Sunday, October 1, 2023
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Beta-cell dysfunction is a major defect in patients with type 2 diabetes mellitus (T2DM).[1] Typically, at the time of clinical diagnosis, patients with T2DM have lost, on average, 50% of their beta-cell function.[2] In addition, beta-cell function tends to decline over time.[3] In the UK Prospective Diabetes Study (UKPDS), untreated patients with T2DM lost about 4% of their beta-cell function per year.[2] Given the fact that T2DM is a disease of progressive beta-cell decline, most patients will eventually require insulin therapy to control their disease.
One of the barriers to insulin therapy is concern about weight gain. The common patient perception that associates mounting weight with insulin therapy has been confirmed by several, large, prospective studies, such as the UKPDS. In the UKPDS, most patients gained weight over the study period, but patients who were assigned to insulin therapy gained the most weight in the shortest period of time.[4] Weight gain was significantly greater in the intensive-treatment group compared with the conventional-treatment group. Across all therapies (ie, sulfonylurea, insulin) patients in the intensive-treatment group gained, on average, 3.1 kg more than patients in the conventional-treatment group. In addition, in the subset of patients treated with insulin therapy, patients in the intensive-treatment group (more insulin used) gained an average of 4.0 kg compared with patients in the conventional-treatment group.[5] The difference in glycated hemoglobin (A1C) levels between the intensive-treatment group and the conventional-treatment group was only 0.9%. This suggests that an A1C drop of 1% may translate into a 4-kg weight gain over time.
Why do patients gain a significant amount of weight when on insulin therapy? Several proposed theories include decreased glycosuria due to improved glycemic control, the anabolic effects of insulin itself, decreased metabolic rate, aggressive treatment of hypoglycemia, and defensive eating to prevent hypoglycemia or deal with the fear of hypoglycemia.[6-9]
Because the majority of patients with T2DM are already overweight, the weight gain associated with insulin therapy may delay insulin initiation. In addition, weight gain itself may have deleterious metabolic and health consequences. The cardiovascular risk profile and obesity are often positively correlated.[10,11] Weight gain may also increase low-density lipoprotein (LDL) cholesterol, worsen hypertension, and lower high-density lipoprotein (HDL) cholesterol,[12,13] all of which are independent risk factors for atherosclerosis. Therefore, interventions that may help minimize the weight gain associated with insulin therapy are always welcomed.
Several strategies may be used to avoid weight gain during insulin treatment. Lifestyle interventions should be an integral part of any diabetes treatment. These interventions should take a team approach that includes the patient, physician, diabetes educator, and dietitian. Support from family members and friends is also valuable. The patient should avoid any foods that are high in fat content and sugars. A consistent and structured exercise regimen is also an essential component of successful diabetes treatment. Several studies have convinced us that lifestyle interventions are extremely effective. Data from the Finnish Diabetes Prevention Study[14] and the Diabetes Prevention Program Research Study[15] demonstrated that changes in lifestyle led to ~5% weight loss over 4 years in overweight and obese men and women with impaired glucose tolerance. In the RIO-Diabetes study (Rimonabant In Overweight/Obesity),[16] obese patients with T2DM lost a mean of 1.4 kg over 52 weeks on dietary intervention alone.
The use of combination therapy should be considered. For example, because metformin is an insulin sensitizer,[17] continuation of metformin after adding insulin may reduce the dose of insulin needed to achieve glycemic goal.[18]
The use of newer analog insulins instead of NPH-based therapy may also be beneficial. Insulin detemir is formed by the removal of the amino acid threonine at the B30 locus, with myristic acid (14-carbon fatty acid) acylated to lysine at locus B29.[19] Acylation of the molecule with a fatty acid allows for reversible albumin binding and stabilizes self-association of the molecule. These changes lead to the favorable characteristics of prolonged duration of action with a relatively flat action profile, primarily by retarding absorption.
A study by Heise and colleagues[20] suggested that the intrasubject variation is much less with insulin detemir vs NPH or insulin glargine. Less intrasubject variation may reduce the risk for hypoglycemia and the weight gain associated with treatment of hypoglycemia.
Indeed, several studies have shown that insulin detemir may be associated with less weight gain while achieving the same level of glycemic control.[18,21] In a study using a treat-to-target titration protocol assessing the efficacy of insulin detemir or NPH insulin added to oral antidiabetic drugs (OADs), insulin detemir was associated with significantly less weight gain compared with NPH insulin (2.6 lb/24 weeks vs 6.2 lb/24 weeks), although both groups had similar improvements in A1C levels (baseline 8.6% vs less than 7% at end of study).[22] In the same study, the insulin detemir-treated group had lower risks for overall and nocturnal hypoglycemia (47% and 55% lower, respectively). Three other prospective studies[23-25] of 20-26 weeks' duration also consistently showed less weight gain with insulin detemir compared with NPH-based therapy (Philis-Tsimikas: -2 lb; Raslova: -1.4 lb; Haak: -1.8 lb).
These findings are supported by 2 observational studies. In the German cohort of PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation),[26] T2DM patients who were switched from NPH, insulin glargine, or OADs to insulin detemir-based therapy had lower A1C levels, less hypoglycemia, and a 0.9-kg weight loss.
In the US Predictive 303 study,[27,28] another observational study, T2DM patients with a variety of treatment backgrounds were switched to insulin detemir and followed for 24 weeks. Insulin detemir was either added to OADs or substituted for NPH or insulin glargine. One group had the dose of insulin detemir adjusted per investigators (standard-of-care group); another group had insulin detemir dose adjusted per protocol (303 algorithm). The addition/substitution of detemir led to further improvements in A1C (OAD group: 1% to 1.1%; NPH group: 0.2%; glargine group: 0.2% to 0.3%; all statistically significant except the "standard-of-care" NPH subgroup). The amount of weight gain during the 6 months was minimal in the insulin-naive group (2.46 lb, 303 algorithm; 0.46 lb standard-of-care). More important, the NPH-based group, when switched to detemir, had some weight loss during 6 months of follow-up (303 algorithm group: -3.08 lb; standard-of-care: -4.18 lb). Similar results were seen in the glargine-based group when switched to detemir (303 algorithm group: -1.1 lb; standard-of-care: -1.54 lb).
The mechanisms that may account for the "weight-sparing" effects of insulin detemir are not yet conclusive. Reduced risk for hypoglycemia and less intrasubject variation of insulin detemir may both play a role. In addition, central nervous system satiety effects and differential effects on hepatic vs peripheral insulin levels due to the albumin binding of insulin detemir have also been proposed as the cause.[8,21]
One of the major barriers to insulin therapy for T2DM patients is the fear of additional and unnecessary weight gain. A healthy diet, vigorous and consistent exercise, and the use of insulin-sparing agents with insulin should reduce the problem of weight gain. The insulin analog detemir may play an additional role in minimizing weight gain.
This activity is supported by an independent educational grant from Novo Nordisk.
