Optimizing diabetes treatment in the presence of obesity
ABSTRACT
Evidence of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes has led to a search for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c, but also have weight loss as a potential side effect. The authors review medications approved for the treatment of type 2 diabetes mellitus (including pramlintide, also approved for type 1 diabetes) that also have weight loss as a side effect. Drugs discussed include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, the authors comment on the cardiovascular effects of these drugs.
KEY POINTS
- The rationale for GLP-1 receptor agonists is that peripheral GLP-1 activates a cascade of centrally mediated signals that ultimately result in secretion of insulin by the pancreas and slowing of gastrointestinal motility. It also exerts an anorexic effect by acting on central pathways that mediate satiation.
- SGLT-2 inhibitors have relatively weak glycemic efficacy. Inhibition of SGLT-2 alleviates hyperglycemia by decreasing glucose reabsorption in the kidneys and by increasing excretion in the urine, suggesting urinary loss of glucose (and hence caloric loss). This is thought to contribute to weight reduction in addition to initial weight loss from fluid loss due to osmotic diuresis.
- Meta-analyses so far have shown that alpha-glucosidase inhibitors have either a neutral or a beneficial effect on body weight.
ALPHA-GLUCOSIDASE INHIBITORS
Mechanism of action
Alpha-glucosidase inhibitors competitively inhibit the alpha-glucosidase enzymes at the brush border of the small intestine. Taken orally before meals, these drugs mitigate postprandial hyperglycemia by preventing the breakdown of complex carbohydrates into simpler monosaccharides, thus delaying their absorption.47 These agents may be used as monotherapy or in combination with other antihyperglycemic agents. They work independently from insulin, although they have been shown to potentiate GLP-1 secretion.48 Acarbose and miglitol are currently approved in the United States. Acarbose has been more extensively studied worldwide.
HbA1c
Alpha-glucosidase inhibitors have been reported to reduce mean HbA1c by 0.8% (95% CI −0.9% to −0.7%), as well as fasting and postprandial glucose, and postprandial insulin levels.49
Weight loss
There is conflicting evidence on whether alpha-glucosidase inhibitor therapy has a neutral or beneficial effect on body weight. A Cochrane meta-analysis observed significant BMI reduction with acarbose, although no effect on body weight was noted,49 whereas in another meta-analysis, body weight was significantly reduced by 0.96 kg (95% CI −1.80 to −0.12 kg) when acarbose was added to metformin.50 A review of pooled data from worldwide post-marketing studies for acarbose reported a weight reduction after 3 months of 0.98 ± 2.11 kg in overweight patients and 1.67 ± 3.02 kg in obese patients.51
Cardiovascular outcomes
In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), when compared with placebo, treatment of patients with impaired glucose tolerance with acarbose significantly reduced the incidence of cardiovascular events (HR 0.51, 95% CI 0.28 to 0.95, P = .03), myocardial infarction (HR 0.09, 95% CI 0.01 to 0.72, P = .02), and newly diagnosed hypertension (HR 0.66, 95% CI 0.49 to 0.89, P = .006).52
Adverse effects
Although mild, gastrointestinal effects of flatulence and diarrhea can be bothersome and result in discontinuation of the drug in most patients.
METFORMIN
Mechanism of action
Metformin is the first-line antihyperglycemic agent for type 2 DM recommended by the American Diabetes Association and European Association for the Study of Diabetes.53,54 The main action of metformin is to decrease glucose production in the liver. In the small intestine, metformin stimulates the L cells to produce GLP-1, and in skeletal muscle, it increases glucose uptake and disposal.55
HbA1c
As monotherapy, metformin has resulted in HbA1c reductions of 0.88% to 1.2%.55
Weight loss
Reduced food intake56,57 and gastrointestinal intolerance58 occurring early in therapy have been noted to account for weight loss in short-term studies of non-diabetic obese patients treated with metformin.59 Long-term trials of patients with and without diabetes have yielded mixed results on weight reduction from metformin as monotherapy or adjunct therapy. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin had resulted in approximately 1.5 kg of weight gain (slightly less than the 4-kg weight gain in the glibenclamide group).60 Improved antihyperglycemic efficacy of other antihyperglycemic agents (insulin, sulfonylureas, and thiazolidinediones) with addition of metformin led to dose-lowering of the antihyperglycemic agents, ultimately resulting in amelioration of weight gain; this has also led to small weight reductions in some studies.59 In the Diabetes Prevention Program study of patients with impaired glucose tolerance, metformin treatment resulted in an average weight loss of 2.1 kg compared with placebo (−0.1 kg) and lifestyle intervention (−5.6 kg; P <.001).61
Cardiovascular outcomes
Metformin has been observed to decrease micro- and macrovascular complications. Compared with diet alone, metformin was associated with a 39% reduction in the risk of myocardial infarction, and a 30% lower risk of a composite of macrovascular diseases (myocardial infarction, sudden death, angina, stroke, and peripheral disease).60
Adverse effects
The most common adverse effect of metformin is gastrointestinal intolerance from abdominal pain, flatulence, and diarrhea.62 Metformin-associated lactic acidosis is a serious and potentially life-threatening effect; and vitamin B12 deficiency may occur with long-term treatment.62
TAKE-HOME POINTS
As more medications and interventions are being developed to counter obesity, it also makes sense to select diabetes medications that do not contribute to weight gain in patients who are already overweight or obese. The effects of available medications can be maximized and treatment regimens individualized (based on patients’ needs and preferences, within the limitations of drug costs and side effects), along with lifestyle modification, to target diabesity.
