the cost-effectiveness of a genetic testing policy for HNF1A-, HNF4A-, and GCK-MODY in a hypothetical cohort of type 2 diabetic patients 25–40 years old with a MODY prevalence of 2%.RESEARCH DESIGN AND METHODSWe used a simulation model of type 2 diabetes complications based on UK Prospective Diabetes Study data, modified to account for the natural history of disease by genetic subtype to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of −1.5% compared with usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs) based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER) (USD/QALY).RESULTSThe testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of 205,000 USD. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼50,000 USD. If MODY prevalence was >30%, the testing policy was cost saving. Reducing genetic testing costs to 700 USD also resulted in an ICER of ∼50,000 USD.CONCLUSIONSOur simulated model suggests that a policy of testing for MODY in selected populations is cost-effective for the U.S. based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.
Neonatal diabetes mellitus (NDM) is the term commonly used to describe diabetes with onset before 6 months‐of‐age. It occurs in approximately one out of every 100,000–300,000 live births. Although this term encompasses diabetes of any etiology, it is recognized that NDM diagnosed before 6 months‐of‐age is most often monogenic in nature. Clinically, NDM subgroups include transient (TNDM) and permanent NDM (PNDM), as well as syndromic cases of NDM. TNDM often develops within the first few weeks of life and remits by a few months of age. However, relapse occurs in 50% of cases, typically in adolescence or adulthood. TNDM is most frequently caused by abnormalities in the imprinted region of chromosome 6q24, leading to overexpression of paternally derived genes. Mutations in KCNJ11 and ABCC8, encoding the two subunits of the adenosine triphosphate‐sensitive potassium channel on the β‐cell membrane, can cause TNDM, but more often result in PNDM. NDM as a result of mutations in KCNJ11 and ABCC8 often responds to sulfonylureas, allowing transition from insulin therapy. Mutations in other genes important to β‐cell function and regulation, and in the insulin gene itself, also cause NDM. In 40% of NDM cases, the genetic cause remains unknown. Correctly identifying monogenic NDM has important implications for appropriate treatment, expected disease course and associated conditions, and genetic testing for at‐risk family members. Early recognition of monogenic NDM allows for the implementation of appropriate therapy, leading to improved outcomes and potential societal cost savings. (J Diabetes Invest, doi:10.1111/j.2040‐1124.2011.00106.x, 2011)
There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (KATP), KCNJ11 and ABCC8, and the insulin gene (INS), as well as abnormalities in chromosome 6q24. Patients with activating mutations in KCNJ11 and ABCC8 can be treated with oral sulfonylureas in lieu of insulin injections. This compelling example of personalized genetic medicine leading to improved glucose regulation and quality of life may—with continued research—be repeated for other forms of neonatal diabetes in the future.
Aims/hypothesis Individuals with heterozygous activating mutations of the KCNJ11 gene encoding a subunit of the ATP-sensitive potassium channel (KATP) can usually be treated with oral sulfonylurea (SU) pills in lieu of insulin injections. The aim of this study was to test our hypothesis that younger age at the time of initiation of SU therapy is correlated with lower required doses of SU therapy, shorter transition time and decreased likelihood of requiring additional diabetes medications. Methods We performed a retrospective cohort study using data on 58 individuals with neonatal diabetes due to KCNJ11mutations identified through the University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry). We assessed the influence of age at initiation of SU therapy on treatment outcomes. Results HbA1c fell from an average of 8.5% (69 mmol/mol) before transition to 6.2% (44 mmol/mol) after SU therapy (p < 0.001). Age of initiation of SU correlated with the dose (mg kg−1 day−1) of SU required at follow-up (r = 0.80, p < 0.001). Similar associations were observed across mutation subtypes. Ten participants required additional glucose-lowering medications and all had initiated SU at age 13 years or older. No serious adverse events were reported. Conclusions/interpretation Earlier age at initiation of SU treatment is associated with improved response to SU therapy. Declining sensitivity to SU may be due to loss of beta cell mass over time in those treated with insulin. Our data support the need for early genetic diagnosis and appropriate personalised treatment in all cases of neonatal diabetes.
Neonatal diabetes mellitus occurs in approximately 1 out of every 100,000 live births. It can be either permanent or transient, and recent studies indicate that is likely to have an underlying genetic cause, particularly when diagnosed before 6 months of age. Permanent neonatal diabetes is most commonly due to activating mutations in either of the genes encoding the two subunits of the ATP-sensitive potassium channel. In most of these patients, switching from insulin to oral sulfonylurea therapy leads to improved metabolic control, as well as possible amelioration of occasional associated neurodevelopmental disabilities. It remains to be determined what is the most appropriate treatment of other causes. The diagnosis and treatment of neonatal diabetes, therefore, represents a model for personalized medicine.
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