Treating the Obese Diabetic

Julia Kenkre; Tricia Tan; Stephen Bloom

Expert Rev Clin Pharmacol. 2013;6(2):171-183.

Abstract and Introduction

Abstract

Type 2 diabetes and obesity are intimately linked; reduction of bodyweight improves glycemic control, mortality and morbidity. Treating obesity in the diabetic is hampered as some diabetic treatments lead to weight gain. Bariatric surgery is currently the most effective antiobesity treatment and causes long-term remission of diabetes in many patients. However, surgery has a high cost and is associated with a significant risk of complications, and in practical terms only limited numbers can undergo this therapy. The choice of pharmacological agents suitable for treatment of diabetes and obesity is currently limited. The glucagon-like peptide-1 receptor agonists improve glycemia and induce a modest weight loss, but there are doubts over their long-term safety. New drugs such as lorcaserin and phentermine/topiramate are being approved for obesity and have modest, salutary effects on glycemia, but again long-term safety is unclear. This article will also examine some future avenues for development, including gut hormone analogues that promise to combine powerful weight reduction with beneficial effects on glucose metabolism.

Introduction

According to the International Diabetes Federation, Type 2 diabetes had a worldwide prevalence of 366 million in 2011. This is predicted to rise to 552 million by 2030.^[201] There is a well-known close association between Type 2 diabetes and obesity frequently expressed by the term 'diabesity'.^[1] It is currently challenging to treat coexistent Type 2 diabetes and obesity because some antidiabetic agents, including thiazolidinediones (TZDs), insulin and sulphonylureas (SUs), are associated with weight gain, meaning that Type 2 diabetics are at risk of a vicious circle of increasing weight and increasing insulin resistance, thus requiring further intensification of glycemic treatment.

In this report, the authors will examine the role of current diabetes treatments on weight, together with the impact of newly introduced treatments for obesity on comorbid diabetes. The authors will then discuss the potential promise that gut hormone-based strategies hold for the treatment of diabesity.

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Next Section

Abstract and Introduction
Effect of Current Diabetic Medications on Weight
GLP-1 Analogues
DPP-IV Inhibitors
Sodium–Glucose Cotransporter 2 Inhibitors
The Effect of Antiobesity Treatments on Glycemic Control
Pharmacological Treatments
Expert Commentary
Five-year View
References
Sidebar

Table 1. Glycemic and bodyweight changes observed with current antidiabetic medication.
Medication	Mechanism of action	Medication	Expected decrease in HbA1c (%)	Range of weight change seen (kg)	Main side effects	Comments	Ref.
MF	Inhibition of hepatic gluconeogenesis and glycogenolysis, and insulin sensitizer	MF vs placebo MF vs SU	WMD: 0.9 (95% CI: 1.1–0.7)No significant difference	No significant difference-1.2 vs +1.7	Gastrointestinal side effects, usually transient. May impair absorption of folic acid and vitamin B12.Rarely lactic acidosis	UKPDS study: reduced CV mortality	[2,3]
SUs	Bind to the ATP-sensitive potassium channel leading to depolarization, calcium channel opening and ultimately insulin release		1–2	+1 to +5	Hypoglycemia	In combination with metformin, increased risk of CV hospitalization or mortality	[4–7]
TZDs	Modulation of PPAR-γ		0.5–1.4	+1 to +5	Edema and heart failure, bone loss and fracture, bladder cancer		[5,8]
Pramlintide	Synthetic amylin analogue that delays gastric emptying and suppresses glucagon release	In addition to existing insulin	0.33	-2.2 to -2.6	Nausea, hypoglycemia	USA only	[9]
Colesevelam	Bile acid sequestrant; unclear mechanism leading to improvement of glycemia	In addition to existing MF, SU or insulin	0.5	Weight neutral	Bloating, constipation, dyspepsia, raised triglycerides	USA only. LDL lowering effect	[10]
Bromocriptine quick release	Dopamine receptor agonist thought to increase suppression of hepatic glucose output by a central action	In addition to MF, TZDs, SUs or diet alone	0.5–0.7	Weight neutral	Nausea, dizziness, fatigue, headache, gastrointestinal side effects	USA only. Rare reports of worsening psychosis. Association of ergot-derived dopamine agonists with pulmonary, retroperitoneal and pericardial fibrosis	[11]
Insulin	Stimulation of the insulin receptor		1.5–3.5	Approximately +4	Hypoglycemia		[8,12,13]
GLP-1 analogues	Stimulation of the GLP-1 receptor leading to insulin release, suppression of glucagon and delayed gastric emptying		0.5–1	WMD: -2.8	Gastrointestinal: nausea and vomiting. Pancreatitis (rare)	C-cell hyperplasia and adenomas in rodents. Possible positive effect on β-cell survival	[8,14]
DPP-IV inhibitors	Reduced breakdown of GLP-1		0.5–0.8	Weight neutral	URTI, UTI, headache	Hypothetical concern about effect on immune function	[8,15,42]
SGLT2 inhibitors	Prevents glucose reabsorption at the sodium–glucose cotransporter, thus increasing renal loss		Phase III trial data suggests placebo-subtracted reductions of 0.5–0.7	Early weight loss of 2–3, unclear if sustained	Genitourinary infections, constipation, diarrhea, nausea, hypoglycemia	Concern about possible increased risk of bladder and breast cancer	[16–18]

CV: Cardiovascular; HbA_1c: Glycated hemoglobin; MF: Metformin; SU: Sulphonylurea; TZD: Thiazolidinedione; URTI: Upper respiratory tract infection; UTI: Urinary tract infection; WMD: Weighted mean difference.

Table 2. Features of currently available DPP-IV inhibitors.
Drug	Indications	Decrease in HbA_1c (%)	Δ in bodyweight (kg)	Comments and adverse events	Ref.
Sitagliptin	USA: monotherapy, or added to MF or TZD EU: monotherapy, or added to MF, TZD, SU, MF + SU, insulin	WMD vs placebo: 0.82 (95% CI: 0.95–0.70)	-0.4 to +0.6	Infections including URTI and UTI, headache, nausea in combination with MF, leg swelling in combination with TZD, hypoglycemia in combination with SU. Potential increased risk of pancreatitis	[115,116]
Saxagliptin	Monotherapy or added to MF, TZD, SU, MF + SU, insulin	WMD vs placebo: 0.70 (95% CI: 0.84–0.56)	-0.4	URTI, UTI, headache. Peripheral edema in combination with TZD. Hypoglycemia in combination with insulin or SU. Postmarketing reports of acute pancreatitis and hypersensitivity reactions	[115]
Vildagliptin	In combination with MF, SU or TZD	0.6	WMD: 0.56 (95% CI: 0.27–0.84)	EU only. Hypoglycemia when used in combination. Liver enzyme rises at higher doses. Headache. Potential increased risk of pancreatitis	[42,116]
Linagliptin	Monotherapy or combination with MF, SU and TZD Nonrenal excretion, therefore no dose adjustment in renal failure	0.47–0.69 in placebo-controlled trials	Not associated with weight gain except in combination with TZDs	Hypoglycemia in combination with SU. Nasopharyngitis, cough, hyperlipidemia, hypertriglyceridemia. Potential increased risk of pancreatitis	[117]
Alogliptin	Approved for use as a monotherapy or in combination with TZD or α-glucosidase inhibitors	WMD vs placebo: 0.48 (12.5 mg dose), 0.55 (25 mg dose)	WMD: +0.23 (12.5 mg dose), +0.13 (25 mg dose)	Japan only. Dry skin, rash, eczema and pruritis, nasopharyngitis, headache and URTI	[118,119]

HbA_1c: Gylcated hemoglobin; MF: Metformin; SU: Sulphonylurea; TZD: Thiazolidinedione; URTI: Upper respiratory tract infection; UTI: Urinary tract infection; WMD: Weighted mean difference.

Table 3. Complications of bariatric surgery.
Procedure	30-day operative mortality (%)	Postoperative complications	Ref.
VGB/GB	0.1	Early vomiting, food particle lodging within the band, band eroding into the stomach, leaks, weight regain, port site infection, band prolapse, pouch–esophageal dilatation	[65,120,121,122]
RYGB	0.5	Dumping syndrome, vitamin and mineral deficiency, abdominal pain, small bowel or Roux limb obstruction which can lead to gastric dilatation, cholelithiasis, anastomotic stricture, wound infection, anastomotic leaks, gastric ulceration and internal hernias	[65,120,121,122]
BPD/DS	1.1	Vitamin, mineral and macronutrient deficiencies, diarrhea and flatulence, abdominal pain, anastomotic leak, gastric ulceration, intestinal obstruction, cholelithiasis, renal calculi	[65,120,121,122]
Sleeve gastrectomy	0.11	Anastomotic leak, gastroesophageal reflux, gastric distension, nutritional deficiency	[65,120,121,123]