Cardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus: Part 2.

Ideal drugs to improve outcomes in type 2 diabetes mellitus (T2DM) are those with antiglycemic efficacy, as well as cardiovascular safety that has to be determined in appropriately designed cardiovascular outcome trials as mandated by regulatory agencies. The more recent antihyperglycemic medications have shown promise with regards to cardiovascular disease (CVD) risk reduction in T2DM patients at a high cardiovascular risk. Sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists are associated with better cardiovascular outcomes and mortality in T2DM patients than are dipeptidylpeptidase-4 inhibitors, leading to the Food and Drug Administration's approval of empagliflozin to reduce mortality, and of liraglutide to reduce CVD risk in high-risk T2DM patients. For heart failure outcomes, sodium glucose cotransporter-2 inhibitors are beneficial, while glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are neutral. Ongoing and planned randomized controlled trials of these newer drugs should clarify the possibility of class effects and of CVD risk reduction benefits in low-moderate cardiovascular risk patients. While we eagerly await the results on ongoing studies, these medications should be appropriately prescribed in T2DM patients with baseline CVD or those at a high CVD risk after carefully evaluating the elevated risk for adverse events like gastrointestinal disturbances, bladder cancer, genital infections, and amputations. Studies to understand the pleotropic and novel pathophysiological mechanisms demonstrated by the sodium glucose cotransporter-2 inhibitors will shed light on the effects of the modulation of microvascular, inflammatory, and thrombotic milieu for improving the CVD risk in T2DM patients. This is part 2 of the series on noninsulin antihyperglycemic drugs for the treatment of T2DM.

Cardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus-Part 1.

Cardiovascular disease (CVD) is a major contributor to the morbidity and mortality associated with type 2 diabetes mellitus (T2DM). With T2DM growing in pandemic proportions, there will be profound healthcare implications of CVD in person with diabetes. The ideal drugs to improve outcomes in T2DM are those having antiglycemic efficacy in addition to cardiovascular (CV) safety, which has to be determined in appropriately designed CV outcome trials as mandated by regulatory agencies. Available evidence is largely supportive of metformin's CV safety and potential CVD risk reduction effects, whereas sulfonylureas are either CV risk neutral or are associated with variable CVD risk. Pioglitazone was also associated with improved CVD risk in patients with diabetes. The more recent antihyperglycemic medications have shown promise with regards to CVD risk reduction in T2DM patients at a high CV risk. Glucagon-like peptide-1 receptor agonists, a type of incretin-based therapy, were associated with better CV outcomes and mortality in T2DM patients, leading to the Food and Drug Administration approval of liraglutide to reduce CVD risk in high-risk T2DM patients. Ongoing and planned randomized controlled trials of the newer drugs should clarify the possibility of class effects, and of CVD risk reduction benefits in low-moderate CV risk patients. While metformin remains the first-line antiglycemic therapy in T2DM, glucagon-like peptide-1 receptor agonists should be appropriately prescribed in T2DM patients with baseline CVD or in those at a high CVD risk to improve CV outcomes. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors are discussed in the second part of this review.

Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus.

Diabetes mellitus is a growing in exponential proportions. If the current growth trend continues, it may result in every third adult in the United States having diabetes mellitus by 2050, and every 10th adult worldwide. Type 2 diabetes mellitus (T2DM) confers a 2- to 3-fold increased risk of cardiovascular (CV) events compared with non-diabetic patients, and CV mortality is responsible for around 80% mortality in this population. Patients with T2DM can have other features of insulin resistance-metabolic syndrome like hypertension, lipid abnormalities, and obesity which are all associated with increased CV disease and stroke risk even in the absence of T2DM. The management of a T2DM calls for employing a holistic risk factor control approach. Metformin is the first line therapy for T2DM and has been shown to have cardiovascular beneficial effects. Intense debate regarding the risk of myocardial infarction with rosiglitazone led to regulatory agencies necessitating cardiovascular outcome trials with upcoming anti-diabetic medications. Glucagon like peptide-1 agonists and sodium glucose co-transporter-2 inhibitors have shown promising CV safety and additional CV benefit in recent clinical trials. These drugs have favorable effects on traditional CV risk factors. The findings from these studies further support that fact that CV risk factor control plays an important role in reducing morbidity and mortality in T2DM patients. This review article will discuss briefly the cardiovascular safety and benefits of the oral medications which are currently being used for T2DM and will then discuss in detail about the newer medications being investigated for the treatment of T2DM.

Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes.

Suppression of GABAergic neurotransmission in the ventromedial hypothalamus (VMH) is crucial for full activation of counterregulatory responses to hypoglycemia, and increased γ-aminobutyric acid (GABA) output contributes to counterregulatory failure in recurrently hypoglycemic (RH) and diabetic rats. The goal of this study was to establish whether lactate contributes to raising VMH GABA levels in these two conditions. We used microdialysis to deliver artificial extracellular fluid or L-lactate into the VMH and sample for GABA. We then microinjected a GABAA receptor antagonist, an inhibitor of lactate transport (4CIN), or an inhibitor of lactate dehydrogenase, oxamate (OX), into the VMH prior to inducing hypoglycemia. To assess whether lactate contributes to raising GABA in RH and diabetes, we injected 4CIN or OX into the VMH of RH and diabetic rats before inducing hypoglycemia. L-lactate raised VMH GABA levels and suppressed counterregulatory responses to hypoglycemia. While blocking GABAA receptors did not prevent the lactate-induced rise in GABA, inhibition of lactate transport or utilization did, despite the presence of lactate. All three treatments restored the counterregulatory responses, suggesting that lactate suppresses these responses by enhancing GABA release. Both RH and diabetic rats had higher baseline GABA levels and were unable to reduce GABA levels sufficiently to fully activate counterregulatory responses during hypoglycemia. 4CIN or OX lowered VMH GABA levels in both RH and diabetic rats and restored the counterregulatory responses. Lactate likely contributes to counterregulatory failure in RH and diabetes by increasing VMH GABA levels.

Modulation of ß-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia.

OBJECTIVE: Norepinephrine is locally released into the ventromedial hypothalamus (VMH), a key brain glucose-sensing region in the response to hypoglycemia. As a result, this neurotransmitter may play a role in modulating counterregulatory responses. This study examines whether norepinephrine acts to promote glucose counterregulation via specific VMH ß-adrenergic receptors (BAR). RESEARCH DESIGN AND METHODS: Awake male Sprague-Dawley rats received, via implanted guide cannulae, bilateral VMH microinjections of 1) artificial extracellular fluid, 2) B2AR agonist, or 3) B2AR antagonist. Subsequently, a hyperinsulinemic-hypoglycemic clamp study was performed. The same protocol was also used to assess the effect of VMH delivery of a selective B1AR or B3AR antagonist. RESULTS: Despite similar insulin and glucose concentrations during the clamp, activation of B2AR in the VMH significantly lowered by 32% (P < 0.01), whereas VMH B2AR blockade raised by 27% exogenous glucose requirements during hypoglycemia (P < 0.05) compared with the control study. These changes were associated with alternations in counterregulatory hormone release. Epinephrine responses throughout hypoglycemia were significantly increased by 50% when the B2AR agonist was delivered to the VMH (P < 0.01) and suppressed by 32% with the B2AR antagonist (P < 0.05). The glucagon response was also increased by B2AR activation by 63% (P < 0.01). Neither blockade of VMH B1AR nor B3AR suppressed counterregulatory responses to hypoglycemia. Indeed, the B1AR antagonist increased rather than decreased epinephrine release (P < 0.05). CONCLUSIONS: Local catecholamine release into the VMH enhances counterregulatory responses to hypoglycemia via stimulation of B2AR. These observations suggest that B2AR agonists might have therapeutic benefit in diabetic patients with defective glucose counterregulation.

Chronic reduction of insulin receptors in the ventromedial hypothalamus produces glucose intolerance and islet dysfunction in the absence of weight gain.

Insulin is believed to regulate glucose homeostasis mainly via direct effects on the liver, muscle, and adipose tissues. The contribution of insulin's central nervous system effects to disorders of glucose metabolism has received less attention. To evaluate whether postnatal reduction of insulin receptors (IRs) within the ventromedial hypothalamus (VMH), a brain region critical for glucose sensing, contributes to disorders of peripheral glucose metabolism, we microinjected a lentiviral vector expressing an antisense sequence to knockdown IRs or a control lentiviral vector into the VMH of nonobese nondiabetic rats. After 3-4 mo, we assessed 1) glucose tolerance, 2) hepatic insulin sensitivity, and 3) insulin and glucagon secretion, using the glucose clamp technique. Knockdown of IRs locally in the VMH caused glucose intolerance without altering body weight. Increments of plasma insulin during a euglycemic clamp study failed to suppress endogenous glucose production and produced a paradoxical rise in plasma glucagon in the VMH-IR knockdown rats. Unexpectedly, these animals also displayed a 40% reduction (P < 0.05) in insulin secretion in response to an identical hyperglycemic stimulus (∼220 mg/dl). Our data demonstrate that chronic suppression of VMH-IR gene expression is sufficient to impair glucose metabolism as well as α-cell and ß-cell function in nondiabetic, nonobese rats. These data suggest that insulin resistance within the VMH may be a significant contributor to the development of type 2 diabetes.

Increased GABAergic output in the ventromedial hypothalamus contributes to impaired hypoglycemic counterregulation in diabetic rats.

OBJECTIVE: Impaired glucose counterregulation during hypoglycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that the inhibitory neurotransmitter γ-aminobutyric acid (GABA), in a crucial glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), plays an important role in modulating the magnitude of the glucagon and epinephrine responses to hypoglycemia and investigated whether VMH GABAergic tone is altered in diabetes and therefore might contribute to defective counterregulatory responses. RESEARCH DESIGN AND METHODS: We used immunoblots to measure GAD(65) protein (a rate-limiting enzyme in GABA synthesis) and microdialysis to measure extracellular GABA levels in the VMH of two diabetic rat models, the diabetic BB rat and the streptozotocin (STZ)-induced diabetic rat, and compared them with nondiabetic controls. RESULTS: Both diabetic rat models exhibited an ~50% increase in GAD(65) protein as well as a twofold increase in VMH GABA levels compared with controls under baseline conditions. Moreover, during hypoglycemia, VMH GABA levels did not change in the diabetic animals, whereas they significantly declined in nondiabetic animals. As expected, glucagon responses were absent and epinephrine responses were attenuated in diabetic rats compared with their nondiabetic control counterparts. The defective counterregulatory response in STZ-diabetic animals was restored to normal with either local blockade of GABA(A) receptors or knockdown of GAD(65) in the VMH. CONCLUSIONS: These data suggest that increased VMH GABAergic inhibition is an important contributor to the absent glucagon response to hypoglycemia and the development of counterregulatory failure in type 1 diabetes.

Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo.

OBJECTIVE: Insulin released by the beta-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention. RESEARCH DESIGN AND METHODS: Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 microU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions. RESULTS: As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist. CONCLUSIONS: Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.

Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose counterregulatory responses during hypoglycemia.

Local delivery of glucose into a critical glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), can suppress glucose counterregulatory responses to systemic hypoglycemia. Here, we investigated whether this suppression was accomplished through changes in GABA output in the VMH. Sprague-Dawley rats had catheters and guide cannulas implanted. Eight to ten days later, microdialysis-microinjection probes were inserted into the VMH, and they were dialyzed with varying concentrations of glucose from 0 to 100 mM. Two groups of rats were microdialyzed with 100 mM glucose and microinjected with either the K(ATP) channel opener diazoxide or a GABA(A) receptor antagonist. These animals were then subjected to a hyperinsulinemic-hypoglycemic glucose clamp. As expected, perfusion of glucose into the VMH suppressed the counterregulatory responses. Extracellular VMH GABA levels positively correlated with the concentration of glucose in the perfusate. In turn, extracellular GABA concentrations in the VMH were inversely related to the degree of counterregulatory hormone release. Of note, microinjection of either diazoxide or the GABA(A) receptor antagonist reversed the suppressive effects of VMH glucose delivery on counterregulatory responses. Some GABAergic neurons in the VMH respond to changes in local glucose concentration. Glucose in the VMH dose-dependently stimulates GABA release, and this in turn dose-dependently suppresses the glucagon and epinephrine responses to hypoglycemia. These data suggest that during hypoglycemia a decrease in glucose concentration within the VMH may provide an important signal that rapidly inactivates VMH GABAergic neurons, reducing inhibitory GABAergic tone, which in turn enhances the counterregulatory responses to hypoglycemia.