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 Insulin A 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
Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.
Diabetes Metab Feb;39(1):6-15. doi: /j.diabet Epub 2012 Sep 27.
Incretin-based therapy in combination with basal insulin: A promising tactic for the treatment of type 2 diabetes.
Vora J, Bain SC, Damci T, Dzida G, Hollander P, Meneghini LF, Ross SA.
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
Rizos EC, Ntzani EE, Papanas N, Tsimihodimos V, Mitrogianni Z, Maltezos E, Elisaf MS. Combination Therapies of DPP4 Inhibitors and GLP1 Analogues with Insulin in Type 2 Diabetic Patients: A Systematic Review. Curr Vasc Pharmacol Jun 22. [Epub ahead of print] PubMed PMID:
Table 3 (figure from table; no permission needed).
FXCX:
Rizos 2012: graphed from table 3 p5/9
DPP-4=dipeptidyl peptidase-4; Alo=Alogliptin; mg=milligram; INS=insulin; A1C=glycated hemoglobin; Wt=weight; T2DM=type 2 diabetes mellitus.
Rizos EC, et al. Curr Vasc Pharmacol Jun 22. [Epub ahead of print].
6 arms of 5 RCTs published

11. Dipeptidyl Peptidase-4 Inhibitors with insulin DPP-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 of b-cell function as determined by homeostaticmodel assessment-b (HOMA-b) [109–113]. In clinical 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, and vildagliptin 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 decreases in HbA1c levels and other measures of glycemiain patients whose T2DM is inadequately controlled with a combination of metforminand a SU [112, 119, 122] or with metformin and pioglitazone [123].Sitagliptin [124], saxagliptin [125],ildagliptin [126], alogliptin [127], or linagliptin [128] added to insulin therapy (with or without metformin) produced greater reductions 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 insulin requirement was numerically lower in patientsreceiving a DPP-4 inhibitor versus placebo [125]. Changes in body weight were similar betweenplacebo and DPP-4 inhibitor groups. The incidence of hypoglycemia in patients receivinga DPP-4 inhibitor plus insulin versus insulin alone varied across the studies [124–127].Overall, DPP-4 inhibitors are weight neutral and pose a minimal risk of hypoglycemia whenin the incidence of hypoglycemia with DPP-4 inhibitors, 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 greater incidence of upper respiratory tract infection,studies of 7,136 patients randomized to DPP-4 inhibitors and 6,745 patients randomized toanother antidiabetes medication found thatDPP-4 inhibitors were not associated with anincreased risk for these infections, compared with the other medications [132]. There havebeen postmarketing reports [129, 130] and clinical study findings [131] of acutepancreatitis and hypersensitivity reactions (urticaria, angioedema, and localized skin foliation) associated with the use of DPP-4nhibitors. Recently published articles have also suggested an association between pancreatitisand pancreatic cancer and DPP-4 inhibitors [107, 108].Analyses of major adverse cardiovascular events occurring during the clinicaldevelopment of DPP-4 inhibitors have suggested that these drugs do not increase therisk for cardiovascular events [133, 134] and may potentially reduce the risk [135, 136].Moreover, a meta-analysis of 70 clinical trials of DPP-4 inhibitors concluded that this class ofdrugs reduces the risk of cardiovascular events, morrtality [137]. Several long-term prospective cardiovascular 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)