Insulin and Weight Gain

By Dwight Deter, PA-C

Editor's Note

ADVANCE for Physician Assistants and the Eugene Applebaum College of Pharmacy and Health Sciences, and Wayne State University School of Medicine, are pleased to offer this continuing education opportunity.

The Wayne State University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Wayne State University School of Medicine designates this educational activity for a maximum of one AMA PRA Category 1 Credit(s)(tm). Physicians should only claim credit commensurate with the extent of their participation in the activity.

To receive 1 hour of AMA PRA Category 1 CME credit, read this article and follow the directions on the answer form at the end of the article.

Learning Objectives

1. Discuss the association between type 2 diabetes and obesity.

2. Understand the risks associated with weight gain in type 2 diabetes patients.

3. Review the side effects of weight gain with insulin therapy.

4. Describe treatment approaches to reduce weight gain in type 2 diabetes patients.

Disclosure of Conflict of Interest

The author discloses that he is a consultant for Sanofi-Aventis and GlaxoSmithKline and is on the speakers' program for Novo Nordisk, Sanofi-Aventis and GlaxoSmithKline. Novo Nordisk provided the author with funding that helped support preparation of this manuscript, and Nicole Cooper offered writing and editorial support.

The CME coordinator for ADVANCE for Physician Assistants, John McGinnity, MS, PA-C, discloses receiving honoraria from AstraZeneca and from Bristol Myers-Squibb/Sanofi-Aventis and that he is on the speakers' bureau for Pfizer.

Diabetes and obesity represent two major challenges to public health in the United States and worldwide. Recent data suggest that nearly one-third of U.S. adults are obese and that about one-sixth of children and adolescents are overweight.¹ The prevalence of diabetes is equally alarming: 20.8 million people, or 7% of the U.S. population, had diabetes in 2005.²

One of the major drawbacks of pharmacologic strategies for managing diabetes is that the improvement in glycemic control observed with intensive therapy often is accompanied by considerable increases in weight. Although the benefits of intensive glycemic control in reducing the risk of long-term diabetes complications are unequivocal,^3,4 weight gain observed with therapies used to control hyperglycemia may offset these benefits by increasing cardiovascular risk factors and prompting poor patient adherence.^5-7 Since up to 90% of people with type 2 diabetes are already overweight or obese, therapy that promotes further weight gain is undesirable.⁸

Owing to the progressive nature of type 2 diabetes, most patients ultimately will require insulin therapy to effectively control hyperglycemia.^3,9 Although insulin is the most effective therapy for controlling glycemic levels when dosed appropriately,¹⁰ the use of insulin has been associated with weight gain, particularly in patients with type 2 diabetes who are overweight before beginning therapy. Weight gain also occurs with insulin use in patients with insulin-dependent (type 1) diabetes; however, weight gain in these patients usually is less severe, and type 1 diabetes is much less prevalent in the population (accounting for only 5% to 10% of patients with diabetes in the United States).^11,12

Recent evidence suggests that significant weight gain is no longer an inevitable consequence of insulin therapy.^13-15 Clinical trials with insulin detemir, a new basal insulin analog, consistently demonstrate comparable glycemic control to neutral protamine Hagedorn (NPH) and insulin glargine, along with less weight gain.^13-16

Combining insulin therapies with agents that have positive or neutral weight effects, such as metformin and pramlintide, also can minimize insulin-related weight gain.^17,18 With a focus on patients with type 2 diabetes, the causes and consequences of insulin-related weight gain, as well as strategies to minimize weight gain with insulin therapy, will be reviewed.

Consequences of Weight Gain

Weight gain can increase insulin resistance, thereby worsening hyperglycemia, hyperinsulinemia and glucose intolerance.⁸ Weight gain also can increase blood pressure, dyslipidemia and cardiometabolic risk. In fact, increases in blood pressure, low-density lipoprotein cholesterol, central obesity and insulin resistance have been reported among patients with type 2 diabetes who gained weight using insulin therapy.^6,19 Weight gain and its adverse effects may result in poor cardiovascular outcomes and increased morbidity.^3,12,20

The adverse consequences of weight gain associated with improved glycemic control may have contributed to the divergent results of the United Kingdom Prospective Diabetes Study (UKPDS).^3,5,20 In the UKPDS, intensive therapy reduced the risk of microvascular complications compared with conventional therapy in patients with type 2 diabetes.³ However, intensive therapy with insulin, sulfonylureas or both agents did not improve macrovascular outcomes but did result in the greatest weight gain.^3,20 In contrast, intensively treated patients assigned to metformin did not gain weight and had a 30% reduction in the risk of macrovascular events compared with conventionally treated patients.^3,20 Even so, the reduction in macrovascular risk with metformin did not significantly differ from the change in risk seen with the other groups receiving intensive treatment.

Weight gain accompanying intensive insulin therapy in type 2 diabetes may cause a vicious cycle of escalating insulin doses and increasing obesity risks: Weight rises with improved control, which increases insulin resistance, causing the need for more intensive insulin regimens and higher insulin doses.⁷ The use of higher doses of insulin can lead to additional weight gain, continuing the cycle. Because effective glycemic control is the primary objective of diabetes therapy, regardless of its effects on weight, this cycle can be difficult to break for many patients with type 2 diabetes.

Moreover, weight gain with insulin therapy may cause distress among patients with diabetes who are asked to lose weight or maintain their current weight.⁵ Increases in weight also may reduce patients' acceptance of and adherence to intensive therapy, justifying the avoidance or delay of insulin therapy.⁷ Weight gain that results in obesity also may have psychologic consequences, such as poor self-esteem, an increased incidence of depression and negative effects on well-being.²¹

Insulin Therapy and Weight Gain

In clinical trials of patients with type 2 diabetes, intensive insulin therapy has been associated with weight increases of up to about 8 kg in the first year of therapy.²² Patients who received insulin therapy in the UKPDS gained approximately 4.0 kg more than patients receiving conventional treatment (Figure).³ Typically, the degree of weight gain increases proportionately with increasing daily insulin doses and the degree of improvement in glycosylated hemoglobin (A1C).²³ Although the amount of weight gain with insulin therapy is variable, each 1% reduction in A1C with insulin is generally associated with a 2 kg increase in weight.^22,24-26

In individuals without diabetes, basal insulin secretion occurs at a low rate, while large peaks in serum insulin levels at mealtime limit postprandial glucose excursions. Therefore, the most physiologic insulin regimens are those that use a basal insulin and bolus injections of a rapid-acting insulin analog at mealtimes. In the past, NPH was used to meet basal insulin requirements in patients with diabetes; however, its relatively short duration of action, distinct peak of action and unpredictable action profile limit its utility and tolerability.^27,28 The newer long-acting insulin analogs, insulin glargine and insulin detemir, were developed to address these limitations by providing relatively peakless insulin coverage that lasts up to 24 hours.^27-30 Insulin therapies used to meet postprandial insulin requirements include regular human insulin and the rapid-acting insulin analogs—insulin lispro, insulin aspart and insulin glulisine.

It has been suggested that long-acting insulin therapies may be primarily responsible for increases in body fat mass with insulin therapy, while combination therapy with long-acting and mealtime insulin therapies may be associated with the greatest increases in weight.^12,31,32 Most studies have reported that weight gain is similar with insulin glargine and NPH.^25,26,33 For instance, in a treat-to-target trial comparing the addition of insulin glargine or NPH insulin with therapy with oral agents, both treatments produced similar increases in weight (approximately 3.0 kg with both treatments) and equivalent glycemic control (A1C of 7.0% at endpoint in both groups), although insulin glargine was associated with a reduced risk of hypoglycemia.²⁵

Causes of Weight Gain With Insulin

A number of mechanisms have been proposed to explain the impact of insulin therapy on weight, including the reduction of glycosuria and resulting retention of energy, the anabolic effects of insulin, increased appetite and "defensive" eating to avoid hypoglycemia.⁵ Retrospective data indicate that weight loss occurs in patients with poorly controlled glycemia. Therefore, weight gain following initiation of insulin may compensate for weight lost because of glucosuria.^34,35 When glycemic control is achieved with insulin therapy, improvement in glycemia increases the likelihood that excess energy will be retained as fat owing to increased glucose uptake in peripheral tissues.⁷ Weight gain also might result from the tendency of subcutaneous insulin to exert peripheral rather than hepatic effects, which may increase the tendency of excess energy intake to be retained and stored as fat.⁷

Insulin therapy has anabolic effects on adipose and muscle tissue, which leads to water and sodium retention. When patients using intensive insulin therapy experience mild hypoglycemia, it can stimulate appetite and increase food intake.^5,36-38 Patients using insulin who fear hypoglycemia also may increase their food intake to prevent hypoglycemia.³⁸ All of these factors may contribute to the associated weight gain.^34,39,40

Weight Interventions With Insulin

Multiple strategies have been used to control weight in patients with type 2 diabetes beginning insulin therapy. The most important interventions are lifestyle modifications that include diet and exercise. Diet and exercise should be recommended early in the management of type 2 diabetes and be continued throughout the patient's management, especially for the overweight or obese.

Insulin Detemir

Insulin detemir is a relatively new, long-acting, soluble insulin analog approved for use as basal therapy in patients with type 1 and type 2 diabetes. In numerous clinical trials, insulin detemir has been consistently associated with less weight gain than NPH (Table).^13-16,41,43

In patients with type 2 diabetes, 26 weeks of basal-bolus therapy with insulin detemir and insulin aspart was associated with less weight gain than therapy with NPH insulin and insulin aspart (1.0 vs. 1.8 kg, P = 0.017), even though comparable improvements in A1C were observed (-0.2% with detemir and -0.4% with NPH).¹⁴ Similar findings were reported when insulin detemir and insulin aspart were compared with NPH insulin and regular human insulin.¹³

A treat-to-target study of insulin detemir or NPH insulin added to oral hypoglycemic agents (OHAs) also reported less weight gain with insulin detemir (1.2 vs. 2.8 kg, P < 0.001).15 Insulin doses were aggressively titrated to achieve FPG ² 108 mg/dL. Although both insulin detemir and NPH produced excellent glycemic control (mean A1C at endpoint: 6.8% for detemir and 6.6% for NPH), the risk of overall hypoglycemia and nocturnal hypoglycemia with insulin detemir was reduced by approximately 50% compared with NPH (P < 0.001). Moreover, a post hoc analysis found that the weight benefit of detemir increased with baseline body mass index (BMI): as BMI at baseline increased, weight gain with insulin detemir decreased.⁴⁴ This trend was not observed with NPH.

Another recent treat-to-target trial compared the efficacy and tolerability of insulin detemir and insulin glargine when added to OHAs in patients with type 2 diabetes.¹⁶ In this study, similar improvements in A1C (1.4% vs. 1.5% with detemir and glargine, respectively) and FPG (Ð67 vs. Ð68 mg/dL) were observed with both treatments; however, patients receiving insulin glargine gained significantly more weight (3.9 vs. 3.0 kg, P = 0.012) than with insulin detemir over the course of this 52-week trial. Both groups reported a similar incidence of overall and nocturnal hypoglycemia.

These findings suggest that insulin detemir may offer a significant weight advantage, particularly in patients with type 2 diabetes who are overweight or obese at baseline.^13-16

Although the mechanism underlying the more favorable impact of insulin detemir on weight is still under investigation, several hypotheses that attempt to explain its weight profile have been proposed. For example, it has been suggested that the more physiologic and more predictable profile of insulin activity seen with insulin detemir,^14,30,45 which likely results from its unique mechanism of protraction,⁴⁶ may affect its impact on weight. Unlike NPH insulin or insulin glargine, which precipitate in solution and after administration, respectively, insulin detemir remains soluble, eliminating the potential variability that can result from dissolution of the precipitate.⁴⁶ The extended duration of action of insulin detemir results from its ability to self-associate and reversibly bind to albumin.46 This mechanism of protraction provides a long, relatively flat insulin time-action profile with a more consistent and predictable glycemic effect than NPH and glargine.^29,30 More predictable insulin profiles may reduce the risk of hypoglycemia and the need for increased food intake to prevent or treat hypoglycemia.

The ability of insulin detemir to bind to plasma albumin,⁴⁶ leading to preferential insulin activity in the liver relative to the periphery, could also be responsible for its beneficial or weight-neutral action.⁷ It also has been speculated that insulin detemir may cross the blood-brain barrier more easily and thus act on central nervous system receptors more effectively than do other exogenous insulin therapies, thus leading to appetite reduction.⁷

Combination Hypoglycemic Therapy

Another strategy to limit weight gain in patients with type 2 diabetes using insulin is to combine insulin therapy with agents that exert a favorable impact on weight, such as metformin and the amylin analog pramlintide.

Metformin. Continuing therapy with metformin frequently is recommended as a way of limiting weight gain in individuals beginning insulin therapy.^5,17,47 Clinical trials have demonstrated that combining metformin with insulin therapy attenuates weight gain, reduces the risk of hypoglycemia, reduces insulin requirements and produces significantly greater glycemic control compared with insulin alone.^17,47 In one study comparing NPH at bedtime, in combination with either glyburide, metformin, glyburide and metformin, or with a second injection of NPH in the morning, body weight remained unchanged with metformin but increased by approximately 3 kg to 5 kg in all other groups (including the group receiving glyburide and metformin) after one year.¹⁷ The group receiving metformin as the only oral agent also experienced the greatest decrease in A1C and the fewest episodes of hypoglycemia.

Pramlintide. Amylin is a glucoregulatory hormone that is normally secreted with insulin in response to meals. Amylin is deficient in patients with diabetes.48 Complementing the effects of insulin, amylin regulates the rate of glucose entry into the circulation, suppressing postprandial glucagon secretion and slowing gastric emptying.^48-51 Amylin may also regulate food intake and body weight.

Recent studies have demonstrated that adding pramlintide, an amylin agonist, to insulin in patients with type 2 diabetes produces improved glycemic control with concomitant weight loss.^18,48 In one such study, patients treated with pramlintide 120 mcg twice daily for one year experienced a weight loss of 1.4 kg (vs. a gain of 0.7 kg with placebo, P < 0.05) and a sustained reduction in A1C (-0.62% vs. -0.2% with placebo, P < 0.05).18 Pramlintide is indicated as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.

Weight-loss medications. Medications used to facilitate weight loss, such as orlistat, have been investigated in combination with insulin in overweight and obese patients with type 2 diabetes. In a one-year study of 535 obese insulin-treated patients with suboptimal metabolic control (mean BMI at baseline, 36 kg/m2), patients receiving orlistat lost 3.9 kg of their body weight at baseline, while patients receiving placebo lost only 1.3 kg (P < 0.001).52 Use of orlistat with insulin also produced greater decreases in A1C (-0.6% vs. -0.3%; P = 0.002) and FPG (Ð29 vs. Ð19 mg/dL).

Bariatric surgery. Weight loss is a fundamental component of managing diabetes, particularly in morbidly obese patients. Bariatric surgery is among the most successful strategies for weight loss in these patients. Studies of obese patients with type 2 diabetes have demonstrated that gastric bypass surgery can produce significant weight loss, euglycemia and restoration of insulin sensitivity.^53,54 One trial of the impact of gastric bypass one year or more after surgery in morbidly obese patients with type 2 diabetes reported weight reductions of 32.6% and A1C reductions of 5.4% (P < 0.05) compared with baseline.⁵³ In fact, 89% of patients were able to discontinue oral hypoglycemic therapies, insulin or both after surgery.

Conclusions

Weight gain is a significant drawback of the pharmacologic management of type 2 diabetes. Significant increases in weight are common particularly among patients using insulin therapy. Although the benefits of effective glycemic control with insulin therapy in reducing the risk of diabetes complications are clear, reluctance to initiate or intensify insulin due to a fear of weight gain may lead to suboptimal therapy. In addition, because weight gain may adversely affect cardiovascular risk, patient adherence, and potentially, long-term outcomes and complicate diabetes treatment, minimizing increases in weight is an important part of managing type 2 diabetes.

Therefore, agents that limit weight gain, promote weight loss or both while improving glycemic control in patients with type 2 diabetes may facilitate patient management and improve patient outcomes. New agents in development, such as rimonabant, the first selective blocker of the endocannabinoid receptor, may be a promising treatment option for obese patients with type 2 diabetes desiring weight loss.

The relatively new basal insulin analog, insulin detemir, provides effective glycemic control without significant weight gain, possibly due to its increased predictability and more consistent profile of insulin action. Combining insulin therapy with metformin, pramlintide, weight loss medications or, in the very obese, bariatric surgery may also maintain or significantly reduce weight while improving glycemic control. The neutral or positive effects of these interventions on weight, along with their beneficial effects on glycemic control, may help improve the short-term and long-term health of patients with type 2 diabetes.

Dwight Deter is a physician assistant with Southwest Endocrine Consultants in El Paso, Texas.

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