Small steps forward: Adjunctive therapy for T1D

An important observation is that features of type 2 diabetes (T2D) are now being seen in many individuals with type 1 diabetes (T1D). In a 6-year follow-up of the Diabetes Complications and Control Trial (DCCT), among those initially randomized to intensive glycemic management, approximately 10% had a positive family history of T2D, with final triglyceride level 92 versus 76, low-density lipoprotein cholesterol 118 versus 111, and apolipoprotein B 90 versus 82 mg/dl among those not having such a history, and these individuals gained more weight during the trial, with final body mass index (BMI) 27.8 versus 26.4 kg/m, respectively. Hypoglycemia is usually treated by ingestion of rapidly absorbed carbohydrate, and as a consequence frequent low glucose may contribute to weight gain; in the DCCT, those in the lowest tertile of hypoglycemia frequency had less weight gain than those in the second and third tertiles. Higher glycosylated hemoglobin (HbA1c) during the DCCT was also associated with greater weight gain. Weight gain appears to be a mediator of adverse outcome of glycemic treatment, and in a different analysis of DCCT participants randomized to intensive glycemic management, of those in the highest quartile of weight gain, 22% and 48% met the metabolic syndrome criterion for excess waist circumference at DCCT closeout and after 6 years of follow-up, respectively, while just 3% and 14% of those in the first through third quartiles of weight gain had excess waist circumference at these times. Furthermore, those in the highest weight gain quartile had higher HbA1c, insulin dose, and levels of triglyceride, non–high-density lipoprotein cholesterol, and blood pressure, with this degree of weight gain showing significant association with carotid intima-medial thickness, a marker of atherosclerotic cardiovascular disease (ASCVD). Based on these observations, it has been a concern that individuals with T1D are increasingly likely to be overweight or obese. This was observed in follow-up of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study prospective cohort from 1986 to 2007. The T1D Exchange Clinic Registry reports that among their population of 22 697 persons with T1D treated from 2016 to 2018, 42% of adolescents, 48% of those ages 18–25, and 69% of those age 26 and older were overweight or obese. A number of complications are associated with insulin resistance. Approximately one quarter of the US population has evidence of nonalcoholic fatty liver disease (NAFLD), seen in association with greater body weight, and it should not therefore be surprising that NAFLD is now being reported with increasing frequency in T1D. A meta-analysis of 20 studies of 3901 persons with T1D reported an overall NAFLD prevalence of 19% on imaging studies, with recent imaging studies using hepatic elastography reporting NAFLD prevalence of 20% and 47% among persons with T1D. A study of 4899 persons with T1D with indices based on age, BMI, and laboratory test results suggested NAFLD prevalence as high as 71%. Analysis of ASCVD events among 36 869 persons with T1D at median age 35 matched 1:5 with controls shows 6-fold greater likelihood of CVD mortality and 5-fold greater likelihood of CVD hospitalization. The mechanism of the association of greater body weight with adverse consequence in T1D is likely to be insulin resistance, with insulin-resistant persons with T1D showing marked increase in development of coronary disease in comparison to those who are insulin sensitive.12–14 Using the waist circumference, HbA1c, and blood pressure to derive an estimate of the glucose disposition rate (eGDR), several groups have shown lower eGDR to be associated with ASCVD and mortality, and using such an approach to estimate the change in insulin sensitivity over time in 1375 participants in the DCCT at entry and at 18.5-year follow-up, those with lower insulin sensitivity at both time points had greater likelihood of development of CVD events. Although insulin therapy is the mainstay of treatment of T1D to attain glucose control, and although glycemia is certainly the most important predictor of outcome among persons with T1D, intensive therapy may, then, compound weight gain, in turn leading to a variety of conditions associated with insulin resistance and adverse outcome. Consideration of measures to reduce weight Accepted: 21 September 2022