Practice Update: Endocrinology | Volume 1. Number 2. 2016

DIABETES

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EXPERT OPINION FDA revises recommendation for metformin use in patients with chronic kidney disease Dr Silvio Inzucchi, Professor of Medicine at the Yale University School of Medicine in New Haven, Connecticut, discusses the recent change to the package label for metformin relating to its use in patients with chronic kidney disease. T he US Food and Drug Administration just recently decided to change the package label for metformin as related to use in

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com

renal function were overly restrictive and pre- vented the use of this important, effective, and cheap medication in hundreds of thousands of patients in the US. Although lactic acidosis is a serious and potentially life-threatening condi- tion, it is actually no more common in patients prescribed metformin. Moreover, surveys showed high rates of metformin use in patients with mild to moderate chronic kidney disease, despite the earlier FDA guidelines in place since drug ap- proval in 1995. Despite this fact, lactic acidosis rates were not observed to have increased. In fact, when a metformin-treated patient develops lactic acidosis, it is almost always due to some other event, such as a major cardiac event or sepsis. So, metformin is felt to be an “innocent bystander” in these cases. Here are the essential changes (very similar to those in use in the UK): • Base assessment on eGFR, not serum creatinine. • Obtain eGFR before starting metformin and annually; more frequently in those at risk for renal impairment (eg, the elderly). • Metformin can be used when the eGFR is <60 mL/min but remains contraindicated in patients with an eGFR <30. • Don’t start metformin in patients with an eGFR in the 30–45 range. • If the eGFR falls <45 in someone on metform- in, assess the overall benefits and risks before continuing treatment. Stop metformin if the eGFR falls <30. • Hold metformin before iodinated contrast pro- cedures if the eGFR is 30–60; also if there is any liver disease, alcoholism, or heart failure; or if intra-arterial contrast is used. Recheck the eGFR 48 hours after the procedure; restart metformin if renal function is stable. The recent FDA communication certainly does not mean that the drug can be used in those with advanced renal disease. It remains a drug abso- lutely contraindicated when the eGFR is <30.

My only criticism of the new guidelines is that they do not include recommendations for dose adjustment in those with an eGFR 30–45. This is what our group had recommended in two reviews published on this topic. 3,4 Therein we advised that the dose be cut in half when an eGFR of 45 was reached to minimise any chance of getting to a toxic level in patients with that degree of kidney disease. I’d also caution not to use the drug if renal function is or expected to become unstable. This FDA decision is a very important one for those of us managing patients with type 2 diabetes. It has been estimated that somewhere around 800,000 to 1.6 million patients will now be eligible for metformin in the US. Indeed, how often do we wish we could continue metformin in someone who’s developed mild CKD? The al- ternative often is a more expensive and/or riskier medication. So, I and many of my colleagues are very enthusiastic about this change. References 1. Food and Drug Administration. Metformin-containing drugs: drug safety communication – revised warnings for certain patients with reduced kidney function. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm494829. htm. Accessed on April 12, 2016. 2. Food and Drug Administration. FDA drug safety com- munication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with re- duced kidney function. Available at: www.fda.gov/Drugs/ DrugSafety/ ucm493244.htm . Accessed on April 12, 2016. 3. Lipska KJ, Bailey CJ, Inzucchi SE. Diabetes Care 2011;34:1431-1437. 4. Inzucchi SE, Lipska KJ, Mayo H, et al. JAMA 2014; 312:2668-2675.

chronic kidney disease (CKD) patients. 1,2 This was in response to two citizen petitions that were filed with the agency in 2013, one from our group. The prior label restricted its use to men with serum creatinine <1.5 mg/dL and women with serum creatinine <1.4 mg/dL. Evidence has emerged over the past 20 years that the prior guidelines for those with impaired EXPERT COMMENTARY By Prof Sof Andrikopoulos T he FDA’s decision to change the package label for metformin for its use in patients with eGFR <60 mL/min (but >30 mL/ min) is a positive one. It’s important to note that there is no evidence suggesting that using metformin when eGFR <60 but >30 is harmful as long as the dose of metformin is titrated, the patient is closely monitored and the patient’s kidney function is measured annually. If these measures are taken, as most endocrinologists would, then it’s very useful to use metformin. It’s an effective drug and we know it’s a safe drug. I’ve had discussions with the Therapeutic Goods Administration about changing the pack- age label of metformin in Australia, in line with that in the US, and the TGA is currently review- ing this. Prof Sof Andrikopoulos is President of the Australian Diabetes Society, Head of the Islet Biology and Metabolism Research Group at the Department of Medicine, University of Melbourne, Editor-in-Chief

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Dr Silvio Inzucchi is Professor of Medicine (Endocrinology); Clinical Director, Section of Endocrinology; Director, Yale Diabetes Center;

Director, Endocrinology and Metabolism Fellowship, Yale School of Medicine, New Haven, Connecticut.

of the Journal of Endocrinology and Journal of Molecular Endocrinology.

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JOURNAL SCAN Teenage girls with type 1 diabetes have poorer metabolic control than boys and face more complications in early adulthood Journal of Diabetes and Its Complications Take-home message As adults, more females had retin- opathy, P < 0.05. Females had higher mean HbA 1c values at diagnosis, 11.2 vs

was found in adolescent females, and they had a higher frequency of mi- crovascular complications. Improved paediatric diabetes care is of great im- portance for increasing the likelihood of lower mortality and morbidity later in life. Teenage girls with type 1 diabetes have poorer metabolic control than boys and face more complications in early adulthood. J Diabetes Compli- cat 2016;30:917–922, Samuelsson U, Anderzén J, Gudbjörnsdottir S, et al.

10.9% (99 vs 96 mmol/mol), P < 0.03, during adolescence, 8.5 vs 8.2% (69 vs 66 mmol/mol) P < 0.01, but not as young adults. CONCLUSIONS Worse glycaemic control

• The goal of this study was to evaluate differences in metabolic control between adolescent males and females with type 1 diabetes. Investigators categorised HbA 1c values into three groups: < 7.4% (57 mmol/mol); 7.4% to 9.3% (57–78 mmol/mol); and > 9.3% (78 mmol/mol). Females were over- represented in the highest HbA 1c group (51.7% vs 46.2% expected) and underrepresented in the lowest HbA 1c group (34.2%; P < 0.001). As young adults, females were more likely to have retinopathy (P < 0.05). Increased HbA 1c values in females compared with males were seen at diagnosis (11.2% vs 10.9%) and in adolescence (8.5% vs 8.2%), but not as young adults. • Adolescent females with type 1 diabetes have worse glycaemic control than males with type 1 diabetes. This difference resolves in young adulthood, but young adult females have higher rates of retinopathy.

RESULTS When dividing HbA 1c values in three groups; < 7.4% (57 mmol/mol), 7.4–9.3% (57–78 mmol/mol) and >9.3% (78 mmol/mol), there was a higher proportion of females in the highest group during adolescence. In the group with the highest HbA 1c values during adolescence and as adults, 51.7% were females, expected value 46.2%; in the group with low HbA 1c values in both reg- istries, 34.2% were females, P < 0.001.

AIMS To compare metabolic control between males and females with type 1 diabetes during adolescence and as young adults, and relate it to microvas- cular complications. METHODS Data concerning 4000 adoles- cents with type 1 diabetes registered in the Swedish paediatric diabetes quality registry, and above the age of 18 years in the Swedish National Diabetes Reg- istry was used.

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VOL. 1 • No. 2 • 2016