Intensifying Therapy in Type 2 Diabetes: Sequential Insulin Strategies

1. Approaches to Intensifying Therapy in Patients Not At Goal on Basal Insulin

2. Adding Prandial Insulin to Basal Insulin: Key Challenges

3. Sequential Insulin Strategies in T2D After Noninsulin Regimens

4. What to Do Next After Basal Insulin?

5. Scientific Rationale for Combining Basal Insulin with a GLP-1 agonist

6. Incretin-Based Therapy in Combination With Basal InsulinA Promising Tactic for the Treatment of Patients With T2DM • Consider non-insulin options with synergistic mechanisms of action and low hypoglycemia risk when intensifying regimens beyond basal insulin • DPP-4 inhibitors when A1C reductions of <1.0% are needed • GLP-1 receptor agonists when A1C reductions ≥1.0% are needed (and patients may benefit from possible weight loss) • Insulin doses may be able to be lowered or may need to be lowered • Target insulin deficiency and glucagon excess DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; A1C=glycated hemoglobin; T2DM=type 2 diabetes mellitus.

7. Incretins in Type-2 Patients on Insulin My Experience: On basal, Reduce need for bolus insulin: If on no other Rx ~80% need bolus; With DPP-4 inh only ~50%need bolus; With GLP-1 RA only ~20% need bolus

10. DPP-4 Inhibitors in Combination with Insulin in T2DM—Systematic Review Trends in A1C Weight Change at Endpoint 6 arms of 5 RCTs published 2007-2011. Rizos EC, et al. Curr Vasc Pharmacol. 2012 Jun 22. [Epub ahead of print]. DPP-4=dipeptidyl peptidase-4; Alo=Alogliptin; mg=milligram; INS=insulin; A1C=glycated hemoglobin; Wt=weight; T2DM=type 2 diabetes mellitus.

11. Dipeptidyl Peptidase-4 Inhibitors with insulinDPP-4 inhibitors prolong the half-life ofendogenous GLP-1, leading to enhancement ofglucose-dependent insulin secretion and adecrease in glucose-dependent glucagonsecretion [82]. Approved DPP-4 inhibitorsinclude sitagliptin, saxagliptin, linagliptin,vildagliptin (European Union only), andalogliptin. As a group, DPP-4 inhibitorsdecrease HbA1c levels, FPG, and PPG. They alsohave been shown to improve a surrogate ofb-cell function as determined by homeostaticmodel assessment-b (HOMA-b) [109–113]. Inclinical trials as monotherapy, placebocorrectedchanges in HbA1c of up to -0.94, -0.73, -0.69, and -0.90% have been reportedfor sitagliptin [114], saxagliptin [115],linagliptin [111], and vildagliptin [116],respectively. As add-on therapy in patientsinadequately controlled with metformin,maximum placebo-corrected changes in HbA1cfor sitagliptin, saxagliptin, linagliptin, andvildagliptin were -0.65% [109], -0.83% [110],-0.64% [113], and -1.1%, respectively [117].DPP-4 inhibitors when added to SU [112, 118,improved glycemic control relative to placeboor active control [112, 118–121]. DPP-4inhibitors also produced additional decreasesin HbA1c levels and other measures of glycemiain patients whose T2DM is inadequatelycontrolled with a combination of metforminand a SU [112, 119, 122] or with metformin andpioglitazone [123].Sitagliptin [124], saxagliptin [125],ildagliptin [126], alogliptin [127], orlinagliptin [128] added to insulin therapy (with or without metformin) produced greaterreductions in HbA1c (placebo-corrected values,-0.60, -0.41, -0.30, -0.58, and –0.65%,respectively) and PPG than insulin alone. Atstudy end, the increase in daily insulinrequirement was numerically lower in patientsreceiving a DPP-4 inhibitor versus placebo [125].Changes in body weight were similar betweenplacebo and DPP-4 inhibitor groups. Theincidence of hypoglycemia in patients receivinga DPP-4 inhibitor plus insulin versus insulinalone varied across the studies [124–127].Overall, DPP-4 inhibitors are weight neutraland pose a minimal risk of hypoglycemia whenin the incidence of hypoglycemia with DPP-4inhibitors, compared with placebo, have beenreported in some add-on studies with SU [112,119, 124]. In clinical trials, patients treated withDPP-4 inhibitors experienced a greaterincidence of upper respiratory tract infection,studies of 7,136 patients randomized to DPP-4inhibitors and 6,745 patients randomized toanother antidiabetes medication found thatDPP-4 inhibitors were not associated with anincreased risk for these infections, comparedwith the other medications [132]. There havebeen postmarketing reports [129, 130] andclinical study findings [131] of acutepancreatitis and hypersensitivity reactions(urticaria, angioedema, and localized skinfoliation) associated with the use of DPP-4nhibitors. Recently published articles have alsosuggested an association between pancreatitisand pancreatic cancer and DPP-4 inhibitors[107, 108].Analyses of major adverse cardiovascularevents occurring during the clinicaldevelopment of DPP-4 inhibitors havesuggested that these drugs do not increase therisk for cardiovascular events [133, 134] andmay potentially reduce the risk [135, 136].Moreover, a meta-analysis of 70 clinical trialsof DPP-4 inhibitors concluded that this class ofdrugs reduces the risk of cardiovascular events,morrtality [137]. Several long-term prospectivecardiovascular outcome trials with DPP-4inhibitors are ongoing [138, 139]. r

12. DPP- 4 Inhibitors as Add-ons to Basal Insulin

14. DPP-4 Inhibitors as Add-on Therapy to Basal Insulin (With or Without Oral Agents)