PracticeUpdate: Endocrinology

OBESITY

13

Double diabetes does not have to mean double complications Comment by Peter Lin, MD, CCFP T ypically, we think of diabetes as either a lack of insulin (type 1) or insulin resistance (type 2), in which the insulin is not work- metabolic syndrome. This combination was given the nickname of double diabetes (DD). In other words, these DD patients have both insulin deficiency and insulin resistance.

blood glucose. This collection of metabolic de- rangements was labelled themetabolic syndrome (MS). Patients with these features were found to be at a much higher risk for cardiovascular events, and these patients were easy to recognise – they were the patients with the big bellies. Now, typically we don’t think of patients with type 1 diabetes as having big bellies and so we don’t usually think in terms of metabolic syndrome in patients with type 1 disease. But why can’t a patient who is missing insulin also have insulin resistance and all those metabolic derangements as well? This paper looked at that specific patient group. Patients with type 1 diabetes and

in the type 1 patients. The exact cause is not yet clear but that is a sound hypothesis. Unfortunately, what is clear is that patients with DD have higher microvascular and mac- rovascular disease complications.

The researchers found that, of 31,119 type 1 patients, 25.5% had MS. That is a much higher proportion than one would expect. The authors suggested that, maybe in the past, patients had to adjust what they ate to their insulin dose so they tended not to over-eat, and hence obesity and MS was less likely. How- ever, now with more flexible insulin dosing, patients can eat what they want and they can increase the insulin to match what they ate. This would lead to more obesity and more MS comorbidities (coronary heart disease 8.0% versus 3.0% w/o MS, stroke 3.6% versus 1.6%, diabetic foot syndrome 5.5% versus 2.1%). Also microvascular diseases were increased in people with double diabetes (retinopathy 32.4% versus 21.7%, nephrop- athy 28.3% versus 17.8%). Both macrovascular and microvascular comorbidities were increased inde- pendent of glucose control, even if patients with good metabolic control (HbA1c <7.0%, 53 mmol/mol) showed significantly less macrovascular (coronary heart disease 2.3% versus 1.8%, p<0.0001) and microvascular problems (retinopathy 8.7% versus 6.6%, p<0.0001). CONCLUSIONS Double diabetes seems to be an independent and important risk factor for persons with T1DM in developing macrovascular and micro- vascular comorbidities. Therefore, patients should be identified and development of MS should be avoided. Longterm studies are needed to observe the effect of insulin resistance on patients with au- toimmune diabetes. Diabetes Res Clin Pract 2016;119:48-56, Merger SR, Kerner W, Stadler M, et al.

ing well. We recognise that, along with insulin resistance in type 2 diabetes, often comes a col- lection of five metabolic derangements. These include increased visceral fat as measured by waist circumference, elevated blood pressure, high triglycerides, low HDL, and high fasting In those patients with MS, we must protect them from both macro- and microvascular disease.

MACROVASCULAR

MS

NO MS

Coronary heart disease

8.0%

3.0%

Stroke

3.6%

1.6%

Diabetic foot syndrome

5.5%

2.1%

MICROVASCULAR

Retinopathy

32.4%

21.7%

Nephropathy

28.3%

17.8%

Prevalence and comorbidities of double diabetes Diabetes Research and Clinical Practice Take-home message

The good news is that patients with DD who had HbA1c <7% had fewer complications than DD patients with higher HbA1c. So there is hope that we can intervene to reduce their risk. The key message from this study is that MS is a set of toxic metabolic derangements that can be found in patients with type 1 or type 2 diabetes. We must be on the lookout for it, and, in those patients withMS, we must protect them from both macro- and microvascular dis- ease. We can do this by providing good glucose, blood pressure, lipid, and weight control for all of these patients in order to help reduce their risk. So, double diabetes does not have to mean double the complications.

• “This large study (N = 31,119) of individuals in Germany demonstrates that the presence of meta- bolic syndrome among people with type 1 diabetes (25% prevalence) significantly contributes to both microvascular and macrovascular complications, independent of glycemic control. This study provides clinicians with an evidence base to target both obesity and glycemic control in patients with type 1 diabetes.” • Further long-term studies are required to investigate the effects of insulin resistance on patients with autoimmune diabetes, and any development of metabolic syndrome in patients should be prevented. Abstract

diabetes mellitus were analysed for signs of MS and presence of late complications. Double diabetes was defined as T1DM coexisting with MS (obesity, hypertension, dyslipidemia). Multiple linear or logis- tic regression analyses were performed to identify associations between double diabetes and late complications. RESULTS 25.5% (n=7926) of persons with T1DM pre- sented additionally the MS. Persons with double diabetes showed significantly more macrovascular

BACKGROUND A growing number of people with type 1 diabetes (T1DM) are identified with features of met- abolic syndrome (MS) known as “double diabetes”, but epidemiologic data on the prevalence of MS in T1DM and its comorbidities are still lacking. Aim of this cross sectional study is to better estimate the prevalence of MS in T1DM, and to assess its association with comorbidities. METHODS Data of 31,119 persons with autoimmune

Dr Lin is Director, Primary Care Initiatives, Canadian Heart Research Centre.

Dual therapy reduces body weight, prediabetes, and systolic blood pressure in obese nondiabetic individuals

Dapagliflozin QD and exenatide QWdual therapy: a 24-week randomized, placebo-controlled, phase 2 study examining effects on bodyweight and prediabetes in obese nondiabetic adults Diabetes, Obesity & Metabolism Take-home message • This study evaluated 43 adults over 24 weeks of treatment. In the dapa- gliflozin/exenatide group compared with the placebo group, prediabetes was reduced to 34.8% from 85% (P < 0.01), body weight decreased by 4.13 kg (P < 0.001), and systolic blood pressure (SBP) was also reduced (a difference of 6.7 mm Hg). Anticipated adverse reactions to injection were higher in the dapagliflozin group than the placebo group. • A reduction in body weight, prediabetes, and SBP in obese nondiabetic adults resulted from dapagliflozin/exenatide dual therapy versus placebo, with no adverse effects reported. Abstract AIMS Dapagliflozin as well as exenatide reduce bodyweight in patients with type 2 diabetes. We explored the effects of dual therapy with these agents on bodyweight, body composition, glycemic parameters, and systolic blood pressure (SBP) in obese nondiabetic adults. MATERIALS AND METHODS This single-center, double-blind trial randomized 50 obese nondiabetic adults (aged 18-70 years; body mass index 30-45kg/m2) to oral dapagliflozin 10mg once daily plus subcutaneous long-acting exenatide 2mg once weekly or placebo. Magnetic resonance imaging (MRI) assessed change in body composition. Participants were instructed to follow a balanced diet and exercise moderately. RESULTS Of 25 dapagliflozin/exenatide- and 25 placebo-treated participants, 23 (92%) and 20 (80%) completed 24 weeks of treatment, respectively. At baseline, mean age was 52 years, 61% were female, mean bodyweight was 104.6kg, and 73.5% had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks: dapagliflozin/exenatide versus placebo difference in bodyweight loss was –4.13kg (95% confidence interval: –6.44, –1.81; p<0.001), mostly attribut- able to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% achieved ≥5% bodyweight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%; p<0.01). Dapagliflozin/exenatide versus placebo difference in SBP reduction was -6.7 mmHg. As expected, nausea and injection-site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only 2 and 3 participants, respectively, discontinued due to adverse events. CONCLUSIONS Compared with placebo, dapagliflozin/exenatide dual therapy reduced bodyweight, prediabetes, and SBP over 24 weeks and was well toler- ated in obese nondiabetic adults. Diabetes Obes Metab 2016 Aug 23;[Epub ahead of print], Lundkvist P, David Sjöström C, Amini S, et al.

Comment by Silvio Inzucchi, MD T here is obviously a lot of in- terest in the combined dose of the two diabetes drug cat- egories associated with weight loss, the GLP-1 receptor agonists and the SGLT2 inhibitors. In addition to potential enhanced effects on BMI, at least one member of each of these classes has been associated with improved cardiovascular outcomes in high-risk patients, namely empa- gliflozin and liraglutide. Notably, in the most recent set of recommenda- tions about glucose-lowering therapy in type 2 diabetes, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) do not endorse this combination since, at the time the guidelines were released (early 2015), there were no published stud- ies of this specific combination. This paper tests the drug combination in a small cohort of obese but nondia- betic individuals. The drugs appear to work reasonably well together, although I was a bit underwhelmed by the effects on body weight. We look forward to future pub- lications of this and similar drug combinations in patients with

type 2 diabetes. We would point out, however, that current out-of- pocket costs for this combination, depending on dose, can be in excess of US$1000 per month! This seems extraordinary for a glucose-reducing strategy, no matter how effective it might be.

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

and Metabolism Fellowship, Yale School of Medicine, Connecticut.

VOL. 1 • No. 3 • 2016