Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes

Abstract

BackgroundOverweight or obesity contributes to the development of type 2 diabetes mellitus (T2DM) and increases cardiovascular risk. Exenatide, a glucagon-like peptide-1 receptor agonist, significantly reduces glycated hemoglobin (A1C) and body weight and improves cardiovascular risk markers in patients with T2DM. As weight loss alone has been shown to reduce A1C and cardiovascular risk markers, this analysis explored whether weight loss contributed importantly to clinical responses to exenatide once weekly.MethodsA pooled analysis from eight studies of exenatide once weekly was conducted. Patients were distributed into quartiles from greatest weight loss (Quartile 1) to least loss or gain (Quartile 4). Parameters evaluated for each quartile included A1C, fasting plasma glucose (FPG), blood pressure (BP), heart rate, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).ResultsThe median changes from baseline in body weight in Quartiles 1–4 were −6.0, –3.0, −1.0, and +1.0 kg, respectively. All quartiles had reductions in A1C (median changes −1.6, −1.4, −1.1, and −1.2%, respectively) and FPG (−41, −40, −31, and −25 mg/dL, respectively), with the greatest decreases in Quartiles 1 and 2. Most cardiovascular risk markers (except diastolic BP) and liver enzymes improved in Quartiles 1 through 3 and were relatively unchanged in Quartile 4. Higher rates of gastrointestinal adverse events and hypoglycemia were observed in Quartile 1 compared with Quartiles 2 through 4.ConclusionsExenatide once weekly improved glycemic parameters independent of weight change, although the magnitude of improvement increased with increasing weight loss. The greatest trend of improvement in glycemic parameters, cardiovascular risk factors including systolic BP, LDL-C, total cholesterol, and triglycerides, and in liver enzymes, was seen in the patient quartiles with the greatest reductions in body weight.

Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial

“…The effect on HbA1c was larger than in most RCTs [31] because patients randomized to placebo experienced a worsening in glycemic control. Intuitively, a significant decline in body weight is expected to be accompanied by improvements in the lipid profile, as observed with GLP-1 receptor agonists [32–34]. It is also noteworthy that the effects on HDL may be differ according to the ethnic group, as observed for metformin [35].…”

Unexplained reciprocal regulation of diabetes and lipoproteins

“…These drugs have been found to modestly improve lipoprotein profiles, by reducing chylomicron production, without affecting lipoprotein clearance [75–77]. The molecular mechanisms are unclear, but may be pharmacologic, as endogenous GLP-1 and GLP-2 appear to be minor contributors to postprandial chylomicron production [78].…”

The Clinical Impact of GLP-1 Receptor Agonists in Type 2 Diabetes: Focus on the Long-Acting Analogs

“…The gastrointestinal side effects are less frequent and mild than for the other GLP-1 RAs, presumably because the final therapeutic blood level is achieved relatively slowly due to the gradual accumulation of the peptide over a period of up to 6-7 weeks. The phase 3 clinical trials of exenatide ER, consisting of six studies, were designated as the DURATION studies, [27][28][29][30][31][32][33][34][35][36] (Table 2). These included two randomized placebo-controlled trials 27,31 and four open-label studies.…”