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

DIABETES

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EXPERT COMMENTARY Hypoglycaemia remains a most challenging obstacle By Dr Raimund Herzog T o this day, hypoglycaemia remains the most challenging obstacle in the achievement of tight glycaemic control All-cause mortality and cardiovascular disease associated with prior history of hypoglycaemia in type 1 diabetes Diabetes Care Take-home message

hypoglycaemia-associated autonomic failure that heightens the risk for subsequent severe hypoglycaemic episodes differs from that in patients experiencing large excursions into the hyperglycaemic and hypoglycaemic range. While the latter might – as an important ca- veat – present to our practice with the same average plasma glucose and A1c, they will be much more likely to be frequently admitted to the emergency roomwith severe hypoglycaemic episodes. It is contingent upon us as clinicians to identify these patients early to make appro- priate adjustments to their insulin regimens to reduce the risk of adverse outcomes. It is contingent upon us as physician scientists to try to identify and develop predictive biomarkers that will allow early identification – and ide- ally treatment – of contributing inflammation, endothelial dysfunction, and other factors in these patients who are at particular risk for car- diovascular events and death from other causes. This study by Lu and colleagues is an excellent example of how carefully collected national health insurance data (in this case from Taiwan) help assess the specific circumstances of severe hypoglycaemia-associated morbidity and mortality in a type 1 diabetic patient population.

in type 1 diabetic patients. The more wide- spread use of continuous glucose monitors has revealed more hypoglycaemic episodes in this population than we ever knew of when relying on finger-stick glucose measurements alone. Investigators over the past several years have identified additional complications of severe hypoglycaemia, which go beyond its incapaci- tating effects on the brain such as impaired cognition, seizures, loss of consciousness, and permanent brain injury. Cardiovascular com- plications and increased all-cause mortality were recently highlighted in large studies of type 1 and type 2 diabetic patients experienc- ing frequent hypoglycaemia under intensive diabetes control. This study by Lu and colleagues is an excel- lent example of how carefully collected national health insurance data (in this case fromTaiwan) help assess the specific circumstances of severe hypoglycaemia-associated morbidity and mor- tality in a type 1 diabetic patient population. The investigators report a significant association between severe hypoglycaemia and cardiovas- cular and all-cause mortality during the year immediately preceding the events, while only all-cause mortality was associated with severe hypoglycaemia occurring between 1 and 3 and 3 and 5 years prior to the event in question. One can envision a scenario where frequent mild recurrent hypoglycaemia and the ensuing

• The goal of this case-control study was to investigate the association between severe hypoglycaemia and future risk for all-cause mortality and cardiovascular disease (CVD) in people with type 1 diabetes. Researchers found that individuals who had severe hypogly- caemic events less than a year prior had an increased risk for all-cause mortality and CVD (ORs, 2.74 and 2.02, respectively). Additionally, individuals who had severe hypoglycaemic events within 1 to 3 years or 3 to 5 years before death had an increased risk for all-cause mortality (OR, 1.94 and 1.68, respectively). • Severe hypoglycaemic events in patients with type 1 diabetes were associated with increased CVD risk for up to 1 year, and risk for all-cause mortality remained elevated for up to 5 years after a hypoglycaemic event.

Abstract OBJECTIVE This study investigated the effects of severe hypoglycaemia on risks of all-cause mor- tality and cardiovascular disease (CVD) incidence in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Two nested case-control studies with age- and sex-matched control subjects and using the time-density sam- pling method were performed separately within a cohort of 10,411 patients with T1DM in Taiwan. The study enrolled 564 nonsurvivors and 1,615 control subjects as well as 743 CVD case sub- jects and 1,439 control subjects between 1997 and 2011. History of severe hypoglycaemia was identified during 1 year, 1–3 years, and 3-5 years before the occurrence of the study outcomes. Conditional logistic regression analyses were performed to estimate the odds ratio (OR) and 95% CI of the study outcomes. RESULTS Prior severe hypoglycaemic events with- in 1 year were associated with higher risks of all- cause mortality and CVD (adjusted OR 2.74 [95%

CI 1.96–3.85] and 2.02 [1.35–3.01], respectively). Events occurring within 1–3 years and 3–5 years before death were also associated with adjusted ORs of 1.94 (95% CI 1.39–2.71) and 1.68 (1.15–2.44), respectively. Significant dose-gradient effects of severe hypoglycaemia frequency on mortality and CVD were observed within 5 years. CONCLUSIONS Although the CVD incidence may be associated with severe hypoglycae- mic events occurring in the previous year, the risk of all-cause mortality was associated with severe hypoglycaemic events occurring in the preceding 5 years. Exposure to repeated severe hypoglycaemic events can lead to higher risks of mortality and CVD. A population-based study of all-cause mortal- ity and cardiovascular disease in association with prior history of hypoglycemia among patients with type 1 diabetes. Diabetes Care 2016 Jul 06;[EPub ahead of print], Lu CL, Shen HN, Hu SC, et al.

Dr Raimund Herzog is Assistant Professor in Endocrinology at Yale School of Medicine.

EXPERT COMMENTARY Short-term investigations not set up to assess long-term safety, clinical outcomes

By Dr Silvio Inzucchi T his is the very latest meta-analysis concerning non-insulin therapies for type 2 diabetes, funded by the Agency for Healthcare Research and Quality (AHRQ) of the US De- partment of Health and Human Services. TheAHRQ evaluates and prioritises medical evidence in an effort to promote safer, higher-quality, and more equitable and affordable care. The paper assessed the relative efficacy of drugs as monotherapy and in combination with metformin and incorporated 204 individual studies. Its main findings should not be surprising. HbA 1c reduc- tions were similar across most monotherapies as well as when drugs were combined with metformin, with the exception of the DPP-4 inhibitors, which are somewhat less potent. There was a notable absence of recently reported large randomised trials, including EMPA-REG OUTCOME and LEADER, likely because these trials did not specifically compare a single drug with another but instead assessed the CV effects of an agent vs standard care. Metformin provides a cardiovascular (CV) mortality benefit to sulfonylureas. Metformin, DPP-4 inhibitors, GLP-1 receptor ago- nists, and SGLT2 inhibitors are either weight-neutral or result in some weight loss, whereas sulfonylureas and TZDs lead to weight gain. Sulfonylureas increase the risk of hypoglycaemia. GI side effects are more common with metformin and GLP-1 agonists. Genital mycotic infections are increased with SGLT2 inhibitors. Unfortunately, most of the studies in this meta-analysis were short-term investigations and were not set up to assess long-term

empagliflozin and the GLP-1 agonist liraglutide, respectively) vs standard care. Those investigations demonstrated reduced CV events in the active therapy arms and may influence future guidelines to recommend that they be used preferentially after metformin when CV disease is already established.

safety or clinical outcomes. There was a notable absence of recently reported large randomised trials, including EMPA- REG OUTCOME and LEADER, likely because these trials did not specifically compare a single drug with another but in- stead assessed the CV effects of an agent (the SGLT2 inhibitor

Monotherapy vs metformin-based combination therapy for type 2 diabetes Annals of Internal Medicine Take-home message

that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycaemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP- 1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. LIMITATION Most studies were short, with limited ability to assess rare safety and long- term clinical outcomes. CONCLUSION The evidence supports met- formin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on haemoglobin A1c, weight, and cardiovas- cular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: A systematic review and meta-analysis. Ann Intern Med 2016;164:740–751, Maruthur NM, Tseng E, Hutfless S, et al.

• A meta-analysis of 179 trials and 25 observational studies of head-to-head mono- therapy or metformin-based combinations compared the effectiveness and safety of various monotherapies and selected metformin-based combinations in adults with type 2 diabetes. • Compared with sulfonylureas, metformin was safer and had more beneficial effects on haemoglobin A1c, weight, and cardiovascular mortality. Benefits with add-on therapies to metformin appeared to be similar to those observed with monotherapies.

search updated through December 2015). STUDY SELECTION Paired reviewers indepen- dently identified 179 trials and 25 observa- tional studies of head-to-head monotherapy or metformin-based combinations. DATAEXTRACTION Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. DATA SYNTHESIS Cardiovascular mortality was lower for metformin versus sulfonylu- reas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascu- lar complications was insufficient or of low strength. Reductions in haemoglobin A1c values were similar across monotherapies and metformin-based combinations, except

BACKGROUND Clinicians and patients need updated evidence on the comparative effec- tiveness and safety of diabetes medications to make informed treatment choices. PURPOSE To evaluate the comparative ef- fectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodi- um-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selectedmetformin-based com- binations in adults with type 2 diabetes. DATA SOURCES English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE

PRACTICEUPDATE ENDOCRINOLOGY